BioPAX pathway converted from "Fatty acid metabolism" in the Reactome database. Fatty acid metabolism The synthesis and breakdown of fatty acids are a central part of human energy metabolism, and the eicosanoid class of fatty acid derivatives regulate diverse processes in the body (Vance & Vance 2008 - URL). Processes annotated in this module include the synthesis of fatty acids from acetyl-CoA, mitochondrial and peroxisomal breakdown of fatty acids, and the metabolism of eicosanoids and related molecules. Authored: Jassal, B, Gillespie, ME, Gopinathrao, G, D'Eustachio, P, 2007-02-02 21:56:36 Reviewed: Jassal, B, Gillespie, ME, Gopinathrao, G, D'Eustachio, P, 2007-02-02 21:56:36 Edited: Jassal, B, Gillespie, ME, Gopinathrao, G, D'Eustachio, P, 2007-02-02 21:56:36 Fatty acyl-CoA biosynthesis Fatty acyl-CoA biosynthesis involves following steps:<BR> -Palmitate synthesis catalyzed by Acetyl-CoA carboxylase and Fatty acid synthase<BR>-Conversion of palmitic acid to long chain fatty acids and<BR>-Conversion of long chain fatty acids to fatty acyl-CoA by acyl-CoA synthases.<BR> Authored: Gopinathrao, G, 2003-10-03 00:00:00 Edited: Gopinathrao, G, 2003-10-03 00:00:00 LEFT-TO-RIGHT Transport of Citrate from Mitochondrial Matrix to cytosol SLC25A1, in the inner mitochondrial membrane, mediates the exchange of mitochondrial citrate for cytosolic malate (Edvarson et al.2013, Gnoni et al.2009). MAL (S)-Malate (S)-malic acid L-Malate L-Apple acid L-Malic acid L-2-Hydroxybutanedioic acid Reactome DB_ID: 198498 cytosol GENE ONTOLOGY GO:0005829 (S)-malate(2-) [ChEBI:15589] (S)-malate(2-) (S)-malate ChEBI CHEBI:15589 Reactome Database ID Release 82 198498 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198498 Reactome R-ALL-198498 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-198498.4 Reactome http://www.reactome.org COMPOUND C00149 additional information MI MI:0361 CIT Citrate citric acid 2-Hydroxy-1,2,3-propanetricarboxylic acid 2-Hydroxytricarballylic acid Reactome DB_ID: 29654 mitochondrial matrix GENE ONTOLOGY GO:0005759 citric acid [ChEBI:30769] citric acid ChEBI CHEBI:30769 Reactome Database ID Release 82 29654 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29654 Reactome R-ALL-29654 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29654.3 COMPOUND C00158 MAL (S)-Malate (S)-malic acid L-Malate L-Apple acid L-Malic acid L-2-Hydroxybutanedioic acid Reactome DB_ID: 113544 Reactome Database ID Release 82 113544 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113544 Reactome R-ALL-113544 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113544.4 COMPOUND C00149 CIT Citrate citric acid Reactome DB_ID: 76190 Reactome Database ID Release 82 76190 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76190 Reactome R-ALL-76190 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-76190.3 COMPOUND C00158 ACTIVATION SLC25A1 tricarboxylate (citrate) transporter Reactome DB_ID: 372445 mitochondrial inner membrane GENE ONTOLOGY GO:0005743 UniProt:P53007 SLC25A1 SLC25A1 SLC20A3 FUNCTION Citrate transporter that mediates the exchange of mitochondrial citrate for cytosolic malate (PubMed:29031613, PubMed:29238895). Also able to mediate the exchange of citrate for isocitrate, phosphoenolpyruvate, cis- but not trans-aconitate and to a lesser extend maleate and succinate (PubMed:29031613). Important for the bioenergetics of hepatic cells as it provides a carbon source for fatty acid and sterol biosyntheses, and NAD(+) for the glycolytic pathway. Required for proper neuromuscular junction formation (Probable).SIMILARITY Belongs to the mitochondrial carrier (TC 2.A.29) family. Homo sapiens NCBI Taxonomy 9606 UniProt P53007 14 EQUAL 311 EQUAL Reactome Database ID Release 82 372445 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=372445 Reactome R-HSA-372445 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-372445.1 GENE ONTOLOGY GO:0015142 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 82 372450 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=372450 Reactome Database ID Release 82 75849 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75849 Reactome R-HSA-75849 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75849.3 19787704 Pubmed 2009 The mitochondrial citrate carrier: metabolic role and regulation of its activity and expression Gnoni, Gabriele V Priore, Paola Geelen, Math J H Siculella, Luisa IUBMB Life 61:987-94 23393310 Pubmed 2013 Agenesis of corpus callosum and optic nerve hypoplasia due to mutations in SLC25A1 encoding the mitochondrial citrate transporter Edvardson, S Porcelli, Vito Jalas, Chaim Soiferman, Devorah Kellner, Yuval Shaag, Avraham Korman, Stanley H Pierri, Ciro Leonardo Scarcia, Pasquale Fraenkel, Nitay D Segel, Reeval Schechter, Abraham Frumkin, Ayala Pines, Ophry Saada, Ann Palmieri, L Elpeleg, O J. Med. Genet. 50:240-5 LEFT-TO-RIGHT 2.3.3.8 ACLY tetramer transforms CIT to Ac-CoA Generation of Cytoplasmic Acetyl CoA from Citrate While fatty acid synthesis from acetyl CoA (Ac-CoA) proceeds in the cytosol, most Ac-CoA in the cell is generated within the mitochondria, by oxidative decarboxylation of the pyruvate derived from glycolysis, as well as from a number of reactions of amino acid catabolism. Mitochondrial Ac-CoA is transported to the cytosol as citrate (CIT) to participate in fatty acid biosynthesis. Cytosolic ATP-citrate synthase (ACLY), in tetrameric form, catalyses the transformation of CIT to Ac-CoA and and plays an essential role in lipogenesis, adipogenesis and differentiation of 3T3-L1 preadipocytic cells (Elshourbagy et al. 1992, Lin et al. 2013). Cytosolic MORC family CW-type zinc finger protein 2 (MORC2) positively regulates the activity of ACLY, thus could be a mediator of lipogenesis, adipogenic differentiation, and lipid homeostasis (Sanchez-Solana et al. 2014). Authored: Gopinathrao, G, 2003-10-03 00:00:00 Edited: Jassal, Bijay, 2017-01-09 CoA-SH coenzyme A coenzyme A(4-) Reactome DB_ID: 76194 coenzyme A(4-) [ChEBI:57287] coenzyme A(4-) 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-({3-oxo-3-[(2-sulfanylethyl)amino]propyl}amino)butyl] diphosphate} CoA ChEBI CHEBI:57287 Reactome Database ID Release 82 76194 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76194 Reactome R-ALL-76194 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-76194.4 COMPOUND C00010 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 82 113592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 COMPOUND C00002 OA Oxaloacetate oxaloacetic acid Oxalacetic acid 2-oxobutanedioic acid Oxosuccinic acid Reactome DB_ID: 76213 oxaloacetate(2-) [ChEBI:16452] oxaloacetate(2-) oxosuccinate oxaloacetate dianion oxobutanedioic acid, ion(2-) oxaloacetate oxobutanedioate ChEBI CHEBI:16452 Reactome Database ID Release 82 76213 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76213 Reactome R-ALL-76213 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-76213.4 COMPOUND C00036 Pi Orthophosphate hydrogenphosphate Phosphate Inorganic Phosphate Reactome DB_ID: 29372 hydrogenphosphate [ChEBI:43474] hydrogenphosphate hydrogen phosphate phosphate [PO3(OH)](2-) INORGANIC PHOSPHATE GROUP HYDROGENPHOSPHATE ION HPO4(2-) [P(OH)O3](2-) ChEBI CHEBI:43474 Reactome Database ID Release 82 29372 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29372 Reactome R-ALL-29372 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29372.4 COMPOUND C00009 Ac-CoA Acetyl coenzyme A acetyl-CoA acetyl-CoA(4-) Reactome DB_ID: 76183 acetyl-CoA(4-) [ChEBI:57288] acetyl-CoA(4-) acetyl-CoA 3'-phosphonatoadenosine 5'-(3-{(3R)-4-[(3-{[2-(acetylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-3-hydroxy-2,2-dimethyl-4-oxobutyl} diphosphate) acetyl-coenzyme A(4-) acetyl-CoA tetraanion AcCoA(4-) ChEBI CHEBI:57288 Reactome Database ID Release 82 76183 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76183 Reactome R-ALL-76183 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-76183.4 COMPOUND C00024 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 82 29370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 ACTIVATION ACLY tetramer Citrate lyase homotetramer Reactome DB_ID: 76188 ACLY citrate lyase monomer ATP citrate lyase ATP-citrate synthase ATP-citrate (pro-S-)-lyase Citrate cleavage enzyme Reactome DB_ID: 76187 UniProt:P53396 ACLY ACLY FUNCTION Catalyzes the cleavage of citrate into oxaloacetate and acetyl-CoA, the latter serving as common substrate for de novo cholesterol and fatty acid synthesis.ACTIVITY REGULATION Phosphorylation results in activation of its activity (PubMed:10653665). Glucose 6-phosphate, fructose 6-phosphate, fructose 2,6-bisphosphate, ribulose 5-phosphate, and fructose 1,6-bisphosphate also act as activators (PubMed:10653665).SUBUNIT Homotetramer.PTM Phosphorylated by PKA and GSK3 in a sequential manner; phosphorylation results in activation of its activity (PubMed:10653665). Phosphorylation on Thr-447 and Ser-451 depends on the phosphorylation state of Ser-455 (By similarity). Phosphorylation on Ser-455 is decreased by prior phosphorylation on the other 2 residues (By similarity).PTM ISGylated.PTM Acetylated at Lys-540, Lys-546 and Lys-554 by KAT2B/PCAF (PubMed:23932781). Acetylation is promoted by glucose and stabilizes the protein, probably by preventing ubiquitination at the same sites (PubMed:23932781). Acetylation promotes de novo lipid synthesis (PubMed:23932781). Deacetylated by SIRT2.PTM Ubiquitinated at Lys-540, Lys-546 and Lys-554 by UBR4, leading to its degradation. Ubiquitination is probably inhibited by acetylation at same site (Probable).SIMILARITY In the N-terminal section; belongs to the succinate/malate CoA ligase beta subunit family.SIMILARITY In the C-terminal section; belongs to the succinate/malate CoA ligase alpha subunit family. UniProt P53396 1 EQUAL 1101 EQUAL Reactome Database ID Release 82 76187 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76187 Reactome R-HSA-76187 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-76187.1 4 Reactome Database ID Release 82 76188 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76188 Reactome R-HSA-76188 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-76188.2 GENE ONTOLOGY GO:0003878 Reactome Database ID Release 82 76189 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76189 Reactome Database ID Release 82 75848 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75848 Reactome R-HSA-75848 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75848.4 1371749 Pubmed 1992 Cloning and expression of a human ATP-citrate lyase cDNA Elshourbagy, NA Near, JC Kmetz, PJ Wells, TN Groot, PH Saxty, BA Hughes, SA Franklin, M Gloger, IS Eur J Biochem 204:491-9 24286864 Pubmed 2014 Cytosolic functions of MORC2 in lipogenesis and adipogenesis Sánchez-Solana, Beatriz Li, Da-Qiang Kumar, Rakesh Biochim. Biophys. Acta 1843:316-26 23932781 Pubmed 2013 Acetylation stabilizes ATP-citrate lyase to promote lipid biosynthesis and tumor growth Lin, Ruiting Tao, Ren Gao, Xue Li, Tingting Zhou, Xin Guan, KL Xiong, Y Lei, Qun-Ying Mol. Cell 51:506-18 ACTIVATION Reactome Database ID Release 82 8954446 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8954446 Reactome R-HSA-8954446 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8954446.1 MORC2 MORC family CW-type zinc finger protein 2 MORC2_HUMAN Reactome DB_ID: 8933313 UniProt:Q9Y6X9 MORC2 MORC2 KIAA0852 ZCWCC1 FUNCTION Essential for epigenetic silencing by the HUSH (human silencing hub) complex. Recruited by HUSH to target site in heterochromatin, the ATPase activity and homodimerization are critical for HUSH-mediated silencing (PubMed:28581500, PubMed:29440755,PubMed:32693025). Represses germ cell-related genes and L1 retrotransposons in collaboration with SETDB1 and the HUSH complex, the silencing is dependent of repressive epigenetic modifications, such as H3K9me3 mark. Silencing events often occur within introns of transcriptionally active genes, and lead to the down-regulation of host gene expression (PubMed:29211708). During DNA damage response, regulates chromatin remodeling through ATP hydrolysis. Upon DNA damage, is phosphorylated by PAK1, both colocalize to chromatin and induce H2AX expression. ATPase activity is required and dependent of phosphorylation by PAK1 and presence of DNA (PubMed:23260667). Recruits histone deacetylases, such as HDAC4, to promoter regions, causing local histone H3 deacetylation and transcriptional repression of genes such as CA9 (PubMed:20225202, PubMed:20110259). Exhibits a cytosolic function in lipogenesis, adipogenic differentiation, and lipid homeostasis by increasing the activity of ACLY, possibly preventing its dephosphorylation (PubMed:24286864).ACTIVITY REGULATION ATPase activity is dependent of phosphorylation by PAK1 and presence of DNA.SUBUNIT Homodimerizes upon ATP-binding and dissociate upon ATP hydrolysis; homodimerization is required for gene silencing (PubMed:29440755). Interacts with HDAC4 (PubMed:20110259). Interacts with ACLY (PubMed:24286864). Interacts with TASOR and MPHOSPH8; the interactions associate MORC2 with the HUSH complex which recruits MORC2 to heterochromatic loci (PubMed:28581500).TISSUE SPECIFICITY Highly expressed in smooth muscle, pancreas and testis.PTM Phosphorylated by PAK1 at Ser-739 upon DNA damage. Phosphorylation is required for ATPase activity and recruitment to damaged chromatin. UniProt Q9Y6X9 2 EQUAL 1032 EQUAL Reactome Database ID Release 82 8933313 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8933313 Reactome R-HSA-8933313 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8933313.1 LEFT-TO-RIGHT 6.2.1.3 SLC27A2 ligates CoA to bempedoic acid to form ETC-1002-CoA Bempedoic acid (ETC-1002) is first-in-class ATP-citrate lyase (ACLY) inhibitor used once a day for reducing LDL cholesterol levels in statin-refractory patients. ETC-1002 itself is a prodrug, which is converted to the active metabolite ETC-1002–CoA by endogenous liver acyl-CoA synthetase (SLC27A2, ACSVL1) activity (Pinkosky et al. 2016). Authored: Jassal, Bijay, 2021-06-17 Reviewed: Huddart, Rachel, 2022-03-01 Edited: Jassal, Bijay, 2021-06-17 Edited: Matthews, Lisa, 2022-05-10 bempedoic acid Reactome DB_ID: 9734538 bempedoic acid [Guide to Pharmacology:8321] bempedoic acid ESP-55016 ETC-1002 Nexletol&reg; Nilemdo&reg; Guide to Pharmacology 8321 Reactome Database ID Release 82 9734538 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9734538 Reactome R-ALL-9734538 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9734538.1 PPi pyrophosphate diphosphoric acid pyrophosphoric acid diphosphate Reactome DB_ID: 111294 diphosphate(3-) [ChEBI:33019] diphosphate(3-) ChEBI CHEBI:33019 Reactome Database ID Release 82 111294 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111294 Reactome R-ALL-111294 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-111294.4 COMPOUND C00013 ETC-1002-CoA Reactome DB_ID: 9734541 Reactome Database ID Release 82 9734541 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9734541 Reactome R-ALL-9734541 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9734541.1 AMP adenosine 5'-monophosphate adenosine 5'-monophosphate(2-) Adenylic acid Adenylate 5'-AMP 5'-Adenylic acid 5'-Adenosine monophosphate Reactome DB_ID: 76577 adenosine 5'-monophosphate(2-) [ChEBI:456215] adenosine 5'-monophosphate(2-) AMP Adenosine-5-monophosphate(2-) AMP dianion 5'-O-phosphonatoadenosine Adenosine-5-monophosphate dianion AMP(2-) ChEBI CHEBI:456215 Reactome Database ID Release 82 76577 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76577 Reactome R-ALL-76577 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-76577.5 COMPOUND C00020 ACTIVATION VLCS SLC27A2 Very long-chain acyl-CoA synthetase Reactome DB_ID: 193386 endoplasmic reticulum membrane GENE ONTOLOGY GO:0005789 UniProt:O14975 SLC27A2 SLC27A2 ACSVL1 FACVL1 FATP2 VLACS FUNCTION Mediates the import of long-chain fatty acids (LCFA) into the cell by facilitating their transport across cell membranes, playing an important role in hepatic fatty acid uptake (PubMed:20530735, PubMed:22022213, PubMed:24269233, PubMed:10198260, PubMed:10749848, PubMed:11980911). Also functions as an acyl-CoA ligase catalyzing the ATP-dependent formation of fatty acyl-CoA using LCFA and very-long-chain fatty acids (VLCFA) as substrates, which prevents fatty acid efflux from cells and might drive more fatty acid uptake (PubMed:20530735, PubMed:22022213, PubMed:24269233, PubMed:10198260, PubMed:10749848, PubMed:11980911). Plays a pivotal role in regulating available LCFA substrates from exogenous sources in tissues undergoing high levels of beta-oxidation or triglyceride synthesis (PubMed:20530735). Can also activate branched-chain fatty acids such as phytanic acid and pristanic acid (PubMed:10198260). May contribute to the synthesis of sphingosine-1-phosphate (PubMed:24269233). Does not activate C24 bile acids, cholate and chenodeoxycholate (PubMed:11980911). In vitro, activates 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholestanate (THCA), the C27 precursor of cholic acid deriving from the de novo synthesis from cholesterol (PubMed:11980911). However, it is not critical for THCA activation and bile synthesis in vivo (PubMed:20530735).SIMILARITY Belongs to the ATP-dependent AMP-binding enzyme family. UniProt O14975 1 EQUAL 620 EQUAL Reactome Database ID Release 82 193386 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=193386 Reactome R-HSA-193386 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-193386.1 GENE ONTOLOGY GO:0004467 Reactome Database ID Release 82 193506 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=193506 Reactome Database ID Release 82 9734535 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9734535 Reactome R-HSA-9734535 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9734535.1 27892461 Pubmed 2016 Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis Pinkosky, Stephen L Newton, Roger S Day, Emily A Ford, Rebecca J Lhotak, Sarka Austin, Richard C Birch, Carolyn M Smith, Brennan K Filippov, Sergey Groot, Pieter H E Steinberg, Gregory R Lalwani, Narendra D Nat Commun 7:13457 LEFT-TO-RIGHT 6.4.1.2 Formation of Malonyl-CoA from Acetyl-CoA (liver) acetyl-CoA + bicarbonate + ATP => malonyl-CoA + H2O + ADP + orthophosphate Cytosolic acetyl-CoA carboxylase 1 (ACACA) catalyzes the reaction of bicarbonate, ATP, and acetyl-CoA to form malonyl-CoA, ADP, and orthophosphate. The reaction is positively regulated by citrate. The human ACACA cDNA has been cloned (Abu-Elheiga et al. 1995) and the biochemical properties of the human enzyme have recently been described (Cheng et al. 2007; Locke et al. 2008). Four ACACA isoforms generated by alternative splicing have been identified as mRNAs - the protein product of the first has been characterized experimentally. ACACA uses biotin (Btn) and two Mn2+ ions per subunit as cofactors and its activity is increased by polymerisation (Kim et al. 2010, Ingaramo & Beckett 2012). Cytosolic ACACA is thought to maintain regulation of fatty acid synthesis in all tissues but especially lipogenic tissues such as adipose tissue and lactating mammary glands.<br><br>Mid1-interacting protein 1 (MID1IP1, aka MIG12, SPOT14R, S14R) plays a role in the regulation of lipogenesis in the liver. It is rapidly upregulated by processes that induce lipogenesis (enhanced glucose metabolism, thyroid hormone administration) (Tsatsos et al. 2008). MID1IP1 forms a heterodimer with thyroid hormone-inducible hepatic protein (THRSP, aka SPOT14, S14), proposed to play the same role in lipogenesis as MID1IP1 (Aipoalani et al. 2010). This complex can polymerise acetyl-CoA carboxylases 1 and 2 (ACACA and B), the first committed enzymes in fatty acid (FA) synthesis. Polymerisation enhances ACACA and ACACB enzyme activities (Kim et al. 2010). Authored: Gopinathrao, G, 2003-10-03 00:00:00 HCO3- bicarbonate hydrogencarbonate acid carbonate Reactome DB_ID: 111627 hydrogencarbonate [ChEBI:17544] hydrogencarbonate ChEBI CHEBI:17544 Reactome Database ID Release 82 111627 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111627 Reactome R-ALL-111627 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-111627.3 COMPOUND C00288 Mal-CoA Malonyl coenzyme A malonyl-CoA Reactome DB_ID: 29508 malonyl-CoA(5-) [ChEBI:57384] malonyl-CoA(5-) malonyl-CoA 3'-phosphonatoadenosine 5'-{3-[(3R)-4-{[3-({2-[(3-carboxylatoacetyl)sulfanyl]ethyl}amino)-3-oxopropyl]amino}-3-hydroxy-2,2-dimethyl-4-oxobutyl] diphosphate} ChEBI CHEBI:57384 Reactome Database ID Release 82 29508 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29508 Reactome R-ALL-29508 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29508.4 COMPOUND C00083 ACTIVATION ACC1 Btn-ACACA Acetyl-CoA carboxylase 1 ACACA_HUMAN Reactome DB_ID: 2976730 UniProt:Q13085 ACACA ACACA ACAC ACC1 ACCA FUNCTION Cytosolic enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting step of de novo fatty acid biosynthesis (PubMed:20952656, PubMed:20457939, PubMed:29899443). This is a 2 steps reaction starting with the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain followed by the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA (PubMed:20952656, PubMed:20457939, PubMed:29899443).ACTIVITY REGULATION Inhibited by phosphorylation (PubMed:16326698, PubMed:29899443). Citrate promotes oligomerization of the protein into filaments that correspond to the most active form of the carboxylase (PubMed:29899443). Inhibited by palmitoyl-CoA (PubMed:29899443).PATHWAY Lipid metabolism; malonyl-CoA biosynthesis; malonyl-CoA from acetyl-CoA: step 1/1.SUBUNIT Monomer, homodimer, and homotetramer (PubMed:20952656, PubMed:29899443). Can form filamentous polymers (PubMed:20457939, PubMed:20952656, PubMed:29899443). Interacts in its inactive phosphorylated form with the BRCT domains of BRCA1 which prevents ACACA dephosphorylation and inhibits lipid synthesis (PubMed:12360400, PubMed:16326698, PubMed:18452305, PubMed:29899443). Interacts with MID1IP1; interaction with MID1IP1 promotes oligomerization and increases its activity (PubMed:20457939).TISSUE SPECIFICITY Expressed in brain, placenta, skeletal muscle, renal, pancreatic and adipose tissues; expressed at low level in pulmonary tissue; not detected in the liver.DOMAIN Consists of an N-terminal biotin carboxylation/carboxylase (BC) domain that catalyzes the ATP-dependent transient carboxylation of the biotin covalently attached to the central biotinyl-binding/biotin carboxyl carrier (BCC) domain (Probable). The C-terminal carboxyl transferase (CT) domain catalyzes the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA to produce malonyl-CoA (Probable).PTM Phosphorylation on Ser-1263 is required for interaction with BRCA1.PTM Phosphorylation at Ser-80 by AMPK inactivates enzyme activity.PTM The biotin cofactor is covalently attached to the central biotinyl-binding domain and is required for the catalytic activity. UniProt Q13085 786 EQUAL N6-biotinyl-L-lysine MOD MOD:00126 1 EQUAL 2346 EQUAL Reactome Database ID Release 82 2976730 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2976730 Reactome R-HSA-2976730 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2976730.1 GENE ONTOLOGY GO:0003989 Reactome Database ID Release 82 200565 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200565 Reactome Database ID Release 82 200555 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200555 Reactome R-HSA-200555 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200555.4 7732023 Pubmed 1995 Human acetyl-CoA carboxylase: characterization, molecular cloning, and evidence for two isoforms Abu-Elheiga, L Jayakumar, A Baldini, A Chirala, SS Wakil, SJ Proc Natl Acad Sci U S A 92:4011-5 18455495 Pubmed 2008 Differential activation of recombinant human acetyl-CoA carboxylases 1 and 2 by citrate Locke, GA Cheng, D Witmer, MR Tamura, JK Haque, T Carney, RF Rendina, AR Marcinkeviciene, J Arch Biochem Biophys 475:72-9 16854592 Pubmed 2007 Expression, purification, and characterization of human and rat acetyl coenzyme A carboxylase (ACC) isozymes Cheng, D Chu, CH Chen, L Feder, JN Mintier, GA Wu, Y Cook, JW Harpel, MR Locke, GA An, Y Tamura, JK Protein Expr Purif 51:11-21 ACTIVATION Reactome Database ID Release 82 539127 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=539127 Reactome R-HSA-539127 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-539127.1 LEFT-TO-RIGHT Formation of fatty acid synthase (FAS) dimer Association of cytosolic FAS into multimers is linked to increased catalytic activity (Locke et al. 2008). FAS FASN O-phosphopantetheine-L-ser-FASN Fatty acid synthase Reactome DB_ID: 54659 UniProt:P49327 FASN FASN FAS FUNCTION Fatty acid synthetase is a multifunctional enzyme that catalyzes the de novo biosynthesis of long-chain saturated fatty acids starting from acetyl-CoA and malonyl-CoA in the presence of NADPH. This multifunctional protein contains 7 catalytic activities and a site for the binding of the prosthetic group 4'-phosphopantetheine of the acyl carrier protein ([ACP]) domain.FUNCTION (Microbial infection) Fatty acid synthetase activity is required for SARS coronavirus-2/SARS-CoV-2 replication.ACTIVITY REGULATION Activated by S-nitrosylation which promotes enzyme dimerization (PubMed:26851298). Cerulenin, a potent non-competitive pharmacological inhibitor of FAS, binds covalently to the active site of the condensing enzyme region, inactivating a key enzyme step in fatty acid synthesis (PubMed:16969344).PATHWAY Lipid metabolism; fatty acid biosynthesis.SUBUNIT Homodimer which is arranged in a head to tail fashion (PubMed:17618296, PubMed:18022563, Ref.34). Interacts with CEACAM1; this interaction is insulin and phosphorylation-dependent; reduces fatty-acid synthase activity.TISSUE SPECIFICITY Ubiquitous. Prominent expression in brain, lung, liver and mammary gland.PTM S-nitrosylation of Fatty acid synthase at cysteine residues Cys-1471 or Cys-2091 is important for the enzyme dimerization. In adipocytes, S-nitrosylation of Fatty acid synthase occurs under physiological conditions and gradually increases during adipogenesis.MISCELLANEOUS The relatively low beta-ketoacyl synthase activity may be attributable to the low 4'-phosphopantetheine content of the protein. UniProt P49327 2156 EQUAL O-phosphopantetheine-L-serine MOD MOD:00159 1 EQUAL 2511 EQUAL Reactome Database ID Release 82 54659 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=54659 Reactome R-HSA-54659 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-54659.1 2 FAS dimer FASN dimer Reactome DB_ID: 77380 2 Reactome Database ID Release 82 77380 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=77380 Reactome R-HSA-77380 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-77380.1 Reactome Database ID Release 82 163756 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=163756 Reactome R-HSA-163756 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-163756.2 LEFT-TO-RIGHT 2.3.1.85 Conversion of malonyl-CoA and acetyl-CoA to palmitate acetyl-CoA + 7 malonyl-CoA + 14 NADHP + 14 H+ => palmitate + 7 CO2 + 14 NADP+ + 8 CoASH + 6 H2O Cytosolic fatty acid synthase (FAS) complex catalyzes the reaction of acetyl-CoA with 7 malonyl-CoA and 14 NADHP + 14 H+ to form a molecule of palmitate and 7 CO2, 14 NADP+, 8 CoASH, and 6 H2O. The process proceeds via the successive condensations of malonyl groups onto the growing acyl chain,each followed by loss of CO2 and three steps of reduction (Smith et al. 2003). Authored: Joshi-Tope, G, 2003-10-23 17:11:00 7 TPNH NADPH Reactome DB_ID: 29364 NADPH(4-) [ChEBI:57783] NADPH(4-) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH NADPH tetraanion ChEBI CHEBI:57783 Reactome Database ID Release 82 29364 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29364 Reactome R-ALL-29364 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29364.3 COMPOUND C00005 14 H+ proton hydron Reactome DB_ID: 70106 hydron [ChEBI:15378] hydron ChEBI CHEBI:15378 Reactome Database ID Release 82 70106 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70106 Reactome R-ALL-70106 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-70106.4 COMPOUND C00080 14 CO2 carbon dioxide Reactome DB_ID: 113528 carbon dioxide [ChEBI:16526] carbon dioxide ChEBI CHEBI:16526 Reactome Database ID Release 82 113528 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113528 Reactome R-ALL-113528 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113528.3 COMPOUND C00011 7 PALM palmitic acid hexadecanoic acid Palmitate Reactome DB_ID: 3632881 hexadecanoic acid [ChEBI:15756] hexadecanoic acid ChEBI CHEBI:15756 Reactome Database ID Release 82 3632881 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3632881 Reactome R-ALL-3632881 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-3632881.3 COMPOUND C00249 H2O water Reactome DB_ID: 29356 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 82 29356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29356 Reactome R-ALL-29356 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29356.5 COMPOUND C00001 6 TPN NADP+ NADP NADP(+) Nicotinamide adenine dinucleotide phosphate beta-Nicotinamide adenine dinucleotide phosphate Triphosphopyridine nucleotide NADP(3-) Reactome DB_ID: 29366 NADP(3-) [ChEBI:58349] NADP(3-) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADP(+) NADP trianion ChEBI CHEBI:58349 Reactome Database ID Release 82 29366 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29366 Reactome R-ALL-29366 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29366.4 COMPOUND C00006 14 8 ACTIVATION GENE ONTOLOGY GO:0004312 Reactome Database ID Release 82 539119 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=539119 Reactome Database ID Release 82 75872 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75872 Reactome R-HSA-75872 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75872.3 12689621 Pubmed 2003 Structural and functional organization of the animal fatty acid synthase. Smith, Stuart Witkowski, A Joshi, AK Prog Lipid Res 42:289-317 LEFT-TO-RIGHT 3.1.2.14 decanoyl-FASN dimer + 2 H2O => 2 decanoate + FASN dimer OLAH hydrolyzes decanoyl-FASN dimer to DECA and FASN dimer OLAH, a monomeric cytosolic thiolase, catalyzes the hydrolysis of FASN (fatty acid synthase) charged with decanoyl fatty acyl moieties to yield FASN and decanoate (DECA). OLAH expression is confined to the lactating mammary gland, and its catalytic activity enables the early termination of a portion of fatty acid biosynthesis to produce the medium chain-length fatty acids (annotated here as DECA) found in milk (Insull & Ahrens 1959; Breckenridge et al. 1969). OLAH is known only as an open reading frame identified in the human genome and as an mRNA observed in gene expression screening studies. Its biological properties are inferred from those of its well-studied rat ortholog (Libertini & Smith 1978; Mikkelsen et al. 1987). Reviewed: Jassal, Bijay, 2015-01-29 2 decanoyl-FASN dimer Reactome DB_ID: 5655943 decanoyl-FAS decanoyl-FASN decanoyl-fatty acid synthase Reactome DB_ID: 5655935 2156 EQUAL 1 EQUAL 2511 EQUAL Reactome Database ID Release 82 5655935 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5655935 Reactome R-HSA-5655935 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5655935.1 2 Reactome Database ID Release 82 5655943 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5655943 Reactome R-HSA-5655943 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5655943.1 DECA capric acid decanoic acid Reactome DB_ID: 879620 decanoic acid [ChEBI:30813] decanoic acid ChEBI CHEBI:30813 Reactome Database ID Release 82 879620 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879620 Reactome R-ALL-879620 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-879620.3 2 ACTIVATION OLAH S-acyl fatty acid synthase thioesterase, medium chain ecNumber3.1.2.14 Reactome DB_ID: 5655938 UniProt:Q9NV23 OLAH OLAH THEDC1 FUNCTION Contributes to the release of free fatty acids from fatty acid synthase (FASN). Has broad substrate specificity, giving rise to a range of free fatty acids with chain lengths between 10 and 16 carbon atoms (C10 - C16).SUBUNIT Interacts (via C-terminus) with FASN.TISSUE SPECIFICITY Detected both in lactating and non-lactating breast epithelium (at protein level) (PubMed:6589427). Isoform 2 is up-regulated in bone marrow-derived mononuclear cells of rheumatoid arthritis patients (PubMed:17082220).SIMILARITY Belongs to the thioesterase family. UniProt Q9NV23 1 EQUAL 260 EQUAL Reactome Database ID Release 82 5655938 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5655938 Reactome R-HSA-5655938 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5655938.1 GENE ONTOLOGY GO:0016297 Reactome Database ID Release 82 5655933 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5655933 Reactome Database ID Release 82 5655955 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5655955 Reactome R-HSA-5655955 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5655955.2 3805044 Pubmed 1987 Interaction of rat mammary gland thioesterase II with fatty acid synthetase is dependent on the presence of acyl chains on the synthetase Mikkelsen, Jan Witkowski, Andrzej Smith, Stuart J. Biol. Chem. 262:1570-4 627544 Pubmed 1978 Purification and properties of a thioesterase from lactating rat mammary gland which modifies the product specificity of fatty acid synthetase Libertini, Louis J Smith, Stuart J. Biol. Chem. 253:1393-401 13651131 Pubmed 1959 The fatty acids of human milk from mothers on diets taken ad libitum Insull, William Ahrens, Edward H Biochem. J. 72:27-33 5810867 Pubmed 1969 Triglyceride structure of human milk fat Breckenridge, W Carl Marai, L Kuksis, A Can. J. Biochem. 47:761-9 Synthesis of very long-chain fatty acyl-CoAs Conversion of palmitic acid to very long chain fatty acyl-CoAs Very long-chain fatty acids (VLCFA), ones with more than 20 carbon atoms, have diverse physiological roles, notably as components of ceramides in membrane lipids and as precursors of the eicosanoid hormones that play central roles in the generation and resolution of inflammatory responses. Saturated and monounsaturated VLCFAs can be synthesized by elongation od palmitic acid synthesized de novo or derived from the diet. Polyunsaturated VLCFAs are synthesized from dietary linoleic and linolenic acids - humans lack the desaturase enzymes to synthesize these molecules from stearate.<p>Chemically, the elongation process that yields VLCFA parallels the one by which palmitate (16 carbones) or stearate (18 carbons) are synthesized de novo from acetate. The starting fatty acid is activated by conjugation with coenzyme A (CoA-SH), condensed with malonyl-CoA to form a 3-oxoacyl CoA containing two more carbon atoms than the starting long chain fatty acyl CoA and CO2, reduced with NADPH to a 3-hydroxyacyl CoA, dehydrated to a trans 2,3-enoyl-CoA, and reduced with NADPH to yield a fatty acyl-CoA two carbons longer than the starting one.<p>The process differs from the de novo one in that the enzymatic activities resposible for each step are expressed by different proteins associated with the endoplasmic reticulum membrane, not by separate domains of a single multifunctional cytosolic protein. In humans, activation is catalyzed by one of five acyl-CoA synthetase long-chain (ACSL) enzymes, conjugation by one of seven elongation of very long chain fatty acids (ELOVL) proteins, reduction by one of two HSB17B estradiol dehydrogenases, dehydration by one of four protein tyrosine phosphatase-like / 3-hydroxyacyl-CoA dehydratase (PTPL / HACD) proteins, and reduction by one of two trans-2,3-enoyl-CoA reductase (TECR) proteins. Members of the four enzyme families differ in their tissue-specific expression patterns and in their substrate preferences (chain length, degree of saturation), leading to tissue-specific complements of VLCA (Jakobsson et al. 2006; Kihara 2012; Nugteren 1965).<p>Here the full two-carbon elongation cycle to form stearate from palmitate is annotated, as well as the activation and condensation steps for elongation of arachidonate, the 20-carbon unsaturated fatty acid that plays a central role in the synthesis of prostaglandins and related hormones. Authored: Gopinathrao, G, 2003-03-10 00:00:00 Reviewed: D'Eustachio, Peter, 2015-02-21 Edited: Gopinathrao, G, 2003-03-10 00:00:00 LEFT-TO-RIGHT ACSBG1,2 ligates CoA-SH to VLCFA, forming VLCFA-CoA Long-chain fatty acid-CoA ligases 1 and 2 (ACSBG1 and 2) are capable of activating very long-chain fatty acids (VLCFA) and are thought to play a role in fatty acid metabolism in the brain (ACSBG1 and 2) (Steinberg et al. 2000, Pei et al. 2003), and testes (ACSBG2) (Pei et al. 2006). Authored: Jassal, Bijay, 2015-05-26 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-05-26 VLCFA very long-chain fatty acid Reactome DB_ID: 5695985 very long-chain fatty acid [ChEBI:27283] very long-chain fatty acid VLCFAs higher fatty acid very long-chain fatty acids VLCFA ChEBI CHEBI:27283 Reactome Database ID Release 82 5695985 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5695985 Reactome R-ALL-5695985 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5695985.3 VLCFA-CoA very long-chain fatty acyl-CoA Reactome DB_ID: 5695971 very long-chain fatty acyl-CoA [ChEBI:61910] very long-chain fatty acyl-CoA VLCFA-CoAs VLCFA-CoA VLCFA-coenzyme A very long-chain fatty acyl-coenzyme As VLCA-coenzyme A very long-chain fatty acyl-coenzyme A VLCFA-coenzyme As very long-chain acyl-coenzyme A very long-chain acyl-CoA ChEBI CHEBI:61910 Reactome Database ID Release 82 5695971 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5695971 Reactome R-ALL-5695971 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5695971.3 ACTIVATION Converted from EntitySet in Reactome ACSBG1,2 Reactome DB_ID: 5695958 ACSBG1 Long-chain-fatty-acid--CoA ligase ACSBG1 ecNumber6.2.1.3/ecNumber ACBG1_HUMAN Reactome DB_ID: 5695965 UniProt:Q96GR2 ACSBG1 ACSBG1 BGM KIAA0631 LPD FUNCTION Catalyzes the conversion of fatty acids such as long-chain and very long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:12975357, PubMed:24269233, PubMed:10954726). Can activate diverse saturated, monosaturated and polyunsaturated fatty acids (PubMed:10954726).TISSUE SPECIFICITY Expressed primarily in brain. Expressed at lower level in testis and adrenal gland. Present in all regions of brain except pituitary.SIMILARITY Belongs to the ATP-dependent AMP-binding enzyme family. Bubblegum subfamily. UniProt Q96GR2 1 EQUAL 724 EQUAL Reactome Database ID Release 82 5695965 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5695965 Reactome R-HSA-5695965 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5695965.1 ACSBG2 Long-chain-fatty-acid--CoA ligase ACSBG2 ecNumber6.2.1.3/ecNumber ACBG2_HUMAN Reactome DB_ID: 5695988 UniProt:Q5FVE4 ACSBG2 ACSBG2 BGR UNQ2443/PRO5005 FUNCTION Catalyzes the conversion of fatty acids such as long chain and very long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation. Can activate diverse saturated, monosaturated and polyunsaturated fatty acids (PubMed:16371355, PubMed:16762313). Has increased ability to activate oleic and linoleic acid (PubMed:16371355). May play a role in spermatogenesis (PubMed:15685348).TISSUE SPECIFICITY Testis-specific.DEVELOPMENTAL STAGE Weakly or not expressed in fetal testis. Highly expressed in adult testis and moderately in elderly testis.SIMILARITY Belongs to the ATP-dependent AMP-binding enzyme family. Bubblegum subfamily. UniProt Q5FVE4 1 EQUAL 666 EQUAL Reactome Database ID Release 82 5695988 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5695988 Reactome R-HSA-5695988 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5695988.1 Reactome Database ID Release 82 5695958 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5695958 Reactome R-HSA-5695958 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5695958.1 GENE ONTOLOGY GO:0031957 Reactome Database ID Release 82 5695982 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5695982 Reactome Database ID Release 82 5695957 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5695957 Reactome R-HSA-5695957 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5695957.1 12975357 Pubmed 2003 The acyl-CoA synthetase "bubblegum" (lipidosin): further characterization and role in neuronal fatty acid beta-oxidation. Pei, Z Oey, Nadia A Zuidervaart, Maartje M Jia, Zhenzhen Li, Yuanyuan Steinberg, SJ Smith, KD Watkins, PA J. Biol. Chem. 278:47070-8 10954726 Pubmed 2000 Very long-chain acyl-CoA synthetases. Human "bubblegum" represents a new family of proteins capable of activating very long-chain fatty acids Steinberg, S J Morgenthaler, J Heinzer, A K Smith, K D Watkins, P A J. Biol. Chem. 275:35162-9 16371355 Pubmed 2006 The second member of the human and murine bubblegum family is a testis- and brainstem-specific acyl-CoA synthetase Pei, Z Jia, Zhenzhen Watkins, PA J. Biol. Chem. 281:6632-41 LEFT-TO-RIGHT ACSF3 ligates CoA-SH to VLCFA Acyl-coenzyme A synthetases (ACSs) catalyse the activation of fatty acids by thioesterification to CoA, the fundamental initial reaction in fatty acid metabolism. Mitochondrial acyl-CoA synthetase family member 3 (ACSF3) preferentially ligates CoA-SH to very long-chain fatty acids (VLCFA), around C24 in length (Watkins et al. 2007). Authored: Jassal, Bijay, 2015-05-26 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-05-26 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113593 Reactome Database ID Release 82 113593 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113593 Reactome R-ALL-113593 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113593.4 COMPOUND C00002 VLCFA very long-chain fatty acid Reactome DB_ID: 5696008 Reactome Database ID Release 82 5696008 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696008 Reactome R-ALL-5696008 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5696008.3 CoA CoA-SH coenzyme A Reactome DB_ID: 29374 Reactome Database ID Release 82 29374 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29374 Reactome R-ALL-29374 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29374.4 COMPOUND C00010 AMP adenosine 5'-monophosphate Adenylic acid Adenylate 5'-AMP 5'-Adenylic acid 5'-Adenosine monophosphate adenosine 5'-monophosphate(2-) Reactome DB_ID: 159448 Reactome Database ID Release 82 159448 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=159448 Reactome R-ALL-159448 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-159448.4 COMPOUND C00020 VLCFA-CoA very long-chain fatty acyl-CoA Reactome DB_ID: 5696003 Reactome Database ID Release 82 5696003 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696003 Reactome R-ALL-5696003 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5696003.3 PPi pyrophosphate diphosphoric acid pyrophosphoric acid diphosphate Reactome DB_ID: 159450 Reactome Database ID Release 82 159450 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=159450 Reactome R-ALL-159450 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-159450.4 COMPOUND C00013 ACTIVATION ACSF3 Acyl-CoA synthetase family member 3, mitochondrial ecNumber6.2.1.-/ecNumber ACSF3_HUMAN Reactome DB_ID: 5696011 UniProt:Q4G176 ACSF3 ACSF3 PSEC0197 FUNCTION Catalyzes the initial reaction in intramitochondrial fatty acid synthesis, by activating malonate and methylmalonate, but not acetate, into their respective CoA thioester (PubMed:21846720, PubMed:21841779). May have some preference toward very-long-chain substrates (PubMed:17762044).SIMILARITY Belongs to the ATP-dependent AMP-binding enzyme family. UniProt Q4G176 84 EQUAL 576 EQUAL Reactome Database ID Release 82 5696011 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696011 Reactome R-HSA-5696011 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5696011.1 Reactome Database ID Release 82 5696000 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696000 Reactome Database ID Release 82 5696007 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696007 Reactome R-HSA-5696007 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5696007.1 17762044 Pubmed 2007 Evidence for 26 distinct acyl-coenzyme A synthetase genes in the human genome Watkins, PA Maiguel, Dony Jia, Zhenzhen Pevsner, Jonathan J. Lipid Res. 48:2736-50 LEFT-TO-RIGHT SLC27A3 ligates CoA-SH to VLCFA Acyl-coenzyme A synthetases catalyse the activation of fatty acids by thioesterification to CoA, the fundamental initial reaction in fatty acid oxidation. Members of the long chain acyl-coenzyme A synthetases (ACSVL) subfamily were originally thought to be fatty acid transport proteins (FATPs), hence their approved gene names and symbols are “solute carrier family 27 (fatty acid transporter) member x" (SLC27Ax) but their transport function has never been proven. Instead, their amino acid sequence contains two highly conserved motifs characteristic of acyl-CoA synthetases. Long-chain fatty acid transport protein 3 (SLC27A3, aka ACSVL3, FATP3) preferentially ligates CoA-SH to very long-chain fatty acids (VLCFA) (Watkins et al. 2007). The activity of human SLC27A3 is inferred from mouse Slc27a3 functional studies (Pei et al. 2004). Authored: Jassal, Bijay, 2016-06-01 Reviewed: D'Eustachio, Peter, 2016-07-15 Edited: Jassal, Bijay, 2016-06-01 ACTIVATION SLC27A3 Long-chain fatty acid transport protein 3 S27A3_HUMAN Reactome DB_ID: 5216184 UniProt:Q5K4L6 SLC27A3 SLC27A3 ACSVL3 FATP3 PSEC0067 UNQ367/PRO703 FUNCTION Mainly functions as an acyl-CoA ligase catalyzing the ATP-dependent formation of fatty acyl-CoA using LCFA and very-long-chain fatty acids (VLCFA) as substrates (PubMed:23936004). Can mediate the levels of long-chain fatty acids (LCFA) in the cell by facilitating their transport across membranes (By similarity).TISSUE SPECIFICITY Expressed in bronchial and bronchiolar epithelial cells (at protein level).SIMILARITY Belongs to the ATP-dependent AMP-binding enzyme family. UniProt Q5K4L6 1 EQUAL 730 EQUAL Reactome Database ID Release 82 5216184 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5216184 Reactome R-HSA-5216184 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5216184.1 Reactome Database ID Release 82 8875075 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8875075 Reactome Database ID Release 82 8875077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8875077 Reactome R-HSA-8875077 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8875077.1 15469937 Pubmed 2004 Mouse very long-chain Acyl-CoA synthetase 3/fatty acid transport protein 3 catalyzes fatty acid activation but not fatty acid transport in MA-10 cells Pei, Z Fraisl, Peter Berger, Johannes Jia, Zhenzhen Forss-Petter, Sonja Watkins, PA J. Biol. Chem. 279:54454-62 LEFT-TO-RIGHT 6.2.1.3 Conversion of palmitic acid to palmitoyl-CoA ACSL1,3,5,6 ligate CoA to PALM to form PALM-CoA palmitate + CoASH + ATP => palmitoyl-CoA + AMP + pyrophosphate + H2O Membrane-associated acyl-CoA synthetase long-chain family members 1,3,5 and 6 (ACSL1,3,5,6) catalyse the conjugation of palmitate (PALM) with CoA to form palmitoyl-CoA (PALM-CoA). Human ACSL1 has not been characterized in detail, but available data suggest that it is associated specifically with the membrane of the endoplasmic reticulum and that it can act on oleic acid as well as on palmitic acid (Malhotra et al. 1999, Fujimoto et al. 2007, Gassler et al. 2007). Authored: Gopinathrao, G, 2007-07-29 21:03:03 Reviewed: D'Eustachio, Peter, 2015-02-21 Edited: D'Eustachio, Peter, 2015-02-21 PALM-CoA palmitoyl-CoA Reactome DB_ID: 200993 palmitoyl-CoA(4-) [ChEBI:57379] palmitoyl-CoA(4-) 3'-phosphonatoadenosine 5'-(3-{(3R)-4-[(3-{[2-(hexadecanoylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-3-hydroxy-2,2-dimethyl-4-oxobutyl} diphosphate) hexadecanoyl-CoA ChEBI CHEBI:57379 Reactome Database ID Release 82 200993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200993 Reactome R-ALL-200993 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-200993.4 COMPOUND C00154 ACTIVATION Converted from EntitySet in Reactome ACSL1,3,5,6 Reactome DB_ID: 3878115 ACSL1 acyl-CoA synthetase long-chain family member 1 Reactome DB_ID: 201038 UniProt:P33121 ACSL1 ACSL1 FACL1 FACL2 LACS LACS1 LACS2 FUNCTION Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:24269233, PubMed:22633490, PubMed:21242590). Preferentially uses palmitoleate, oleate and linoleate (PubMed:24269233). Preferentially activates arachidonate than epoxyeicosatrienoic acids (EETs) or hydroxyeicosatrienoic acids (HETEs) (By similarity).ACTIVITY REGULATION Inhibited at high temperature and by arachidonate.TISSUE SPECIFICITY Highly expressed in liver, heart, skeletal muscle, kidney and erythroid cells, and to a lesser extent in brain, lung, placenta and pancreas.DEVELOPMENTAL STAGE Expressed during the early stages of erythroid development while expression is very low in reticulocytes and young erythrocytes.SIMILARITY Belongs to the ATP-dependent AMP-binding enzyme family. UniProt P33121 1 EQUAL 698 EQUAL Reactome Database ID Release 82 201038 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201038 Reactome R-HSA-201038 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201038.1 ACSL3 Long-chain-fatty-acid--CoA ligase 3 Reactome DB_ID: 548787 UniProt:O95573 ACSL3 ACSL3 ACS3 FACL3 LACS3 FUNCTION Acyl-CoA synthetases (ACSL) activates long-chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:22633490). Required for the incorporation of fatty acids into phosphatidylcholine, the major phospholipid located on the surface of VLDL (very low density lipoproteins) (PubMed:18003621). Has mainly an anabolic role in energy metabolism. Mediates hepatic lipogenesis. Preferentially uses myristate, laurate, arachidonate and eicosapentaenoate as substrates. Both isoforms exhibit the same level of activity (By similarity).SIMILARITY Belongs to the ATP-dependent AMP-binding enzyme family. UniProt O95573 1 EQUAL 720 EQUAL Reactome Database ID Release 82 548787 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548787 Reactome R-HSA-548787 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548787.1 ACS5 ACSL5 acyl-CoA synthetase long-chain family member 5 long-chain acyl-CoA synthetase 5 Reactome DB_ID: 165011 UniProt:Q9ULC5 ACSL5 ACSL5 ACS5 FACL5 UNQ633/PRO1250 FUNCTION Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoAs for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:17681178, PubMed:24269233, PubMed:22633490). ACSL5 may activate fatty acids from exogenous sources for the synthesis of triacylglycerol destined for intracellular storage (By similarity). Utilizes a wide range of saturated fatty acids with a preference for C16-C18 unsaturated fatty acids (By similarity). It was suggested that it may also stimulate fatty acid oxidation (By similarity). At the villus tip of the crypt-villus axis of the small intestine may sensitize epithelial cells to apoptosis specifically triggered by the death ligand TRAIL. May have a role in the survival of glioma cells.SIMILARITY Belongs to the ATP-dependent AMP-binding enzyme family. UniProt Q9ULC5 1 EQUAL 683 EQUAL Reactome Database ID Release 82 165011 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165011 Reactome R-HSA-165011 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-165011.1 ACSL6 Long-chain-fatty-acid--CoA ligase 6 Reactome DB_ID: 548687 UniProt:Q9UKU0 ACSL6 ACSL6 ACS2 FACL6 KIAA0837 LACS5 FUNCTION Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoA for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:22633490, PubMed:24269233). Plays an important role in fatty acid metabolism in brain and the acyl-CoAs produced may be utilized exclusively for the synthesis of the brain lipid.TISSUE SPECIFICITY Expressed predominantly in erythrocyte precursors, in particular in reticulocytes, fetal blood cells derived from fetal liver, hemopoietic stem cells from cord blood, bone marrow and brain.DEVELOPMENTAL STAGE Expression is low at earlier stages of erythroid development but is very high in reticulocytes.DISEASE A chromosomal aberration involving ACSL6 may be a cause of myelodysplastic syndrome with basophilia. Translocation t(5;12)(q31;p13) with ETV6.DISEASE A chromosomal aberration involving ACSL6 may be a cause of acute myelogenous leukemia with eosinophilia. Translocation t(5;12)(q31;p13) with ETV6.DISEASE A chromosomal aberration involving ACSL6 may be a cause of acute eosinophilic leukemia (AEL). Translocation t(5;12)(q31;p13) with ETV6.SIMILARITY Belongs to the ATP-dependent AMP-binding enzyme family. UniProt Q9UKU0 1 EQUAL 697 EQUAL Reactome Database ID Release 82 548687 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548687 Reactome R-HSA-548687 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548687.1 Reactome Database ID Release 82 3878115 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3878115 Reactome R-HSA-3878115 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3878115.1 Reactome Database ID Release 82 200992 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200992 Reactome Database ID Release 82 201035 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201035 Reactome R-HSA-201035 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201035.2 17681178 Pubmed 2007 Regulation of enterocyte apoptosis by acyl-CoA synthetase 5 splicing Gassler, N Roth, W Funke, B Schneider, A Herzog, F Tischendorf, JJ Grund, K Penzel, R Bravo, IG Mariadason, J Ehemann, V Sykora, J Haas, TL Walczak, H Ganten, T Zentgraf, H Erb, P Alonso, A Autschbach, F Schirmacher, P Knuchel, Ruth Kopitz, J Gastroenterology 133:587-98 10548543 Pubmed 1999 Identification and molecular characterization of acyl-CoA synthetase in human erythrocytes and erythroid precursors Malhotra, KT Malhotra, K Lubin, BH Kuypers, FA Biochem J 344:135-43 17379924 Pubmed 2007 Involvement of ACSL in local synthesis of neutral lipids in cytoplasmic lipid droplets in human hepatocyte HuH7 Fujimoto, Y Itabe, H Kinoshita, T Homma, KJ Onoduka, J Mori, M Yamaguchi, S Makita, M Higashi, Y Yamashita, A Takano, T J Lipid Res 48:1280-92 LEFT-TO-RIGHT 6.2.1.3 ACSL3,4 ligate CoA to AA to form AA-CoA arachidonate + CoASH + ATP => arachidonoyl-CoA + AMP + pyrophosphate + H2O [ACSL4] Acyl-CoA synthetase long-chain family member 4 (ACSL4) associated with the endoplasmic reticulum membrane catalyses the conjugation of arachidonate (AA) with CoA to form arachidonyl-CoA (AA-CoA) (Longo et al. 2003, Meloni et al. 2003). By similarity, ACSL3 can also preferentially conjugate CoA on to AA (Yao & Ye 2008). These enzymes are involved in the activation of long-chain fatty acids for both synthesis of cellular lipids, and degradation via beta-oxidation. Authored: D'Eustachio, P, 2010-03-14 Reviewed: D'Eustachio, Peter, 2015-02-21 Edited: D'Eustachio, P, 2010-03-14 AA Arachidonate arachidonic acid cis-5,8,11,14-Eicosatetraenoic acid Reactome DB_ID: 29768 arachidonate [ChEBI:32395] arachidonate (20:4n6) (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (5Z,8Z,11Z,14Z)-eicosatetraenoate ChEBI CHEBI:32395 Reactome Database ID Release 82 29768 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29768 Reactome R-ALL-29768 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29768.4 COMPOUND C00219 AA-CoA arachidonoyl-CoA Reactome DB_ID: 548819 arachidonoyl-CoA(4-) [ChEBI:57368] arachidonoyl-CoA(4-) S-[(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoyl]-coenzyme A(4-) arachidonoyl-coenzyme A(4-) cis-Delta(5,8,11,14)-eicosatetraenoyl-CoA(4-) C20:4-CoA(4-) 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-4-({3-[(2-{[(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoyl]sulfanyl}ethyl)amino]-3-oxopropyl}amino)-2,2-dimethyl-4-oxobutyl] diphosphate} (5Z,8Z,11Z,14Z)-5,8,11,14-eicosatetraenoyl-CoA(4-) (5Z,8Z,11Z,14Z)-eicosatetraenoyl-CoA arachidonyl-coenzyme A(4-) cis-Delta(5,8,11,14)-eicosatetraenoyl-coenzyme A(4-) ChEBI CHEBI:57368 Reactome Database ID Release 82 548819 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548819 Reactome R-ALL-548819 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-548819.4 ACTIVATION Converted from EntitySet in Reactome ACSL3,4 Reactome DB_ID: 2901793 ACSL4 Long-chain-fatty-acid--CoA ligase 4 Reactome DB_ID: 548712 UniProt:O60488 ACSL4 ACSL4 ACS4 FACL4 LACS4 FUNCTION Catalyzes the conversion of long-chain fatty acids to their active form acyl-CoA for both synthesis of cellular lipids, and degradation via beta-oxidation (PubMed:24269233, PubMed:22633490, PubMed:21242590). Preferentially activates arachidonate and eicosapentaenoate as substrates (PubMed:21242590). Preferentially activates 8,9-EET &gt; 14,15-EET &gt; 5,6-EET &gt; 11,12-EET. Modulates glucose-stimulated insulin secretion by regulating the levels of unesterified EETs (By similarity). Modulates prostaglandin E2 secretion (PubMed:21242590).ACTIVITY REGULATION Both triacsin C and rosiglitazone inhibit arachidonoyl-CoA ligase activity.SIMILARITY Belongs to the ATP-dependent AMP-binding enzyme family. UniProt O60488 1 EQUAL 711 EQUAL Reactome Database ID Release 82 548712 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548712 Reactome R-HSA-548712 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548712.1 Reactome Database ID Release 82 2901793 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2901793 Reactome R-HSA-2901793 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2901793.1 Reactome Database ID Release 82 548838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548838 Reactome Database ID Release 82 548843 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548843 Reactome R-HSA-548843 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548843.2 18003621 Pubmed 2008 Long chain acyl-CoA synthetase 3-mediated phosphatidylcholine synthesis is required for assembly of very low density lipoproteins in human hepatoma Huh7 cells Yao, Hongbing Ye, Jin J. Biol. Chem. 283:849-54 12525535 Pubmed 2003 A third MRX family (MRX68) is the result of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene: proposal of a rapid enzymatic assay for screening mentally retarded patients Longo, I Frints, SG Fryns, JP Meloni, I Pescucci, C Ariani, F Borghgraef, M Raynaud, M Marynen, P Schwartz, C Renieri, A Froyen, G J Med Genet 40:11-7 11889465 Pubmed 2002 FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation Meloni, I Muscettola, M Raynaud, M Longo, I Bruttini, M Moizard, MP Gomot, M Chelly, J des Portes, V Fryns, JP Ropers, HH Magi, B Bellan, C Volpi, N Yntema, HG Lewis, SE Schaffer, JE Renieri, A Nat Genet 30:436-40 LEFT-TO-RIGHT ELOVL3,6,7 elongate PALM-CoA and Mal-CoA to 3OOD-CoA palmitoyl-CoA + malonyl-CoA => 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA) + CO2 + CoASH The ER membrane-bound elongation of very long chain fatty acids proteins 3, 6 and 7 (ELOVL3,6,7) catalyse the condensation of palmitoyl-CoA (PALM-CoA) with malonyl-CoA (Mal-CoA) to form 3-oxooctadecanoyl-CoA (3OOD-CoA) (Shimamura et al. 2009, Ohno et al. 2010, Naganuma et al. 2011). Authored: D'Eustachio, P, 2010-03-14 Reviewed: D'Eustachio, Peter, 2015-02-21 Edited: D'Eustachio, P, 2010-05-08 3OOD-CoA 3-oxostearoyl-CoA 3-oxooctadecanoyl-CoA Reactome DB_ID: 548812 3-oxooctadecanoyl-CoA(4-) [ChEBI:71407] 3-oxooctadecanoyl-CoA(4-) 3-ketostearoyl-coenzyme A(4-) 3-ketooctadecanoyl-coenzyme A(4-) 3-oxostearoyl-CoA(4-) 3-ketooctadecanoyl-CoA(4-) 3-oxooctadecanoyl-CoA 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-{[3-oxo-3-({2-[(3-oxooctadecanoyl)sulfanyl]ethyl}amino)propyl]amino}butyl] diphosphate} 3-oxostearoyl-coenzyme A(4-) 3-ketostearoyl-CoA(4-) 3-oxooctadecanoyl-coenzyme A(4-) ChEBI CHEBI:71407 Reactome Database ID Release 82 548812 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548812 Reactome R-ALL-548812 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-548812.4 ACTIVATION Converted from EntitySet in Reactome ELOVL3,6,7 Reactome DB_ID: 5676213 ELOVL3 Elongation of very long chain fatty acids protein 3 Reactome DB_ID: 548785 UniProt:Q9HB03 ELOVL3 ELOVL3 CIG30 FUNCTION Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme that exhibits activity toward saturated and unsaturated acyl-CoA substrates with higher activity toward C18 acyl-CoAs, especially C18:0 acyl-CoAs. May participate in the production of saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.PATHWAY Lipid metabolism; polyunsaturated fatty acid biosynthesis.TISSUE SPECIFICITY Testis.DOMAIN The C-terminal di-lysine motif may confer endoplasmic reticulum localization.PTM N-Glycosylated.SIMILARITY Belongs to the ELO family. ELOVL3 subfamily. UniProt Q9HB03 1 EQUAL 270 EQUAL Reactome Database ID Release 82 548785 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548785 Reactome R-HSA-548785 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548785.1 ELOVL6 Elongation of very long chain fatty acids protein 6 Reactome DB_ID: 548680 UniProt:Q9H5J4 ELOVL6 ELOVL6 FACE LCE FUNCTION Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme that elongates fatty acids with 12, 14 and 16 carbons with higher activity toward C16:0 acyl-CoAs. Catalyzes the synthesis of unsaturated C16 long chain fatty acids and, to a lesser extent, C18:0 and those with low desaturation degree. May participate in the production of saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.ACTIVITY REGULATION The reaction is stimulated by the presence of HSD17B12, the enzyme catalyzing the second step of the elongation cycle.PATHWAY Lipid metabolism; fatty acid biosynthesis.TISSUE SPECIFICITY Ubiquitous.PTM N-Glycosylated.SIMILARITY Belongs to the ELO family. ELOVL6 subfamily. UniProt Q9H5J4 1 EQUAL 265 EQUAL Reactome Database ID Release 82 548680 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548680 Reactome R-HSA-548680 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548680.1 ELOVL7 Elongation of very long chain fatty acids protein 7 Reactome DB_ID: 548661 UniProt:A1L3X0 ELOVL7 ELOVL7 FUNCTION Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme with higher activity toward C18 acyl-CoAs, especially C18:3(n-3) acyl-CoAs and C18:3(n-6)-CoAs. Also active toward C20:4-, C18:0-, C18:1-, C18:2- and C16:0-CoAs, and weakly toward C20:0-CoA. Little or no activity toward C22:0-, C24:0-, or C26:0-CoAs. May participate in the production of saturated and polyunsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.PATHWAY Lipid metabolism; fatty acid biosynthesis.TISSUE SPECIFICITY Expressed in most tissues except heart and skeletal muscle.DOMAIN The C-terminal di-lysine motif may confer endoplasmic reticulum localization.SIMILARITY Belongs to the ELO family. ELOVL7 subfamily. UniProt A1L3X0 1 EQUAL 281 EQUAL Reactome Database ID Release 82 548661 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548661 Reactome R-HSA-548661 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548661.1 Reactome Database ID Release 82 5676213 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676213 Reactome R-HSA-5676213 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5676213.1 GENE ONTOLOGY GO:0009922 Reactome Database ID Release 82 548801 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548801 Reactome Database ID Release 82 548814 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548814 Reactome R-HSA-548814 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548814.1 19505953 Pubmed 2009 Identification and characterization of a selective radioligand for ELOVL6 Shimamura, K Takahashi, H Kitazawa, H Miyamoto, Y Nagumo, A Tang, C Dean, D Nagase, T Sato, N Tokita, S J Biochem 146:429-37 21959040 Pubmed 2011 Biochemical characterization of the very long-chain fatty acid elongase ELOVL7 Naganuma, Tatsuro Sato, Yuichiro Sassa, Takayuki Ohno, Yusuke Kihara, Akio FEBS Lett. 585:3337-41 20937905 Pubmed 2010 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis Ohno, Yusuke Suto, S Yamanaka, Masao Mizutani, Y Mitsutake, S Igarashi, Y Sassa, Takayuki Kihara, Akio Proc Natl Acad Sci U S A 107:18439-44 LEFT-TO-RIGHT ELOVL1,4 elongate TCS-CoA and Mal-CoA to 3OHC-CoA lignoceroyl-CoA + malonyl-CoA => 3-oxocerotoyl-CoA + CO2 + CoASH Elongation of very long chain fatty acids proteins 1, 4 (ELOVL1,4) catalyse the elongation of lignoceroyl-CoA (TCS-CoA) and malonyl-CoA (Mal-CoA) to form 3-oxocerotoyl-CoA (3OHC-CoA). ELOVL4 is abundant in retinal cells, where it is localized to the endoplasmic reticulum membrane (Grayson & Molday 2005). The catalytic activity of ELOVL4 has not been examined directly but is inferred from that of the homologous mouse protein, which is also active on polyunsaturated fatty acids (PUFAs) (PUFAs) (Agbada et al. 2008). Authored: D'Eustachio, P, 2010-03-14 Reviewed: D'Eustachio, Peter, 2015-02-21 Edited: D'Eustachio, P, 2010-05-08 TCS-CoA lignoceroyl-CoA tetracosanoyl-CoA Reactome DB_ID: 548808 tetracosanoyl-CoA(4-) [ChEBI:65052] tetracosanoyl-CoA(4-) tetracosanoyl-CoA 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-{[3-({2-[(tetracosanoyl)sulfanyl]ethyl}amino)-3-oxopropyl]amino}butyl] diphosphate} tetracosanoyl-CoA (4-) tetracosanoyl-coenzyme A(4-) lignoceroyl-CoA(4-) C24:0-CoA(4-) C24:0-coenzyme A(4-) ChEBI CHEBI:65052 Reactome Database ID Release 82 548808 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548808 Reactome R-ALL-548808 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-548808.4 3OHC-CoA 3-oxocerotoyl-CoA 3-oxohexacosanoyl-CoA Reactome DB_ID: 548797 3-oxohexacosanoyl-CoA(4-) [ChEBI:73980] 3-oxohexacosanoyl-CoA(4-) 3-ketohexacosanoyl-CoA(4-) 3-oxohexacosanoyl-coenzyme A(4-) 3-ketocerotoyl-CoA(4-) 3-ketohexacosanoyl-coenzyme A(4-) 3-oxohexacosanoyl-CoA 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-{[3-({2-[(3-oxohexacosanoyl)sulfanyl]ethyl}amino)-3-oxopropyl]amino}butyl] diphosphate} 3-oxocerotoyl-CoA(4-) ChEBI CHEBI:73980 Reactome Database ID Release 82 548797 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548797 Reactome R-ALL-548797 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-548797.4 ACTIVATION Converted from EntitySet in Reactome ELOVL1,4 Reactome DB_ID: 5676211 ELOVL1 Elongation of very long chain fatty acids protein 1 Reactome DB_ID: 548764 UniProt:Q9BW60 ELOVL1 ELOVL1 SSC1 CGI-88 FUNCTION Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle (PubMed:29496980, PubMed:30487246). This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme that exhibits activity toward saturated and monounsaturated acyl-CoA substrates, with the highest activity towards C22:0 acyl-CoA. May participate in the production of both saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. Important for saturated C24:0 and monounsaturated C24:1 sphingolipid synthesis (PubMed:20937905). Indirectly inhibits RPE65 via production of VLCFAs.PATHWAY Lipid metabolism; fatty acid biosynthesis.SUBUNIT Interacts with LASS2, TECR and HSD17B12.TISSUE SPECIFICITY Ubiquitous.DOMAIN The C-terminal di-lysine motif may confer endoplasmic reticulum localization.SIMILARITY Belongs to the ELO family. ELOVL1 subfamily. UniProt Q9BW60 1 EQUAL 279 EQUAL Reactome Database ID Release 82 548764 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548764 Reactome R-HSA-548764 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548764.1 ELOVL4 Elongation of very long chain fatty acids protein 4 Reactome DB_ID: 548705 UniProt:Q9GZR5 ELOVL4 ELOVL4 FUNCTION Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme that catalyzes the synthesis of very long chain saturated (VLC-SFA) and polyunsaturated (PUFA) fatty acids that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. May play a critical role in early brain and skin development.PATHWAY Lipid metabolism; fatty acid biosynthesis.SUBUNIT Oligomer.TISSUE SPECIFICITY Expressed in the retina and at much lower level in the brain. Ubiquitous, highest expression in thymus, followed by testis, small intestine, ovary, and prostate. Little or no expression in heart, lung, liver, or leukocates.DOMAIN The C-terminal di-lysine motif confers endoplasmic reticulum localization.PTM N-glycosylated.SIMILARITY Belongs to the ELO family. ELOVL4 subfamily. UniProt Q9GZR5 1 EQUAL 314 EQUAL Reactome Database ID Release 82 548705 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548705 Reactome R-HSA-548705 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548705.1 Reactome Database ID Release 82 5676211 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676211 Reactome R-HSA-5676211 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5676211.1 Reactome Database ID Release 82 548824 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548824 Reactome Database ID Release 82 548830 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548830 Reactome R-HSA-548830 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548830.1 18728184 Pubmed 2008 Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids Agbaga, MP Brush, RS Mandal, MN Henry, K Elliott, MH Anderson, RE Proc Natl Acad Sci U S A 105:12843-8 16036915 Pubmed 2005 Dominant negative mechanism underlies autosomal dominant Stargardt-like macular dystrophy linked to mutations in ELOVL4 Grayson, C Molday, RS J Biol Chem 280:32521-30 LEFT-TO-RIGHT ELOVL1,2,3,5 elongate AA-CoA and Mal-CoA to 3ODCT-CoA arachidonoyl-CoA + malonyl-CoA => 3-oxo-(7,10,13,16)-docosatetraenoyl-CoA + CO2 + CoASH Elongation of very long chain fatty acids proteins 1, 2, 3 and 5 (ELOVL1,2,3,5) catalyse the elongation of arachidonyl-CoA (AA-CoA) and malonyl-CoA (Mal-CoA) to form 3-oxo-(7,10,13,16)-docosatetraenoyl-CoA (3ODCT-CoA) (Leonard et al. 2002, Ohno et al. 2010). Authored: D'Eustachio, P, 2010-03-14 Reviewed: D'Eustachio, Peter, 2015-02-21 Edited: D'Eustachio, P, 2010-05-08 3ODCT-CoA 3-oxo-(7,10,13,16)-docosatetraenoyl-CoA (7Z,10Z,13Z,16Z)-3-oxodocosatetraenoyl-CoA Reactome DB_ID: 548816 (7Z,10Z,13Z,16Z)-3-oxodocosatetraenoyl-CoA [ChEBI:63821] (7Z,10Z,13Z,16Z)-3-oxodocosatetraenoyl-CoA 3-oxo-(7Z,10Z,13Z,16Z)-docosatetraenoyl-CoA all-cis-7,10,13,16-3-oxodocosatetraenoyl-CoA ChEBI CHEBI:63821 Reactome Database ID Release 82 548816 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548816 Reactome R-ALL-548816 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-548816.3 ACTIVATION Converted from EntitySet in Reactome ELOVL1,2,3,5 Reactome DB_ID: 5676214 ELOVL2 Elongation of very long chain fatty acids protein 2 Reactome DB_ID: 548677 UniProt:Q9NXB9 ELOVL2 ELOVL2 ELG3 SSC2 FUNCTION Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme that catalyzes the synthesis of polyunsaturated very long chain fatty acid (C20- and C22-PUFA), acting specifically toward polyunsaturated acyl-CoA with the higher activity toward C20:4(n-6) acyl-CoA. May participate in the production of polyunsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.PATHWAY Lipid metabolism; polyunsaturated fatty acid biosynthesis.TISSUE SPECIFICITY Liver and testis.DOMAIN The C-terminal di-lysine motif may confer endoplasmic reticulum localization.SIMILARITY Belongs to the ELO family. ELOVL2 subfamily. UniProt Q9NXB9 1 EQUAL 296 EQUAL Reactome Database ID Release 82 548677 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548677 Reactome R-HSA-548677 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548677.1 ELOVL5 Elongation of very long chain fatty acids protein 5 Reactome DB_ID: 548679 UniProt:Q9NYP7 ELOVL5 ELOVL5 ELOVL2 PRO0530 FUNCTION Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme that acts specifically toward polyunsaturated acyl-CoA with the higher activity toward C18:3(n-6) acyl-CoA. May participate in the production of monounsaturated and of polyunsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators (By similarity) (PubMed:10970790, PubMed:20937905). In conditions where the essential linoleic and alpha linoleic fatty acids are lacking it is also involved in the synthesis of Mead acid from oleic acid (By similarity).PATHWAY Lipid metabolism; polyunsaturated fatty acid biosynthesis.TISSUE SPECIFICITY Ubiquitous. Highly expressed in the adrenal gland and testis. Weakly expressed in prostate, lung and brain. Expressed in the cerebellum.SIMILARITY Belongs to the ELO family. ELOVL5 subfamily. UniProt Q9NYP7 1 EQUAL 299 EQUAL Reactome Database ID Release 82 548679 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548679 Reactome R-HSA-548679 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548679.1 Reactome Database ID Release 82 5676214 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676214 Reactome R-HSA-5676214 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5676214.1 Reactome Database ID Release 82 548806 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548806 Reactome Database ID Release 82 548800 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548800 Reactome R-HSA-548800 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548800.2 12371743 Pubmed 2002 Identification and expression of mammalian long-chain PUFA elongation enzymes Leonard, AE Kelder, B Bobik, EG Chuang, LT Lewis, CJ Kopchick, JJ Mukerji, P Huang, YS Lipids 37:733-40 LEFT-TO-RIGHT ELOVL7 elongates ICS-CoA and Mal-CoA to 3ODC-CoA arachidoyl-CoA + malonyl-CoA => 3-oxobehenoyl-CoA + CO2 + CoASH [ELOVL7] Elongation of very long chain fatty acids protein 7 (ELOVL7) catalyzes the reaction of arachidoyl-CoA (C20:0) and malonyl-CoA to form 3-oxobehenoyl-CoA, CO2, and CoASH. ELOVL7 is localized to the endoplasmic reticulum in transfected cells expressing the cloned cDNA (Tamura et al. 2009). Authored: D'Eustachio, P, 2010-03-14 Reviewed: D'Eustachio, Peter, 2015-02-21 Edited: D'Eustachio, P, 2010-03-14 ICS-CoA arachidoyl-CoA icosanoyl-CoA Reactome DB_ID: 548794 icosanoyl-CoA(4-) [ChEBI:57380] icosanoyl-CoA(4-) eicosanoyl-CoA 3'-phosphonatoadenosine 5'-(3-{(3R)-3-hydroxy-4-[(3-{[2-(icosanoylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-2,2-dimethyl-4-oxobutyl} diphosphate) eicosanoyl-CoA(4-) ChEBI CHEBI:57380 Reactome Database ID Release 82 548794 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548794 Reactome R-ALL-548794 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-548794.4 3ODC-CoA 3-oxobehenoyl-CoA 3-oxodocosanoyl-CoA Reactome DB_ID: 548829 3-oxodocosanoyl-CoA(4-) [ChEBI:71451] 3-oxodocosanoyl-CoA(4-) 3-oxobehenoyl-CoA 3-ketodocosanoyl-CoA(4-) 3-oxodocosanoyl-coenzyme A(4-) 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-{[3-({2-[(3-oxodocosanoyl)sulfanyl]ethyl}amino)-3-oxopropyl]amino}butyl] diphosphate} 3-oxodocosanoyl-CoA 3-ketodocosanoyl-coenzyme A(4-) ChEBI CHEBI:71451 Reactome Database ID Release 82 548829 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548829 Reactome R-ALL-548829 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-548829.4 ACTIVATION Reactome Database ID Release 82 548807 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548807 Reactome Database ID Release 82 548815 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548815 Reactome R-HSA-548815 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548815.2 19826053 Pubmed 2009 Novel lipogenic enzyme ELOVL7 is involved in prostate cancer growth through saturated long-chain fatty acid metabolism Tamura, K Makino, A Hullin-Matsuda, F Kobayashi, T Furihata, M Chung, S Ashida, S Miki, Tsuneharu Fujioka, T Shuin, T Nakamura, Yusuke Nakagawa, H Cancer Res 69:8133-40 LEFT-TO-RIGHT 1.1.1.211 HSD17B3,12 hydrogenates 3OOD-CoA to 3HODC-CoA 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA) + NADPH + H+ => 3-hydroxyoctadecanoyl-CoA + NADP+ Hydroxysteroid (17-beta) dehydrogenase 12 (HSD17B12) catalyzes the reaction of 3-oxooctadecanoyl-CoA (3-oxostearoyl-CoA) and NADPH + H+ to form 3-hydroxyoctadecanoyl-CoA and NADP+. This activity of HSD17B12 protein and its localization to the endoplasmic reticulum membrane were established in studies of transfected cells expressing the protein (Moon and Horton 2003). Based on the phenotypes of human subjects deficient in the enzyme, HSD17B3 is thought to catalyze the reduction of androstenedione to testosterone (Geissler et al. 1994). A detailed analysis of sequence similarities among the HSD17B protein family reveals close similarity of specificity-determining features of HSD17B12 and HSD12B3, making HSD17B3 a candidate to catalyze 3-OOD-CoA reduction as well (W. Pearson, unpublished, 2012). Authored: D'Eustachio, P, 2010-03-14 Reviewed: D'Eustachio, Peter, 2015-02-21 Edited: D'Eustachio, P, 2010-03-14 3HODC-CoA 3-hydroxyoctadecanoyl-CoA Reactome DB_ID: 548836 3-hydroxyoctadecanoyl-CoA [ChEBI:50583] 3-hydroxyoctadecanoyl-CoA ChEBI CHEBI:50583 Reactome Database ID Release 82 548836 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548836 Reactome R-ALL-548836 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-548836.3 ACTIVATION Converted from EntitySet in Reactome HSD17B3,12 Reactome DB_ID: 3907274 HSD17B12 Estradiol 17-beta-dehydrogenase 12 Reactome DB_ID: 548766 UniProt:Q53GQ0 HSD17B12 HSD17B12 SDR12C1 FUNCTION Catalyzes the second of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of two carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme has a 3-ketoacyl-CoA reductase activity, reducing 3-ketoacyl-CoA to 3-hydroxyacyl-CoA, within each cycle of fatty acid elongation. Thereby, it may participate in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. May also catalyze the transformation of estrone (E1) into estradiol (E2) and play a role in estrogen formation.PATHWAY Lipid metabolism; fatty acid biosynthesis.PATHWAY Steroid biosynthesis; estrogen biosynthesis.SUBUNIT Interacts with ELOVL1 and LASS2.TISSUE SPECIFICITY Expressed in most tissues tested. Highly expressed in the ovary and mammary. Expressed in platelets.DOMAIN The di-lysine motif confers endoplasmic reticulum localization for type I membrane proteins.SIMILARITY Belongs to the short-chain dehydrogenases/reductases (SDR) family. 17-beta-HSD 3 subfamily. UniProt Q53GQ0 1 EQUAL 312 EQUAL Reactome Database ID Release 82 548766 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548766 Reactome R-HSA-548766 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548766.1 HSD17B3 Estradiol 17beta-dehydrogenase Reactome DB_ID: 192162 UniProt:P37058 HSD17B3 HSD17B3 EDH17B3 SDR12C2 FUNCTION Catalyzes the conversion of 17-oxosteroids to 17beta-hydroxysteroids (PubMed:8075637, PubMed:16216911, PubMed:27927697, PubMed:26545797). Favors the reduction of androstenedione to testosterone (PubMed:16216911, PubMed:27927697, PubMed:26545797). Testosterone is the key androgen driving male development and function (PubMed:8075637). Uses NADPH while the two other EDH17B enzymes use NADH (PubMed:26545797, PubMed:8075637, PubMed:16216911). Androgens such as epiandrosterone, dehydroepiandrosterone, androsterone and androstanedione are accepted as substrates and reduced at C-17 (PubMed:16216911). Can reduce 11-ketoandrostenedione as well as 11beta-hydroxyandrostenedione at C-17 to the respective testosterone forms (PubMed:16216911, PubMed:27927697).PATHWAY Hormone biosynthesis; testosterone biosynthesis.PATHWAY Steroid metabolism.TISSUE SPECIFICITY Testis.SIMILARITY Belongs to the short-chain dehydrogenases/reductases (SDR) family. 17-beta-HSD 3 subfamily. UniProt P37058 1 EQUAL 310 EQUAL Reactome Database ID Release 82 192162 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=192162 Reactome R-HSA-192162 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-192162.1 Reactome Database ID Release 82 3907274 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3907274 Reactome R-HSA-3907274 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3907274.1 GENE ONTOLOGY GO:0016509 Reactome Database ID Release 82 548828 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548828 Reactome Database ID Release 82 548818 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548818 Reactome R-HSA-548818 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548818.2 12482854 Pubmed 2003 Identification of two mammalian reductases involved in the two-carbon fatty acyl elongation cascade Moon, YA Horton, JD J Biol Chem 278:7335-43 8075637 Pubmed 1994 Male pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3 Geissler, WM Davis, DL Wu, L Bradshaw, KD Patel, S Mendonca, BB Elliston, KO Wilson, JD Russell, David W Andersson, S Nat Genet 7:34-9 LEFT-TO-RIGHT PTPLs dehydrate VLC3HA-CoA to VLCTDA-CoA Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratases 1-4 (PTPLA, B, D1 and D2 respectively, aka HACD1-4) mediate the dehydration step in VLCFA synthesis. A very-long-chain (3R)-3-hydroxyacyl-CoA (VLC3HA-CoA) is dehydrated to a very-long-chain 2,3-trans-enoyl CoA (2,3-TE-CoA) (Ikeda et al. 2008). Authored: Jassal, Bijay, 2015-02-20 Reviewed: D'Eustachio, Peter, 2015-02-21 Edited: D'Eustachio, Peter, 2015-02-21 VLC3HA-CoA very long chain 3-hydroxyacyl-CoA (R)-3-hydroxyacyl-CoA Reactome DB_ID: 5676631 (R)-3-hydroxyacyl-CoA [ChEBI:15456] (R)-3-hydroxyacyl-CoA (3R)-3-Hydroxyacyl-CoA ChEBI CHEBI:15456 Reactome Database ID Release 82 5676631 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676631 Reactome R-ALL-5676631 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5676631.3 2,3-TE-CoA 2,3-trans-enoyl CoA trans-2-enoyl-CoA very long chain 2,3-trans-enoyl CoA very long chain trans-2,3-dehydroacyl-CoA Reactome DB_ID: 5676634 trans-2-enoyl-CoA [ChEBI:50998] trans-2-enoyl-CoA ChEBI CHEBI:50998 Reactome Database ID Release 82 5676634 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676634 Reactome R-ALL-5676634 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5676634.3 ACTIVATION Converted from EntitySet in Reactome PTPLs HACDs Reactome DB_ID: 5676630 PTPLA Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 1 HACD1 Reactome DB_ID: 5676076 UniProt:B0YJ81 HACD1 HACD1 PTPLA PATHWAY Lipid metabolism; fatty acid biosynthesis.SUBUNIT Isoform 1: May interact with enzymes of the ELO family (including ELOVL1); with those enzymes that mediate condensation, the first of the four steps of the reaction cycle responsible for fatty acids elongation, may be part of a larger fatty acids elongase complex (PubMed:18554506). Isoform 2: Homooligomer. Self-assembles into spheres which then aggregates to form strings and a meshwork that may support hydroxyapatite crystal nucleation (PubMed:25263524).TISSUE SPECIFICITY Isoform 1 is highly expressed in the myocardium, and to a lesser extent in skeletal and smooth muscular tissues including those from stomach, jejunum, and bladder. Also detected in gingival fibroblasts, periodontal ligament cells, osteoblasts and cementoblasts (PubMed:11054553, PubMed:22067203). Isoform 2 is specifically expressed by cementoblasts but also detected in periodontal ligament cells, heart, liver and kidney (at protein level) (PubMed:22067203).DEVELOPMENTAL STAGE Isoform 1 is expressed in fetal heart.PTM N-glycosylated.SIMILARITY Belongs to the very long-chain fatty acids dehydratase HACD family.CAUTION Isoform 1 shares some similarity with tyrosine phosphatase proteins but it has probably no phosphatase activity. UniProt B0YJ81 1 EQUAL 288 EQUAL Reactome Database ID Release 82 5676076 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676076 Reactome R-HSA-5676076 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5676076.1 PTPLB Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 2 HACD2 Reactome DB_ID: 5676075 UniProt:Q6Y1H2 HACD2 HACD2 PTPLB FUNCTION Catalyzes the third of the very long-chain fatty acids (VLCFA) elongation four-step cycle (condensation, reduction, dehydration, and reduction). This endoplasmic reticulum-elongation process is characterized by the addition of two carbons to the lipid chain through each cycle. This enzyme catalyzes the dehydration of the 3-hydroxyacyl-CoA intermediate into trans-2,3-enoyl-CoA, within each cycle of elongation. Therefore, it participates in the production of various VLCFAs involved in multiple biological processes as precursors of membrane lipids and lipid mediators.PATHWAY Lipid metabolism; fatty acid biosynthesis.SUBUNIT May interact with enzymes of the ELO family (including ELOVL1); with those enzymes that mediate condensation, the first of the four steps of the reaction cycle responsible for fatty acids elongation, may be part of a larger fatty acids elongase complex (PubMed:18554506). Interacts with BCAP31 (PubMed:15024066).TISSUE SPECIFICITY Highly expressed in testis, spleen, prostate, colon and heart, followed by moderate expression in thymus, ovary, small intestine, peripheral blood leukocytes, liver, skeletal muscle and pancreas. Weakly detected in kidney, placenta, brain and lung.MISCELLANEOUS Turns over rapidly through degradation by the proteasome system.SIMILARITY Belongs to the very long-chain fatty acids dehydratase HACD family.CAUTION Shares some similarity with tyrosine phosphatase proteins but it has probably no phosphatase activity. UniProt Q6Y1H2 2 EQUAL 254 EQUAL Reactome Database ID Release 82 5676075 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676075 Reactome R-HSA-5676075 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5676075.1 HACD3 PTPLAD1 Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 3 Reactome DB_ID: 5676074 UniProt:Q9P035 HACD3 HACD3 BIND1 PTPLAD1 FUNCTION Catalyzes the third of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of two carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme catalyzes the dehydration of the 3-hydroxyacyl-CoA intermediate into trans-2,3-enoyl-CoA, within each cycle of fatty acid elongation. Thereby, it participates in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. May be involved in Rac1-signaling pathways leading to the modulation of gene expression. Promotes insulin receptor/INSR autophosphorylation and is involved in INSR internalization (PubMed:25687571).PATHWAY Lipid metabolism; fatty acid biosynthesis.SUBUNIT May interact with enzymes of the ELO family (including ELOVL1); with those enzymes that mediate condensation, the first of the four steps of the reaction cycle responsible for fatty acids elongation, may be part of a larger fatty acids elongase complex (PubMed:18554506). Interacts with RAC1 (PubMed:10747961). Associates with internalized insulin receptor/INSR complexes on Golgi/endosomal membranes; HACD3/PTPLAD1 together with ATIC and PRKAA2/AMPK2 is proposed to be part of a signaling network regulating INSR autophosphorylation and endocytosis (PubMed:25687571).TISSUE SPECIFICITY Highly expressed in testis, kidney, brain, liver and weakly in skeletal muscle, spleen and heart. No expression detected in leukocytes.INDUCTION By AKAP12 and histone deacetylase inhibitors such as sodium butyrate.SIMILARITY Belongs to the very long-chain fatty acids dehydratase HACD family.CAUTION Shares some similarity with tyrosine phosphatase proteins but it has probably no phosphatase activity. UniProt Q9P035 1 EQUAL 362 EQUAL Reactome Database ID Release 82 5676074 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676074 Reactome R-HSA-5676074 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5676074.1 HACD4 PTPLAD2 Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase 4 Reactome DB_ID: 5676078 UniProt:Q5VWC8 HACD4 HACD4 PTPLAD2 FUNCTION Catalyzes the third of the four reactions of the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of two carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle. This enzyme catalyzes the dehydration of the 3-hydroxyacyl-CoA intermediate into trans-2,3-enoyl-CoA, within each cycle of fatty acid elongation. Thereby, it participates in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators.PATHWAY Lipid metabolism; fatty acid biosynthesis.SUBUNIT May interact with enzymes of the ELO family (including ELOVL1); with those enzymes that mediate condensation, the first of the four steps of the reaction cycle responsible for fatty acids elongation, may be part of a larger fatty acids elongase complex.TISSUE SPECIFICITY Highly expressed in leukocytes, and low expression in heart, spleen, kidney, and placenta.SIMILARITY Belongs to the very long-chain fatty acids dehydratase HACD family.CAUTION Shares some similarity with tyrosine phosphatase proteins but it has probably no phosphatase activity. UniProt Q5VWC8 1 EQUAL 232 EQUAL Reactome Database ID Release 82 5676078 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676078 Reactome R-HSA-5676078 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5676078.1 Reactome Database ID Release 82 5676630 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676630 Reactome R-HSA-5676630 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5676630.1 GENE ONTOLOGY GO:0080023 Reactome Database ID Release 82 5676640 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676640 Reactome Database ID Release 82 5676637 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5676637 Reactome R-HSA-5676637 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5676637.2 18554506 Pubmed 2008 Characterization of four mammalian 3-hydroxyacyl-CoA dehydratases involved in very long-chain fatty acid synthesis Ikeda, Mika Kanao, Yuki Yamanaka, Masao Sakuraba, Hiroko Mizutani, Y Igarashi, Y Kihara, Akio FEBS Lett. 582:2435-40 LEFT-TO-RIGHT 1.3.99 TECR,TECRL dehydrogenate TOD-CoA to ST-CoA trans-octadec-2-enoyl-CoA + NADPH + H+ => stearoyl-CoA + NADP+ Trans-2,3-enoyl-CoA reductase (TECR) catalyzes the reaction of trans-octadec-2-enoyl-CoA and NADPH + H+ to form stearoyl-CoA and NADP+. This activity of TECR protein and its localization to the endoplasmic reticulum membrane was established in studies of transfected cells expressing the protein (Moon and Horton 2003). Authored: D'Eustachio, P, 2010-03-14 Reviewed: D'Eustachio, Peter, 2015-02-21 Edited: D'Eustachio, Peter, 2015-02-21 TOD-CoA trans-octadec-2-enoyl-CoA trans-2-octadecenoyl-CoA Reactome DB_ID: 548809 trans-2-octadecenoyl-CoA [ChEBI:50570] trans-2-octadecenoyl-CoA ChEBI CHEBI:50570 Reactome Database ID Release 82 548809 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548809 Reactome R-ALL-548809 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-548809.3 ST-CoA stearyl-CoA stearoyl-CoA Reactome DB_ID: 428139 stearoyl-CoA(4-) [ChEBI:57394] stearoyl-CoA(4-) stearoyl-coenzyme A tetraanion stearoyl-CoA tetraanion stearoyl-coenzyme A(4-) octadecanoyl-CoA 3'-phosphonatoadenosine 5'-(3-{(3R)-3-hydroxy-2,2-dimethyl-4-[(3-{[2-(octadecanoylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-4-oxobutyl} diphosphate) ChEBI CHEBI:57394 Reactome Database ID Release 82 428139 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428139 Reactome R-ALL-428139 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-428139.4 ACTIVATION Converted from EntitySet in Reactome TECR,TECRL Reactome DB_ID: 4127425 TECR Trans-2,3-enoyl-CoA reductase Reactome DB_ID: 548663 UniProt:Q9NZ01 TECR TECR GPSN2 SC2 FUNCTION Involved in both the production of very long-chain fatty acids for sphingolipid synthesis and the degradation of the sphingosine moiety in sphingolipids through the sphingosine 1-phosphate metabolic pathway (PubMed:25049234). Catalyzes the last of the four reactions of the long-chain fatty acids elongation cycle (PubMed:12482854). This endoplasmic reticulum-bound enzymatic process, allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle (PubMed:12482854). This enzyme reduces the trans-2,3-enoyl-CoA fatty acid intermediate to an acyl-CoA that can be further elongated by entering a new cycle of elongation (PubMed:12482854). Thereby, it participates in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators (PubMed:12482854). Catalyzes the saturation step of the sphingosine 1-phosphate metabolic pathway, the conversion of trans-2-hexadecenoyl-CoA to palmitoyl-CoA (PubMed:25049234).PATHWAY Lipid metabolism; fatty acid biosynthesis.PATHWAY Lipid metabolism; sphingolipid metabolism.SUBUNIT Interacts with ELOVL1 and LASS2.TISSUE SPECIFICITY Expressed in most tissues tested. Highly expressed in skeletal muscle.PTM Glycosylated.SIMILARITY Belongs to the steroid 5-alpha reductase family. UniProt Q9NZ01 1 EQUAL 308 EQUAL Reactome Database ID Release 82 548663 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548663 Reactome R-HSA-548663 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548663.1 TECRL Trans-2,3-enoyl-CoA reductase-like ecNumber1.3.1.-/ecNumber TECRL_HUMAN Reactome DB_ID: 4127427 UniProt:Q5HYJ1 TECRL TECRL SRD5A2L2 TISSUE SPECIFICITY Predominantly expressed in the heart and skeletal muscle.SIMILARITY Belongs to the steroid 5-alpha reductase family. UniProt Q5HYJ1 1 EQUAL 363 EQUAL Reactome Database ID Release 82 4127427 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4127427 Reactome R-HSA-4127427 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4127427.1 Reactome Database ID Release 82 4127425 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4127425 Reactome R-HSA-4127425 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4127425.1 GENE ONTOLOGY GO:0017099 Reactome Database ID Release 82 548793 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548793 Reactome Database ID Release 82 548831 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=548831 Reactome R-HSA-548831 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-548831.2 Reactome Database ID Release 82 75876 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75876 Reactome R-HSA-75876 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75876.5 16564093 Pubmed 2006 Fatty acid elongases in mammals: their regulation and roles in metabolism Jakobsson, A Westerberg, R Jacobsson, A Prog Lipid Res 45:237-49 22984005 Pubmed 2012 Very long-chain fatty acids: elongation, physiology and related disorders Kihara, Akio J. Biochem. 152:387-95 GENE ONTOLOGY GO:0035338 gene ontology term for cellular process MI MI:0359 LEFT-TO-RIGHT 1.14.19.1 SCD desaturates ST-CoA to OLE-CoA Acyl-CoA desaturase (SCD), located on the ER membrane, is the terminal enzyme of the liver microsomal stearyl-CoA desaturase system and is the rate-limiting enzyme in the cellular synthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids. SCD utilises O2 and electrons from reduced ferrocytochrome b5 (Fe(2+)Cb5) to catalyse the insertion of a double bond into a range of fatty acyl-CoA substrates. This example shows stearoyl-CoA (ST-CoA) desaturation to oleoyl-CoA (OLE-CoA) (Li et al. 1994, Zhang et al. 1999). Studies of tagged recombinant enzyme overexpressed in transiently transfected cells suggest that the enzyme forms dimers and higher oligomers (Zhang et al. 2005). Authored: Jassal, Bijay, 2015-04-29 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-04-29 O2 Oxygen dioxygen Reactome DB_ID: 29368 dioxygen [ChEBI:15379] dioxygen ChEBI CHEBI:15379 Reactome Database ID Release 82 29368 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29368 Reactome R-ALL-29368 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29368.5 COMPOUND C00007 2 Fe(2+)Cb5 ferrocytochrome b5 Reactome DB_ID: 4085415 ferrocytochrome b5 [ChEBI:16518] ferrocytochrome b5 ChEBI CHEBI:16518 Reactome Database ID Release 82 4085415 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4085415 Reactome R-ALL-4085415 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-4085415.3 2 2 Fe(3+)Cb5 ferricytochrome b5 Reactome DB_ID: 4085425 ferricytochrome b5 [ChEBI:18097] ferricytochrome b5 ChEBI CHEBI:18097 Reactome Database ID Release 82 4085425 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4085425 Reactome R-ALL-4085425 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-4085425.3 2 OLE-CoA oleoyl-CoA Reactome DB_ID: 5690558 oleoyl-CoA [ChEBI:15534] oleoyl-CoA ChEBI CHEBI:15534 Reactome Database ID Release 82 5690558 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690558 Reactome R-ALL-5690558 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5690558.3 ACTIVATION SCD dimer Reactome DB_ID: 8854942 SCD Acyl-CoA desaturase ACOD_HUMAN Reactome DB_ID: 400117 UniProt:O00767 SCD SCD FADS5 SCD1 SCDOS FUNCTION Stearoyl-CoA desaturase that utilizes O(2) and electrons from reduced cytochrome b5 to introduce the first double bond into saturated fatty acyl-CoA substrates (PubMed:15907797, PubMed:18765284). Catalyzes the insertion of a cis double bond at the delta-9 position into fatty acyl-CoA substrates including palmitoyl-CoA and stearoyl-CoA (PubMed:15907797, PubMed:18765284). Gives rise to a mixture of 16:1 and 18:1 unsaturated fatty acids (PubMed:15610069). Plays an important role in lipid biosynthesis. Plays an important role in regulating the expression of genes that are involved in lipogenesis and in regulating mitochondrial fatty acid oxidation (By similarity). Plays an important role in body energy homeostasis (By similarity). Contributes to the biosynthesis of membrane phospholipids, cholesterol esters and triglycerides (By similarity).SUBUNIT May self-associate and form homodimers.TISSUE SPECIFICITY Detected in fetal liver, lung and brain. Highly expressed in adult adipose tissue, and at lower levels in adult brain and lung.DOMAIN The histidine box domains are involved in binding the catalytic metal ions.SIMILARITY Belongs to the fatty acid desaturase type 1 family. UniProt O00767 1 EQUAL 359 EQUAL Reactome Database ID Release 82 400117 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400117 Reactome R-HSA-400117 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-400117.1 2 Reactome Database ID Release 82 8854942 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8854942 Reactome R-HSA-8854942 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8854942.1 GENE ONTOLOGY GO:0004768 Reactome Database ID Release 82 5690564 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690564 Reactome Database ID Release 82 5690565 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690565 Reactome R-HSA-5690565 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690565.3 10229681 Pubmed 1999 Human stearoyl-CoA desaturase: alternative transcripts generated from a single gene by usage of tandem polyadenylation sites Zhang, L Ge, L Parimoo, S Stenn, K Prouty, S M Biochem. J. 340:255-64 7909540 Pubmed 1994 Partial characterization of a cDNA for human stearoyl-CoA desaturase and changes in its mRNA expression in some normal and malignant tissues Li, J Ding, SF Habib, NA Fermor, BF Wood, CB Gilmour, RS Int J Cancer 57:348-52 15610069 Pubmed 2005 Characterization of human SCD2, an oligomeric desaturase with improved stability and enzyme activity by cross-linking in intact cells Zhang, Shaobo Yang, Yanzhu Shi, Yuguang Biochem. J. 388:135-42 LEFT-TO-RIGHT 1.14.19.1 SCD5 desaturates ST-CoA to OLE-CoA Stearoyl-CoA desaturase 5 (SCD5, also known as acyl-CoA desaturase 4), located on the ER membrane, utilises O2 and electrons from reduced ferrocytochrome b5 (Fe(2+)Cb5) to catalyse the insertion of a double bond into a range of fatty acyl-CoA substrates. SCD5 is most abundant in brain and pancreas. The reaction annotated here shows stearoyl-CoA (ST-CoA) desaturation to oleoyl-CoA (OLE-CoA). Studies of tagged recombinant enzyme overexpressed in transiently transfected cells suggest that the enzyme forms dimers and higher oligomers (Wang et al. 2005; Zhang et al. 2005). Authored: D'Eustachio, Peter, 2015-11-30 Reviewed: Jassal, Bijay, 2016-01-29 Edited: D'Eustachio, Peter, 2015-11-30 2 2 2 2 ACTIVATION SCD5 dimer Reactome DB_ID: 8847584 SCD5 Stearoyl-CoA desaturase 5 Reactome DB_ID: 8847580 UniProt:Q86SK9 SCD5 SCD5 ACOD4 SCD2 SCD4 FUNCTION Stearoyl-CoA desaturase that utilizes O(2) and electrons from reduced cytochrome b5 to introduce the first double bond into saturated fatty acyl-CoA substrates. Catalyzes the insertion of a cis double bond at the delta-9 position into fatty acyl-CoA substrates including palmitoyl-CoA and stearoyl-CoA (PubMed:15610069, PubMed:15907797, PubMed:22745828). Gives rise to a mixture of 16:1 and 18:1 unsaturated fatty acids (PubMed:15610069, PubMed:15907797). Involved in neuronal cell proliferation and differentiation through down-regulation of EGFR/AKT/MAPK and Wnt signaling pathways (PubMed:22745828).SUBUNIT May self-associate and form homodimers.TISSUE SPECIFICITY Detected in fetal brain, and at lower levels in fetal kidney. Detected in adult brain and pancreas, and at lower levels in kidney and lung. Expressed in spiral ganglion cells and the organ of Corti of fetal cochlea (PubMed:31972369).DOMAIN The histidine box domains are involved in binding the catalytic metal ions.MISCELLANEOUS This protein has no ortholog in rodents.SIMILARITY Belongs to the fatty acid desaturase type 1 family. UniProt Q86SK9 1 EQUAL 330 EQUAL Reactome Database ID Release 82 8847580 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847580 Reactome R-HSA-8847580 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847580.1 2 Reactome Database ID Release 82 8847584 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847584 Reactome R-HSA-8847584 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847584.1 Reactome Database ID Release 82 8847576 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847576 Reactome Database ID Release 82 8847579 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8847579 Reactome R-HSA-8847579 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8847579.3 15907797 Pubmed 2005 Characterization of HSCD5, a novel human stearoyl-CoA desaturase unique to primates Wang, Jian Yu, Lan Schmidt, Robert E Su, Chen Huang, Xiaodi Gould, Kenneth Cao, G Biochem. Biophys. Res. Commun. 332:735-42 LEFT-TO-RIGHT 3.1.2.22 PPT1 hydrolyses palmitoylated proteins The maintenance/regulation of cellular levels of free fatty acids and fatty acyl-CoAs (the activated form of free fatty acids) is extremely important, as imbalances in lipid metabolism can have serious consequences for human health. Free fatty acids can act as detergents to disrupt membranes so their generation is normally tightly regulated to states where they will be rapidly consumed or sequestered. Acyl-coenzyme A thioesterases (ACOTs) hydrolyse the thioester bond in medium- to long-chain fatty acyl-CoAs (of C12-C18 lengths) (MCFAcylCoA, LCFAcylCoA) to their free fatty acids (MCFA, LCFA) (Cohen 2013, Hunt et al. 2012, Kirkby et al. 2010). Lysosomal thioesterase PPT1 is able to specifically hydrolyse palmitic acid (PALM) from palmitoylated proteins (PALM:protein) (Camp & Hofmann 1993, Camp et al. 1994). Authored: Jassal, Bijay, 2015-04-29 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-04-29 H2O water Reactome DB_ID: 1605715 lysosomal lumen GENE ONTOLOGY GO:0043202 Reactome Database ID Release 82 1605715 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1605715 Reactome R-ALL-1605715 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-1605715.3 COMPOUND C00001 PALM:protein Reactome DB_ID: 5690533 protein Reactome DB_ID: 6785219 protein [ChEBI:36080] protein [protein] ChEBI CHEBI:36080 Reactome Database ID Release 82 6785219 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6785219 Reactome R-ALL-6785219 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-6785219.2 1 PALM palmitic acid hexadecanoic acid Palmitate Reactome DB_ID: 5690516 Reactome Database ID Release 82 5690516 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690516 Reactome R-ALL-5690516 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5690516.3 COMPOUND C00249 1 Reactome Database ID Release 82 5690533 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690533 Reactome R-ALL-5690533 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5690533.2 ACTIVATION PPT1 Palmitoyl-protein thioesterase 1 PPT1_HUMAN Reactome DB_ID: 5690068 UniProt:P50897 PPT1 PPT1 CLN1 PPT FUNCTION Removes thioester-linked fatty acyl groups such as palmitate from modified cysteine residues in proteins or peptides during lysosomal degradation. Prefers acyl chain lengths of 14 to 18 carbons (PubMed:8816748).SUBUNIT Interacts with CLN5 (PubMed:19941651). Interacts with ATP5F1A and ATP5F1B (By similarity).PTM Glycosylated.SIMILARITY Belongs to the palmitoyl-protein thioesterase family. UniProt P50897 28 EQUAL 306 EQUAL Reactome Database ID Release 82 5690068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690068 Reactome R-HSA-5690068 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690068.1 GENE ONTOLOGY GO:0008474 Reactome Database ID Release 82 5690547 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690547 Reactome Database ID Release 82 5690517 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690517 Reactome R-HSA-5690517 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690517.1 20470824 Pubmed 2010 Functional and structural properties of mammalian acyl-coenzyme A thioesterases Kirkby, Brenda Roman, Noelia Kobe, Bostjan Kellie, Stuart Forwood, Jade K Prog. Lipid Res. 49:366-77 22465940 Pubmed 2012 The emerging role of acyl-CoA thioesterases and acyltransferases in regulating peroxisomal lipid metabolism Hunt, Mary C Siponen, Marina I Alexson, Stefan E H Biochim. Biophys. Acta 1822:1397-410 7916016 Pubmed 1994 Molecular cloning and expression of palmitoyl-protein thioesterase Camp, L A Verkruyse, L A Afendis, S J Slaughter, CA Hofmann, S L J. Biol. Chem. 269:23212-9 23700546 Pubmed 2013 New players on the metabolic stage: How do you like Them Acots? Cohen, David E Adipocyte 2:3-6 7901201 Pubmed 1993 Purification and properties of a palmitoyl-protein thioesterase that cleaves palmitate from H-Ras Camp, L A Hofmann, S L J. Biol. Chem. 268:22566-74 LEFT-TO-RIGHT PPT2 hydrolyses PALMCoA to PALM The maintenance/regulation of cellular levels of free fatty acids and fatty acyl-CoAs (the activated form of free fatty acids) is extremely important, as imbalances in lipid metabolism can have serious consequences for human health. Free fatty acids can act as detergents to disrupt membranes so their generation is normally tightly regulated to states where they will be rapidly consumed or sequestered. Acyl-coenzyme A thioesterases (ACOTs) hydrolyse the thioester bond in medium- to long-chain fatty acyl-CoAs (of C12-C18 lengths) (MCFAcylCoA, LCFAcylCoA) to their free fatty acids (MCFA, LCFA) (Cohen 2013, Hunt et al. 2012, Kirkby et al. 2010). Lysosomal thioesterase PPT2 is able to specifically hydrolyse palmitoyl-CoA (PALM-CoA) to palmitic acid (PALM) (Soyombo & Hofmann 1997). Authored: Jassal, Bijay, 2015-04-27 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-04-27 PALM-CoA palmitoyl-CoA Reactome DB_ID: 5690537 Reactome Database ID Release 82 5690537 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690537 Reactome R-ALL-5690537 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5690537.4 COMPOUND C00154 CoA-SH coenzyme A Reactome DB_ID: 1678675 Reactome Database ID Release 82 1678675 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1678675 Reactome R-ALL-1678675 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-1678675.4 COMPOUND C00010 ACTIVATION PPT2 Lysosomal thioesterase PPT2 PPT2_HUMAN Reactome DB_ID: 5690039 UniProt:Q9UMR5 PPT2 PPT2 FUNCTION Removes thioester-linked fatty acyl groups from various substrates including S-palmitoyl-CoA. Has the highest S-thioesterase activity for the acyl groups palmitic and myristic acid followed by other short- and long-chain acyl substrates. However, because of structural constraints, is unable to remove palmitate from peptides or proteins.TISSUE SPECIFICITY Broadly expressed, with highest levels in skeletal muscle.SIMILARITY Belongs to the palmitoyl-protein thioesterase family.CAUTION Was originally referred as a palmitoyl-protein thioesterase (palmitoyl-protein hydrolase). UniProt Q9UMR5 28 EQUAL 302 EQUAL Reactome Database ID Release 82 5690039 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690039 Reactome R-HSA-5690039 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690039.1 GENE ONTOLOGY GO:0098599 Reactome Database ID Release 82 5690062 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690062 Reactome Database ID Release 82 5690046 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5690046 Reactome R-HSA-5690046 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5690046.1 9341199 Pubmed 1997 Molecular cloning and expression of palmitoyl-protein thioesterase 2 (PPT2), a homolog of lysosomal palmitoyl-protein thioesterase with a distinct substrate specificity Soyombo, A A Hofmann, S L J. Biol. Chem. 272:27456-63 LEFT-TO-RIGHT 1.1.1.100 2xHSD17B8:2xCBR4 reduces 3OA-ACP to 3HA-ACP Estradiol 17-beta-dehydrogenase 8 (HSD17B8) (Ohno et al. 2008) forms a heterotetramer with carbonyl reductase family member 4 (CBR4) (Chen et al. 2009, Zhang et al. 2005). The heterotetramer has NADPH-dependent 3-ketoacyl-acyl carrier protein reductase activity which is suggested to play a role in biosynthesis of fatty acids in mitochondria (Venkatesan et al. 2014). Authored: Jassal, Bijay, 2016-02-25 Reviewed: D'Eustachio, Peter, 2016-04-05 Edited: Jassal, Bijay, 2016-02-25 H+ hydron Reactome DB_ID: 113529 Reactome Database ID Release 82 113529 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113529 Reactome R-ALL-113529 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113529.4 COMPOUND C00080 3OA-ACP 3-oxoacyl-(acyl-carrier-protein) 3-oxoacyl-[acyl-carrier-protein] 3-oxoacyl-(acyl-carrier protein) Reactome DB_ID: 8862377 3-oxoacyl-[acyl-carrier-protein] [ChEBI:84646] 3-oxoacyl-[acyl-carrier-protein] ChEBI CHEBI:84646 Reactome Database ID Release 82 8862377 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8862377 Reactome R-ALL-8862377 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-8862377.4 TPNH NADPH Reactome DB_ID: 113600 NADPH [ChEBI:16474] NADPH TPNH ChEBI CHEBI:16474 Reactome Database ID Release 82 113600 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113600 Reactome R-ALL-113600 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113600.2 COMPOUND C00005 3HA-ACP (3R)-3-hydroxyacyl-(acyl-carrier-protein) (3R)-3-hydroxyacyl-[acyl-carrier-protein] 3-hydroxyacyl-(acyl-carrier protein) Reactome DB_ID: 8862371 (3R)-3-hydroxyacyl-[acyl-carrier-protein] [ChEBI:84648] (3R)-3-hydroxyacyl-[acyl-carrier-protein] ChEBI CHEBI:84648 Reactome Database ID Release 82 8862371 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8862371 Reactome R-ALL-8862371 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-8862371.4 TPN NADP+ NADP NADP(+) Nicotinamide adenine dinucleotide phosphate beta-Nicotinamide adenine dinucleotide phosphate Triphosphopyridine nucleotide Reactome DB_ID: 113563 NADP(+) [ChEBI:18009] NADP(+) ChEBI CHEBI:18009 Reactome Database ID Release 82 113563 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113563 Reactome R-ALL-113563 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113563.4 COMPOUND C00006 ACTIVATION 2xHSD17B8:2xCBR4 Reactome DB_ID: 8862181 HSD17B8 Estradiol 17-beta-dehydrogenase 8 ecNumber1.1.1.62/ecNumber DHB8_HUMAN Reactome DB_ID: 8862105 UniProt:Q92506 HSD17B8 HSD17B8 FABGL HKE6 RING2 SDR30C1 FUNCTION Required for the solubility and assembly of the heterotetramer 3-ketoacyl-[acyl carrier protein] (ACP) reductase functional complex (KAR or KAR1) that forms part of the mitochondrial fatty acid synthase (mtFAS). Alpha-subunit of the KAR complex that acts as a scaffold protein required for the stability of carbonyl reductase type-4 (CBR4, beta-subunit of the KAR complex) and for its 3-ketoacyl-ACP reductase activity, thereby participating in mitochondrial fatty acid biosynthesis. Catalyzes the NAD-dependent conversion of (3R)-3-hydroxyacyl-CoA into 3-ketoacyl-CoA (3-oxoacyl-CoA) with no chain length preference; this enzymatic activity is not needed for the KAR function (PubMed:19571038, PubMed:25203508, PubMed:30508570). Prefers (3R)-3-hydroxyacyl-CoA over (3S)-3-hydroxyacyl-CoA and displays enzymatic activity only in the presence of NAD(+) (PubMed:19571038). Cooperates with enoyl-CoA hydratase 1 in mitochondria, together they constitute an alternative route to the auxiliary enzyme pathways for the breakdown of Z-PUFA (cis polyunsaturated fatty acid) enoyl-esters (Probable) (PubMed:30508570). NAD-dependent 17-beta-hydroxysteroid dehydrogenase with highest activity towards estradiol (17beta-estradiol or E2). Has very low activity towards testosterone and dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one). Primarily an oxidative enzyme, it can switch to a reductive mode determined in the appropriate physiologic milieu and catalyze the reduction of estrone (E1) to form biologically active 17beta-estradiol (PubMed:17978863).PATHWAY Steroid biosynthesis; estrogen biosynthesis.PATHWAY Lipid metabolism; fatty acid biosynthesis.PATHWAY Lipid metabolism; mitochondrial fatty acid beta-oxidation.SUBUNIT Heterotetramer with CBR4; contains two molecules of HSD17B8 and CBR4.TISSUE SPECIFICITY Widely expressed, particularly abundant in prostate, placenta and kidney (PubMed:17978863). Expressed at protein level in various tissues like brain, cerebellum, heart, lung, kidney, ovary, testis, adrenals and prostate (PubMed:30508570).INDUCTION Up-regulated by estradiol.MISCELLANEOUS The fatty acyl-CoA dehydrogenase activity is several thousand times higher than the estradiol and testosterone 17beta-hydroxysteroid dehydrogenase conversion.SIMILARITY Belongs to the short-chain dehydrogenases/reductases (SDR) family. UniProt Q92506 1 EQUAL 261 EQUAL Reactome Database ID Release 82 8862105 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8862105 Reactome R-HSA-8862105 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8862105.2 2 CBR4 Carbonyl reductase family member 4 ecNumber1.-.-.-/ecNumber CBR4_HUMAN Reactome DB_ID: 8862102 UniProt:Q8N4T8 CBR4 CBR4 SDR45C1 FUNCTION Component of the heterotetramer complex KAR (3-ketoacyl-[acyl carrier protein] reductase or 3-ketoacyl-[ACP] reductase) that forms part of the mitochondrial fatty acid synthase (mtFAS). Beta-subunit of the KAR heterotetramer complex, responsible for the 3-ketoacyl-ACP reductase activity of the mtFAS, reduces 3-oxoacyl-[ACP] to (3R)-hydroxyacyl-[ACP] in a NADPH-dependent manner with no chain length preference, thereby participating in mitochondrial fatty acid biosynthesis (PubMed:25203508). The homotetramer has NADPH-dependent quinone reductase activity (in vitro), hence could play a role in protection against cytotoxicity of exogenous quinones (PubMed:19000905). As a heterotetramer, it can also reduce 9,10-phenanthrenequinone, 1,4-benzoquinone and various other o-quinones and p-quinones (in vitro) (PubMed:19000905, PubMed:19571038, PubMed:25203508).PATHWAY Lipid metabolism; fatty acid biosynthesis.SUBUNIT Homotetramer (in vitro) (PubMed:19000905). Heterotetramer with HSD17B8; contains two molecules each of HSD17B8 and CBR4 (PubMed:19571038, PubMed:25203508). Does not form homotetramers when HSD17B8 is coexpressed, only heterotetramers (in vitro) (PubMed:25203508).TISSUE SPECIFICITY Detected in liver and kidney (at protein level) (PubMed:19000905). Displays the highest expression in neuronal and muscle tissues (PubMed:25203508).SIMILARITY Belongs to the short-chain dehydrogenases/reductases (SDR) family. UniProt Q8N4T8 1 EQUAL 237 EQUAL Reactome Database ID Release 82 8862102 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8862102 Reactome R-HSA-8862102 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8862102.2 2 Reactome Database ID Release 82 8862181 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8862181 Reactome R-HSA-8862181 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8862181.2 GENE ONTOLOGY GO:0004316 Reactome Database ID Release 82 8862163 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8862163 Reactome Database ID Release 82 8862152 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8862152 Reactome R-HSA-8862152 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8862152.2 19571038 Pubmed 2009 17beta-hydroxysteroid dehydrogenase type 8 and carbonyl reductase type 4 assemble as a ketoacyl reductase of human mitochondrial FAS Chen, Zhijun Kastaniotis, Alexander J Miinalainen, Ilkka J Rajaram, Venkatesan Wierenga, RK Hiltunen, J Kalervo FASEB J. 23:3682-91 25203508 Pubmed 2014 Insights into mitochondrial fatty acid synthesis from the structure of heterotetrameric 3-ketoacyl-ACP reductase/3R-hydroxyacyl-CoA dehydrogenase Venkatesan, Rajaram Sah-Teli, Shiv K Awoniyi, Luqman O Jiang, Guangyu Prus, Piotr Kastaniotis, Alexander J Hiltunen, J Kalervo Wierenga, RK Chen, Zhijun Nat Commun 5:4805 15668256 Pubmed 2005 Cloning, expression, and characterization of the human mitochondrial beta-ketoacyl synthase. Complementation of the yeast CEM1 knock-out strain Zhang, Lei Joshi, AK Hofmann, Jörg Schweizer, Eckhart Smith, Stuart J. Biol. Chem. 280:12422-9 17978863 Pubmed 2008 Expression in E. coli and tissue distribution of the human homologue of the mouse Ke 6 gene, 17beta-hydroxysteroid dehydrogenase type 8 Ohno, Shuji Nishikawa, Kouki Honda, Yoko Nakajin, Shizuo Mol. Cell. Biochem. 309:209-15 LEFT-TO-RIGHT 4.2.1 RPP14 (HTD2) dehydrates 3HA-CoA to t2E-CoA Polycistronic transcripts, where a single mRNA can encode several different polypeptide chains, are common in prokaryotes. In humans, only 3 bicistronic transcripts have been characterised to date. Human cDNAs encoding both RPP14 of the RNase P complex and mitochondrial 3-hydroxyacyl thioester dehydratase (HTD2) have been isolated. HTD2 functions in the mitochondrial fatty acid synthesis (FAS) pathway, dehydrating (3R)-hydroxyacyl-CoA (3HA-CoA) to trans-2-enoyl-CoA (t2E-CoA) (Autio et al. 2008). Authored: Jassal, Bijay, 2017-01-25 Reviewed: D'Eustachio, Peter, 2017-01-30 Edited: Jassal, Bijay, 2017-01-25 3HA-CoA 3-hydroxyacyl-CoA (R)-3-hydroxyacyl-CoA Reactome DB_ID: 8957387 Reactome Database ID Release 82 8957387 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8957387 Reactome R-ALL-8957387 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-8957387.3 H2O water Reactome DB_ID: 113521 Reactome Database ID Release 82 113521 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113521 Reactome R-ALL-113521 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113521.3 COMPOUND C00001 t2E-CoA 2,3-trans-enoyl CoA trans-2-enoyl-CoA Reactome DB_ID: 8957386 Reactome Database ID Release 82 8957386 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8957386 Reactome R-ALL-8957386 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-8957386.4 ACTIVATION HTD2 RPP14 fullName evidence="5"Hydroxyacyl-thioester dehydratase type 2, mitochondrial HTD2_HUMAN Reactome DB_ID: 8933306 UniProt:P86397 HTD2 HTD2 FUNCTION Mitochondrial 3-hydroxyacyl-thioester dehydratase, which may be involved in fatty acid biosynthesis.TISSUE SPECIFICITY Highly expressed in heart and liver. Expressed at lower levels in skeletal muscle, spleen, kidney and placenta.MISCELLANEOUS This protein is produced by a bicistronic gene which also produces the RPP14 protein from an overlapping reading frame.SIMILARITY Belongs to the HTD2 family. UniProt P86397 1 EQUAL 168 EQUAL Reactome Database ID Release 82 8933306 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8933306 Reactome R-HSA-8933306 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8933306.1 GENE ONTOLOGY GO:0018812 Reactome Database ID Release 82 8957385 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8957385 Reactome Database ID Release 82 8957389 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8957389 Reactome R-HSA-8957389 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8957389.1 17898086 Pubmed 2008 An ancient genetic link between vertebrate mitochondrial fatty acid synthesis and RNA processing Autio, Kaija J Kastaniotis, Alexander J Pospiech, Helmut Miinalainen, Ilkka J Schonauer, Melissa S Dieckmann, Carol L Hiltunen, J Kalervo FASEB J. 22:569-78 Reactome Database ID Release 82 75105 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75105 Reactome R-HSA-75105 7 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75105.7 25360565 Pubmed 2015 Fatty acid biosynthesis revisited: structure elucidation and metabolic engineering Beld, Joris Lee, D John Burkart, Michael D Mol Biosyst 11:38-59 GENE ONTOLOGY GO:0046949 Arachidonic acid metabolism Eicosanoids, oxygenated, 20-carbon fatty acids, are autocrine and paracrine signaling molecules that modulate physiological processes including pain, fever, inflammation, blood clot formation, smooth muscle contraction and relaxation, and the release of gastric acid. Eicosanoids are synthesized in humans primarily from arachidonic acid (all-cis 5,8,11,14-eicosatetraenoic acid) that is released from membrane phospholipids. Once released, arachidonic acid is acted on by prostaglandin G/H synthases (PTGS, also known as cyclooxygenases (COX)) to form prostaglandins and thromboxanes, by arachidonate lipoxygenases (ALOX) to form leukotrienes, epoxygenases (cytochrome P450s and epoxide hydrolase) to form epoxides such as 15-eicosatetraenoic acids, and omega-hydrolases (cytochrome P450s) to form hydroxyeicosatetraenoic acids (Buczynski et al. 2009, Vance & Vance 2008).<br>Levels of free arachidonic acid in the cell are normally very low so the rate of synthesis of eicosanoids is determined primarily by the activity of phospholipase A2, which mediates phospholipid cleavage to generate free arachidonic acid. The enzymes involved in arachidonic acid metabolism are typically constitutively expressed so the subset of these enzymes expressed by a cell determines the range of eicosanoids it can synthesize.<br>Eicosanoids are unstable, undergoing conversion to inactive forms with half-times under physiological conditions of seconds or minutes. Many of these reactions appear to be spontaneous. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 LEFT-TO-RIGHT Hydrolysis of phosphatidylcholine Once bound to the membrane, cPLA2 hydrolyzes phosphatidylcholine to produce arachidonic acid (AA), a precursor to inflammatory mediators. While several phospholipases can catalyze this reaction in cells overexpressing the enzymes, PLA2G4A is the major enzyme that catalyzes this reaction in vivo (Reed et al. 2011). At the same time, possible physiological roles have been described for soluble phospholipases (sPLA) in the mobilization of arachidonic acid in some cell types or under some physiological conditions (Murakami et al. 2011). Here, the major role of PLA2G4A has been annotated. Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-11-06 PC Phosphatidyl choline 1,2-diacyl-sn-glycero-3-phosphocholine Reactome DB_ID: 426925 1,2-diacyl-sn-glycero-3-phosphocholine [ChEBI:57643] 1,2-diacyl-sn-glycero-3-phosphocholine a 1,2-diacyl-sn-glycero-3-phosphocholine PC 1,2-diacyl-sn-glycero-3-phosphocholine betaine 3-sn-phosphatidylcholine 1,2-diacyl-sn-glycero-3-phosphocholines Phosphatidylcholine Diacyl PC lecithin 3-sn-phosphatidylcholines ChEBI CHEBI:57643 Reactome Database ID Release 82 426925 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426925 Reactome R-ALL-426925 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-426925.4 COMPOUND C00157 AA arachidonic acid Reactome DB_ID: 140356 endoplasmic reticulum lumen GENE ONTOLOGY GO:0005788 Reactome Database ID Release 82 140356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140356 Reactome R-ALL-140356 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-140356.4 LPC 2-Lysophosphatidylcholine 1-Acyl-sn-glycero-3-phosphocholine 1-O-acyl-sn-glycero-3-phosphocholine(1+) 1-Acyl-sn-glycerol-3-phosphocholine 1-Acylglycero-3-phosphocholine Reactome DB_ID: 428981 1-O-acyl-sn-glycero-3-phosphocholine(1+) [ChEBI:17504] 1-O-acyl-sn-glycero-3-phosphocholine(1+) ChEBI CHEBI:17504 Reactome Database ID Release 82 428981 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428981 Reactome R-ALL-428981 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-428981.4 ACTIVATION Active PLA2:phosphatidylcholine Reactome DB_ID: 111860 1 phospho-cPLA2 p-S505,S727-PLA2G4A Phosphatidylcholine 2-acylhydrolase Phospholipase A2 group IVA Reactome DB_ID: 111859 UniProt:P47712 PLA2G4A PLA2G4A CPLA2 PLA2G4 FUNCTION Has primarily calcium-dependent phospholipase and lysophospholipase activities, with a major role in membrane lipid remodeling and biosynthesis of lipid mediators of the inflammatory response (PubMed:7794891, PubMed:8619991, PubMed:8702602, PubMed:9425121, PubMed:10358058, PubMed:14709560, PubMed:16617059, PubMed:17472963, PubMed:27642067, PubMed:18451993). Plays an important role in embryo implantation and parturition through its ability to trigger prostanoid production (By similarity). Preferentially hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) (PubMed:7794891, PubMed:8619991, PubMed:9425121, PubMed:10358058, PubMed:17472963, PubMed:18451993). Selectively hydrolyzes sn-2 arachidonoyl group from membrane phospholipids, providing the precursor for eicosanoid biosynthesis via the cyclooxygenase pathway (PubMed:18451993, PubMed:7794891, PubMed:9425121, PubMed:10358058, PubMed:17472963). In an alternative pathway of eicosanoid biosynthesis, hydrolyzes sn-2 fatty acyl chain of eicosanoid lysophopholipids to release free bioactive eicosanoids (PubMed:27642067). Hydrolyzes the ester bond of the fatty acyl group attached at sn-1 position of phospholipids (phospholipase A1 activity) only if an ether linkage rather than an ester linkage is present at the sn-2 position. This hydrolysis is not stereospecific (PubMed:7794891). Has calcium-independent phospholipase A2 and lysophospholipase activities in the presence of phosphoinositides (PubMed:12672805). Has O-acyltransferase activity. Catalyzes the transfer of fatty acyl chains from phospholipids to a primary hydroxyl group of glycerol (sn-1 or sn-3), potentially contributing to monoacylglycerol synthesis (PubMed:7794891).ACTIVITY REGULATION Activated by cytosolic calcium, which is necessary for binding to membrane lipids (PubMed:12672805). Activated by phosphorylation in response to mitogenic stimuli (PubMed:8381049). Activated by ceramide-1-phosphate. Binding (via C2 domain) to ceramide-1-phosphate increases the affinity for membrane lipids (PubMed:17472963). Can be activated by phosphoinositides in the absence of calcium (PubMed:12672805). Inhibited by ANXA5 in a calcium- and substrate-dependent way (PubMed:9425121).PATHWAY Membrane lipid metabolism; glycerophospholipid metabolism.PATHWAY Lipid metabolism; arachidonate metabolism.PATHWAY Lipid metabolism; prostaglandin biosynthesis.PATHWAY Lipid metabolism; leukotriene B4 biosynthesis.SUBUNIT Interacts with KAT5.TISSUE SPECIFICITY Expressed in various cells and tissues such as macrophages, neutrophils, fibroblasts and lung endothelium. Expressed in platelets (at protein level) (PubMed:25102815).DOMAIN The N-terminal C2 domain associates with lipid membranes upon calcium binding. It modulates enzyme activity by presenting the active site to its substrate in response to elevations of cytosolic calcium (PubMed:9430701, PubMed:9665851, PubMed:11375391). In the presence of phosphoinositides, regulates phospholipase A2 and lysophospholipase activities in a calcium-independent way (PubMed:12672805).PTM Phosphorylated at both Ser-505 and Ser-727 in response to mitogenic stimuli. UniProt P47712 505 EQUAL O-phospho-L-serine MOD MOD:00046 727 EQUAL 1 EQUAL 749 EQUAL Reactome Database ID Release 82 111859 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111859 Reactome R-HSA-111859 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-111859.1 1 Ca2+ Calcium calcium(2+) Reactome DB_ID: 74016 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI CHEBI:29108 Reactome Database ID Release 82 74016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74016 Reactome R-ALL-74016 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-74016.3 COMPOUND C00076 1 Reactome Database ID Release 82 111860 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111860 Reactome R-HSA-111860 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-111860.1 GENE ONTOLOGY GO:0047498 Reactome Database ID Release 82 111882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111882 Reactome Database ID Release 82 111883 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111883 Reactome R-HSA-111883 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-111883.3 21746768 Pubmed 2011 Secreted phospholipase A2 revisited Murakami, Makoto Taketomi, Yoshitaka Sato, Hiroyasu Yamamoto, Kei J. Biochem. 150:233-55 21247147 Pubmed 2011 Functional characterization of mutations in inherited human cPLA? deficiency Reed, Kathleen A Tucker, Dawn E Aloulou, Ahmed Adler, David Ghomashchi, Farideh Gelb, Michael H Leslie, Christina C Oates, John A Boutaud, Olivier Biochemistry 50:1731-8 LEFT-TO-RIGHT Arachidonate diffuses across the ER membrane Arachidonate released by phospholipases diffuses within the membrane and out of the membrane into the ER lumen and cytosol. The relatively low level of arachidonate in the cytoplasm is probably due to reesterification into complex lipids by acyl transferases. Authored: Jupe, S, 2009-07-14 Reviewed: Rush, MG, 2012-11-10 Edited: Jupe, S, 2009-07-14 Reactome Database ID Release 82 428990 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428990 Reactome R-HSA-428990 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428990.3 6810878 Pubmed 1982 How is the level of free arachidonic acid controlled in mammalian cells? Irvine, RF Biochem J 204:3-16 6146314 Pubmed 1984 Inositol trisphosphate and diacylglycerol as second messengers Berridge, MJ Biochem J 220:345-60 LEFT-TO-RIGHT 2.3.1.75 AWAT1 transfers acyl group from acyl-CoA to ARACOH, forming wax esters Arachidyl alcohol (ARACOH) is straight-chain fatty alcohol of C20 length used as an emollient in cosmetics. Esterification of alcohols with fatty acids represents the formation of both storage and cytoprotective molecules in the body. Overproduction of these esters is associated with several disease pathologies, including atherosclerosis and obesity. The ER membrane-associated acyl-CoA wax alcohol acyltransferase 1 (AWAT1) mediates the esterification of its preferred substrate ARACOH (Turkish et al. 2005). Authored: Jassal, Bijay, 2015-05-29 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-05-29 ARACOH arachidyl alcohol icosan-1-ol Reactome DB_ID: 5696426 icosan-1-ol [ChEBI:75627] icosan-1-ol arachidyl alcohol 1-eicosanol arachidic alcohol eicosan-1-ol eicosyl alcohol ChEBI CHEBI:75627 Reactome Database ID Release 82 5696426 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696426 Reactome R-ALL-5696426 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5696426.3 Acyl-CoA Acyl_minus_CoA Reactome DB_ID: 192172 acyl-CoA [ChEBI:17984] acyl-CoA ChEBI CHEBI:17984 Reactome Database ID Release 82 192172 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=192172 Reactome R-ALL-192172 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-192172.2 wax ester arachidyl ester Reactome DB_ID: 5696412 wax ester [ChEBI:10036] wax ester Wax esters ChEBI CHEBI:10036 Reactome Database ID Release 82 5696412 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696412 Reactome R-ALL-5696412 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5696412.3 CoA-SH coenzyme A Reactome DB_ID: 162743 Reactome Database ID Release 82 162743 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=162743 Reactome R-ALL-162743 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-162743.5 COMPOUND C00010 ACTIVATION AWAT1 Acyl-CoA wax alcohol acyltransferase 1 ecNumber2.3.1.75/ecNumber AWAT1_HUMAN Reactome DB_ID: 5696425 UniProt:Q58HT5 AWAT1 AWAT1 DGA2 DGAT2L3 FUNCTION Acyltransferase that catalyzes the formation of ester bonds between fatty alcohols and fatty acyl-CoAs to form wax monoesters (PubMed:15671038). Shows a strong preference for decyl alcohol (C10), with less activity towards C16 and C18 alcohols (PubMed:15671038). Shows a strong preference for saturated acyl-CoAs (PubMed:15671038).TISSUE SPECIFICITY Predominantly expressed in skin, where it is limited to the sebaceous gland. Expressed in more mature, centrally located cells just before their rupture and sebum release. Also expressed in all tissues except spleen. Expressed at higher level in thymus, prostate and testis.SIMILARITY Belongs to the diacylglycerol acyltransferase family. UniProt Q58HT5 1 EQUAL 328 EQUAL Reactome Database ID Release 82 5696425 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696425 Reactome R-HSA-5696425 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5696425.1 GENE ONTOLOGY GO:0047196 Reactome Database ID Release 82 5696418 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696418 Reactome Database ID Release 82 5696424 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696424 Reactome R-HSA-5696424 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5696424.2 15671038 Pubmed 2005 Identification of two novel human acyl-CoA wax alcohol acyltransferases: members of the diacylglycerol acyltransferase 2 (DGAT2) gene superfamily Turkish, Aaron R Henneberry, Annette L Cromley, Debra Padamsee, Mahajabeen Oelkers, P Bazzi, Hisham Christiano, Angela M Billheimer, JT Sturley, Stephen L J. Biol. Chem. 280:14755-64 LEFT-TO-RIGHT FAAH hydrolyses AEA to AA and ETA Fatty acid amides are a class of lipid transmitters that include the endogenous cannabinoid anandamide (AEA) and the sleep-inducing chemical oleamide. The magnitude and duration of their signalling are controlled by enzymatic hydrolysis mediated by fatty-acid amide hydrolases 1 and 2 (FAAH, H2). Hydrolysis of AEA is described here (Wei et al. 2006). FAAH is localised to the ER membrane whereas FAAH2 is localised to lipid droplets (Kaczocha et al. 2010). Authored: Jassal, Bijay, 2015-05-18 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-05-18 AEA anandamide Reactome DB_ID: 5693754 anandamide [ChEBI:2700] anandamide ChEBI CHEBI:2700 Reactome Database ID Release 82 5693754 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693754 Reactome R-ALL-5693754 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5693754.3 ETA ethanolamine Reactome DB_ID: 1498751 ethanolamine [ChEBI:16000] ethanolamine ChEBI CHEBI:16000 Reactome Database ID Release 82 1498751 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1498751 Reactome R-ALL-1498751 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-1498751.3 ACTIVATION FAAH Fatty-acid amide hydrolase 1 ecNumber3.5.1.99/ecNumber FAAH1_HUMAN Reactome DB_ID: 5693746 UniProt:O00519 FAAH FAAH FAAH1 FUNCTION Catalyzes the hydrolysis of endogenous amidated lipids like the sleep-inducing lipid oleamide ((9Z)-octadecenamide), the endocannabinoid anandamide (N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine), as well as other fatty amides, to their corresponding fatty acids, thereby regulating the signaling functions of these molecules (PubMed:9122178, PubMed:17015445, PubMed:19926788). Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates (PubMed:9122178, PubMed:17015445). It can also catalyze the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol) (PubMed:21049984). FAAH cooperates with PM20D1 in the hydrolysis of amino acid-conjugated fatty acids such as N-fatty acyl glycine and N-fatty acyl-L-serine, thereby acting as a physiological regulator of specific subsets of intracellular, but not of extracellular, N-fatty acyl amino acids (By similarity).ACTIVITY REGULATION Inhibited by O-aryl carbamates and alpha-keto heterocycles (PubMed:17015445). Inhibited by trifluoromethyl ketone (PubMed:9122178).SUBUNIT Homodimer.TISSUE SPECIFICITY Highly expressed in the brain, small intestine, pancreas, skeletal muscle and testis. Also expressed in the kidney, liver, lung, placenta and prostate.POLYMORPHISM Genetic variations in FAAH can be associated with susceptibility to polysubstance abuse [MIM:606581]. At homozygosity, variant Thr-129 is strongly associated with drug and alcohol abuse, and methamphetamine dependence.SIMILARITY Belongs to the amidase family. UniProt O00519 1 EQUAL 579 EQUAL Reactome Database ID Release 82 5693746 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693746 Reactome R-HSA-5693746 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5693746.1 GENE ONTOLOGY GO:0017064 Reactome Database ID Release 82 5693749 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693749 Reactome Database ID Release 82 5693742 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693742 Reactome R-HSA-5693742 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5693742.1 19926788 Pubmed 2010 Lipid droplets are novel sites of N-acylethanolamine inactivation by fatty acid amide hydrolase-2 Kaczocha, Martin Glaser, Sherrye T Chae, Janiper Brown, Deborah A Deutsch, Dale G J. Biol. Chem. 285:2796-806 17015445 Pubmed 2006 A second fatty acid amide hydrolase with variable distribution among placental mammals Wei, Binqing Q Mikkelsen, Tarjei S McKinney, Michele K Lander, Eric S Cravatt, BF J. Biol. Chem. 281:36569-78 LEFT-TO-RIGHT FAAH2 hydrolyses AEA to AA and ETA Fatty acid amides are a class of lipid transmitters that include the endogenous cannabinoid anandamide (AEA) and the sleep-inducing chemical oleamide. The magnitude and duration of their signalling are controlled by enzymatic hydrolysis mediated by fatty-acid amide hydrolases 1 and 2 (FAAH, H2). Hydrolysis of AEA is described here (Wei et al. 2006). FAAH is localised to the ER membrane whereas FAAH2 is localised to lipid droplets (Kaczocha et al. 2010). Authored: Jassal, Bijay, 2015-05-18 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-05-18 AEA anandamide Reactome DB_ID: 5693752 lipid droplet GENE ONTOLOGY GO:0005811 Reactome Database ID Release 82 5693752 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693752 Reactome R-ALL-5693752 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5693752.4 H2O water Reactome DB_ID: 5693747 Reactome Database ID Release 82 5693747 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693747 Reactome R-ALL-5693747 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5693747.4 COMPOUND C00001 AA Arachidonate arachidonic acid cis-5,8,11,14-Eicosatetraenoic acid Reactome DB_ID: 5693733 Reactome Database ID Release 82 5693733 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693733 Reactome R-ALL-5693733 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5693733.5 COMPOUND C00219 ETA ethanolamine Reactome DB_ID: 5693736 Reactome Database ID Release 82 5693736 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693736 Reactome R-ALL-5693736 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5693736.4 ACTIVATION FAAH2 Fatty-acid amide hydrolase 2 ecNumber3.5.1.99/ecNumber FAAH2_HUMAN Reactome DB_ID: 5693745 UniProt:Q6GMR7 FAAH2 FAAH2 AMDD FUNCTION Catalyzes the hydrolysis of endogenous amidated lipids like the sleep-inducing lipid oleamide ((9Z)-octadecenamide), the endocannabinoid anandamide (N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine), as well as other fatty amides, to their corresponding fatty acids, thereby regulating the signaling functions of these molecules (PubMed:17015445, PubMed:19926788). Hydrolyzes monounsaturated substrate anandamide preferentially as compared to polyunsaturated substrates.ACTIVITY REGULATION Inhibited by O-aryl carbamates and alpha-keto heterocytes.SUBUNIT Homodimer.TISSUE SPECIFICITY Expressed in kidney, liver, lung, prostate, heart and ovary.SIMILARITY Belongs to the amidase family. UniProt Q6GMR7 1 EQUAL 532 EQUAL Reactome Database ID Release 82 5693745 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693745 Reactome R-HSA-5693745 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5693745.2 Reactome Database ID Release 82 5693738 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693738 Reactome Database ID Release 82 5693751 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693751 Reactome R-HSA-5693751 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5693751.1 Synthesis of Prostaglandins (PG) and Thromboxanes (TX) The bioactive prostaglandin (PG) signalling molecules, including PGA2, PGE2, PGF2a, and PGI2 (prostacyclin) are synthesised from arachidonic acid and its products by various prostaglandin synthase type enzymes. Prostaglandin H2 (PGH2) is the starting point for the synthesis of Thromboxanes (TXs) (Buczynski et al. 2009, Vance & Vance 2008). PGs and TXs are collectively known as the prostanoids.<br>Two enzymes, PTGS1 and 2 (COX1 and 2) both catalyze the two-step conversion of arachidonic acid to PGH2. PTGS1 is constitutively expressed in many cell types while PTGS2 is induced in response to stress and mediates the syntheses of prostaglandins associated with pain, fever, and inflammation. Aspirin irreversibly inactivates both enzymes (though it acts more efficiently on PTGS1), explaining both its antiinflammatory effects and side effects like perturbed gastic acid secretion. Drugs like celecoxib, by specifically inhibiting PTGS2, have a strong anti-inflammatory effect with fewer side effects. These PTGS2-specific drugs, however, probably because of their effects on the balance of prostaglandin synthesis in platelets and endothelial cells, can also promote blood clot formation (Buczynski et al. 2009; Stables & Gilroy 2011). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 LEFT-TO-RIGHT PTGS2 dimer binds PTGS2 inhibitors While closely similar, PTGS1 and 2 differ sufficiently in the structures of their active sites so that the latter enzyme selectively binds and is inhibited by PTGS2 inhibitors (benzquinamide, carprofen, celecoxib, etodolac, etoricoxib, lumiracoxib, rofecoxib, valdecoxib) (Luong et al. 1996; Smith et al. 2000; Dong et al. 2011). Authored: D'Eustachio, P, 2012-06-05 Reviewed: Rush, MG, 2012-11-10 Edited: D'Eustachio, P, 2012-06-05 PTGS2 dimer PGHS2 dimer Reactome DB_ID: 140491 heme b Reactome DB_ID: 2311355 heme b [ChEBI:26355] heme b heme protoheme IX protoheme haem b (7,12-diethenyl-3,8,13,17-tetramethylporphyrin-2,18-dipropanoato)iron [3,7,12,17-tetramethyl-8,13-divinylporphyrin-2,18-dipropanoato(2-)]iron PROTOPORPHYRIN IX CONTAINING FE ChEBI CHEBI:26355 Reactome Database ID Release 82 2311355 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2311355 Reactome R-ALL-2311355 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2311355.2 1 PTGS2 Prostaglandin G/H synthase 2 precursor Cyclooxygenase -2 COX-2 Prostaglandin-endoperoxide synthase 2 Prostaglandin H2 synthase 2 PGH synthase 2 PGHS-2 PHS II Reactome DB_ID: 61605 UniProt:P35354 PTGS2 PTGS2 COX2 FUNCTION Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate, with a particular role in the inflammatory response (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593, PubMed:11939906, PubMed:19540099). The cyclooxygenase activity oxygenates arachidonate (AA, C20:4(n-6)) to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide PGH2, the precursor of all 2-series prostaglandins and thromboxanes (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593). This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593). Similarly catalyzes successive cyclooxygenation and peroxidation of dihomo-gamma-linoleate (DGLA, C20:3(n-6)) and eicosapentaenoate (EPA, C20:5(n-3)) to corresponding PGH1 and PGH3, the precursors of 1- and 3-series prostaglandins (PubMed:11939906, PubMed:19540099). In an alternative pathway of prostanoid biosynthesis, converts 2-arachidonoyl lysophopholipids to prostanoid lysophopholipids, which are then hydrolyzed by intracellular phospholipases to release free prostanoids (PubMed:27642067). Metabolizes 2-arachidonoyl glycerol yielding the glyceryl ester of PGH2, a process that can contribute to pain response (PubMed:22942274). Generates lipid mediators from n-3 and n-6 polyunsaturated fatty acids (PUFAs) via a lipoxygenase-type mechanism. Oxygenates PUFAs to hydroperoxy compounds and then reduces them to corresponding alcohols (PubMed:11034610, PubMed:11192938, PubMed:9048568, PubMed:9261177). Plays a role in the generation of resolution phase interaction products (resolvins) during both sterile and infectious inflammation (PubMed:12391014). Metabolizes docosahexaenoate (DHA, C22:6(n-3)) to 17R-HDHA, a precursor of the D-series resolvins (RvDs) (PubMed:12391014). As a component of the biosynthetic pathway of E-series resolvins (RvEs), converts eicosapentaenoate (EPA, C20:5(n-3)) primarily to 18S-HEPE that is further metabolized by ALOX5 and LTA4H to generate 18S-RvE1 and 18S-RvE2 (PubMed:21206090). In vascular endothelial cells, converts docosapentaenoate (DPA, C22:5(n-3)) to 13R-HDPA, a precursor for 13-series resolvins (RvTs) shown to activate macrophage phagocytosis during bacterial infection (PubMed:26236990). In activated leukocytes, contributes to oxygenation of hydroxyeicosatetraenoates (HETE) to diHETES (5,15-diHETE and 5,11-diHETE) (PubMed:22068350, PubMed:26282205). During neuroinflammation, plays a role in neuronal secretion of specialized preresolving mediators (SPMs) 15R-lipoxin A4 that regulates phagocytic microglia (By similarity).ACTIVITY REGULATION The cyclooxygenase activity is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, flurbiprofen, celecoxib, flufenamic, mefenamic and tolfenamic acids as well as by hydroperoxide scavenger erythrocyte glutathione peroxidase GPX1 (PubMed:26859324, PubMed:27226593, PubMed:7592599, PubMed:9048568). Aspirin triggers enzyme acetylation turning off its ability to generate pro-inflammatory prostaglandins, but switches on its capacity to produce anti-inflammatory lipid mediators involved in inflammation resolution (PubMed:11034610, PubMed:12391014). Aspirin enhances lipoxygenase-type activity toward production of epimers with R stereochemistry such as 15R-HETE, 18R-HEPE, 15R-HEPE and 17R-HDHA (PubMed:11034610, PubMed:11192938, PubMed:22068350, PubMed:12391014, PubMed:9048568, PubMed:21206090). Atorvastatin, a cholesterol-lowering drug, triggers enzyme S-nitrosylation increasing production of 13-series resolvins (RvTs) (PubMed:26236990).PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Homodimer.INDUCTION By cytokines and mitogens. Up-regulated by IL1B (PubMed:26282205, PubMed:9545330). Up-regulated by lipopolysaccharide (LPS) (PubMed:9545330).PTM S-nitrosylation by NOS2 (iNOS) activates enzyme activity. S-nitrosylation may take place on different Cys residues in addition to Cys-526.PTM Acetylated at Ser-565 by SPHK1. During neuroinflammation, acetylation by SPHK1 promotes neuronal secretion of specialized preresolving mediators (SPMs), especially 15-R-lipoxin A4, which results in an increase of phagocytic microglia.MISCELLANEOUS The conversion of arachidonate to prostaglandin H2 is a 2 step reaction: a cyclooxygenase (COX) reaction which converts arachidonate to prostaglandin G2 (PGG2) and a peroxidase reaction in which PGG2 is reduced to prostaglandin H2 (PGH2). The cyclooxygenase reaction occurs in a hydrophobic channel in the core of the enzyme. The peroxidase reaction occurs at a heme-containing active site located near the protein surface. The nonsteroidal anti-inflammatory drugs (NSAIDs) binding site corresponds to the cyclooxygenase active site.MISCELLANEOUS Conversion of arachidonate to prostaglandin H2 is mediated by 2 different isozymes: the constitutive PTGS1 and the inducible PTGS2. PTGS1 is expressed constitutively and generally produces prostanoids acutely in response to hormonal stimuli to fine-tune physiological processes requiring instantaneous, continuous regulation (e.g. hemostasis). PTGS2 is inducible and typically produces prostanoids that mediate responses to physiological stresses such as infection and inflammation.MISCELLANEOUS PTGS1 and PTGS2 are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin and ibuprofen (PubMed:27710942, PubMed:26859324, PubMed:27226593). Aspirin is able to produce an irreversible inactivation of the enzyme through a serine acetylation (PubMed:26859324). Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. PTGS2 is the principal isozyme responsible for production of inflammatory prostaglandins. New generation PTGSs inhibitors strive to be selective for PTGS2, to avoid side effects such as gastrointestinal complications and ulceration.SIMILARITY Belongs to the prostaglandin G/H synthase family. UniProt P35354 18 EQUAL 604 EQUAL Reactome Database ID Release 82 61605 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=61605 Reactome R-HSA-61605 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-61605.1 2 Reactome Database ID Release 82 140491 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140491 Reactome R-HSA-140491 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-140491.1 Converted from EntitySet in Reactome PTGS2 inhibitors COX-2 inhibitors Reactome DB_ID: 9716714 benzquinamide Reactome DB_ID: 9716734 benzquinamide [Guide to Pharmacology:7124] benzquinamide P-2647 Quantril&reg; Guide to Pharmacology 7124 Reactome Database ID Release 82 9716734 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716734 Reactome R-ALL-9716734 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716734.1 ChEBI 27662 carprofen Reactome DB_ID: 9716728 carprofen [Guide to Pharmacology:7141] carprofen Ro-205720000 Guide to Pharmacology 7141 Reactome Database ID Release 82 9716728 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716728 Reactome R-ALL-9716728 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716728.1 ChEBI 364453 celecoxib Reactome DB_ID: 9716723 celecoxib [Guide to Pharmacology:2892] celecoxib Celecox&reg; Onsenal&reg; SC-58635 SC58635 Guide to Pharmacology 2892 Reactome Database ID Release 82 9716723 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716723 Reactome R-ALL-9716723 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716723.1 ChEBI 41423 etodolac Reactome DB_ID: 9716725 etodolac [Guide to Pharmacology:7185] etodolac AY-24236 Lodine&reg; Guide to Pharmacology 7185 Reactome Database ID Release 82 9716725 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716725 Reactome R-ALL-9716725 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716725.1 ChEBI 60371 etoricoxib Reactome DB_ID: 9716732 etoricoxib [Guide to Pharmacology:2896] etoricoxib Arcoxia&reg; MK0663 MK 0663 MK-0663 Guide to Pharmacology 2896 Reactome Database ID Release 82 9716732 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716732 Reactome R-ALL-9716732 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716732.1 ChEBI 6339 lumiracoxib Reactome DB_ID: 9716731 lumiracoxib [Guide to Pharmacology:2897] lumiracoxib Prexige&reg; Guide to Pharmacology 2897 Reactome Database ID Release 82 9716731 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716731 Reactome R-ALL-9716731 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716731.1 ChEBI 73044 rofecoxib Reactome DB_ID: 9716716 rofecoxib [Guide to Pharmacology:2893] rofecoxib Ceoxx&reg; MK 966 Vioxx&reg; Guide to Pharmacology 2893 Reactome Database ID Release 82 9716716 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716716 Reactome R-ALL-9716716 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716716.1 ChEBI 8887 valdecoxib Reactome DB_ID: 9716713 valdecoxib [Guide to Pharmacology:2894] valdecoxib Bextra&reg; SC-65872 Guide to Pharmacology 2894 Reactome Database ID Release 82 9716713 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716713 Reactome R-ALL-9716713 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716713.1 ChEBI 63634 Reactome Database ID Release 82 9716714 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716714 Reactome R-ALL-9716714 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716714.1 PTGS2 dimer:PTGS2 inhibitors Reactome DB_ID: 2309778 1 1 Reactome Database ID Release 82 2309778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309778 Reactome R-HSA-2309778 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2309778.3 Reactome Database ID Release 82 2309779 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309779 Reactome R-HSA-2309779 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2309779.4 10966456 Pubmed 2000 Cyclooxygenases: structural, cellular, and molecular biology Smith, William L DeWitt, David L Garavito, R Michael Annu Rev Biochem 69:145-82 8901870 Pubmed 1996 Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2 Luong, Christine Miller, Aaron Barnett, Jim Chow, Joan Ramesha, Chakk Browner, Michelle F Nat. Struct. Biol. 3:927-33 21467029 Pubmed 2011 Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer Dong, Liang Vecchio, Alex J Sharma, Narayan P Jurban, Brice J Malkowski, Michael G Smith, William L J. Biol. Chem. 286:19035-46 LEFT-TO-RIGHT ASA- acetylates PTGS1 The ionized form of aspirin, acetylsalicylate (ASA-) reacts spontaneously with one subunit of PTGS1 dimer to acetylate serine residue 516. The modified enzyme is no longer capable of catalyzing the conversion of arachidonic acid to PGH2. The identity of the acetylated residue is inferred from data for the humann PTGS2 enzyme (Lecomte et al. 1994) and the ovine PGHS1 enzyme (Loll et al. 1995). Authored: D'Eustachio, P, 2012-06-07 Reviewed: Rush, MG, 2012-11-10 Edited: D'Eustachio, P, 2012-06-07 COX1 PTGS1 dimer PGHS1 homodimer Reactome DB_ID: 428986 1 COX1 PTGS1 Prostaglandin G/H synthase 1 PGH1_HUMAN Cyclooxygenase-1 Reactome DB_ID: 428931 UniProt:P23219 PTGS1 PTGS1 COX1 FUNCTION Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate, with a particular role in the inflammatory response. The cyclooxygenase activity oxygenates arachidonate (AA, C20:4(n-6)) to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide PGH2, the precursor of all 2-series prostaglandins and thromboxanes. This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:7947975). Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells (Probable).ACTIVITY REGULATION The cyclooxygenase activity is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen, flurbiprofen, ketoprofen, naproxen, flurbiprofen, anirolac, fenclofenac and diclofenac.PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Homodimer.MISCELLANEOUS The conversion of arachidonate to prostaglandin H2 is a 2 step reaction: a cyclooxygenase (COX) reaction which converts arachidonate to prostaglandin G2 (PGG2) and a peroxidase reaction in which PGG2 is reduced to prostaglandin H2 (PGH2). The cyclooxygenase reaction occurs in a hydrophobic channel in the core of the enzyme. The peroxidase reaction occurs at a heme-containing active site located near the protein surface. The nonsteroidal anti-inflammatory drugs (NSAIDs) binding site corresponds to the cyclooxygenase active site.MISCELLANEOUS Conversion of arachidonate to prostaglandin H2 is mediated by 2 different isozymes: the constitutive PTGS1 and the inducible PTGS2. PTGS1 is expressed constitutively and generally produces prostanoids acutely in response to hormonal stimuli to fine-tune physiological processes requiring instantaneous, continuous regulation (e.g. hemostasis). PTGS2 is inducible and typically produces prostanoids that mediate responses to physiological stresses such as infection and inflammation.MISCELLANEOUS PTGS1 and PTGS2 are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin and ibuprofen. Aspirin is able to produce an irreversible inactivation of the enzyme through a serine acetylation. Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. PTGS2 is the principal isozyme responsible for production of inflammatory prostaglandins. New generation PTGSs inhibitors strive to be selective for PTGS2, to avoid side effects such as gastrointestinal complications and ulceration.SIMILARITY Belongs to the prostaglandin G/H synthase family. UniProt P23219 24 EQUAL 599 EQUAL Reactome Database ID Release 82 428931 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428931 Reactome R-HSA-428931 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428931.1 2 Reactome Database ID Release 82 428986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428986 Reactome R-HSA-428986 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428986.1 ASA- acetylsalicylate(1-) Reactome DB_ID: 2314693 acetylsalicylate [ChEBI:13719] acetylsalicylate ChEBI CHEBI:13719 Reactome Database ID Release 82 2314693 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314693 Reactome R-ALL-2314693 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2314693.4 Ac-PTGS1 dimer Reactome DB_ID: 2314695 1 1 Ac-PTGS1 O-acetyl-L-serine-PTGS1 Reactome DB_ID: 2314694 529 EQUAL O-acetyl-L-serine MOD MOD:00369 24 EQUAL 599 EQUAL Reactome Database ID Release 82 2314694 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314694 Reactome R-HSA-2314694 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314694.1 1 Reactome Database ID Release 82 2314695 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314695 Reactome R-HSA-2314695 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314695.1 ST salicylate Reactome DB_ID: 2314690 salicylate [ChEBI:30762] salicylate sal o-hydroxybenzoate 2-hydroxybenzoic acid ion(1-) ChEBI CHEBI:30762 Reactome Database ID Release 82 2314690 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314690 Reactome R-ALL-2314690 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2314690.3 Reactome Database ID Release 82 2314678 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314678 Reactome R-HSA-2314678 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314678.4 7552725 Pubmed 1995 The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase Loll, Patrick J Picot, Daniel Garavito, R Michael Nat. Struct. Biol. 2:637-43 8175750 Pubmed 1994 Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin Lecomte, Marc Laneuville, Odette Ji, Chuan DeWitt, David L Smith, William L J. Biol. Chem. 269:13207-15 LEFT-TO-RIGHT ASA- acetylates PTGS2 The ionized form of aspirin, acetylsalicylate (ASA-) reacts spontaneously with one subunit of PTGS2 dimer (Dong et al. 2011) to acetylate serine residue 516 (Lecomte et al. 1994). The modified enzyme is no longer capable of catalyzing the conversion of arachidonic acid to PGH2, but acquires the ability to convert it to 15R-HETE. Authored: D'Eustachio, P, 2012-06-07 Reviewed: Rush, MG, 2012-11-10 Edited: D'Eustachio, P, 2012-06-07 Ac-PTGS2 dimer Reactome DB_ID: 2314687 1 Ac-PTGS2 O-acetyl-L-serine-PTGS2 acetyl-PTGS2 Cyclooxygenase -2 Ac-COX-2 Ac-Prostaglandin-endoperoxide synthase 2 Ac-Prostaglandin H2 synthase 2 Ac-PGH synthase 2 Ac-PGHS-2 Ac-PHS II Reactome DB_ID: 2161824 516 EQUAL 18 EQUAL 604 EQUAL Reactome Database ID Release 82 2161824 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161824 Reactome R-HSA-2161824 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161824.1 1 1 Reactome Database ID Release 82 2314687 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314687 Reactome R-HSA-2314687 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314687.1 Reactome Database ID Release 82 2314686 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314686 Reactome R-HSA-2314686 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314686.3 LEFT-TO-RIGHT 1.14.99.1 Arachidonic acid oxidised to PGG2 Arachidonic acid is oxidised to PGG2 by PTGS1 Prostaglandin G/H synthase PTGS1 exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The cyclooxygenase function catalyzes the initial conversion of arachidonic acid to an intermediate, prostaglandin G2 (PGG2) (Hamberg et al. 1974, Nugteren 1973). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-05-28 09:06:10 Edited: Jassal, Bijay, 2008-05-19 O2 Oxygen dioxygen Reactome DB_ID: 113534 Reactome Database ID Release 82 113534 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113534 Reactome R-ALL-113534 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113534.3 COMPOUND C00007 2 PGG2 prostaglandin G2 Reactome DB_ID: 140357 prostaglandin G2 [ChEBI:27647] prostaglandin G2 ChEBI CHEBI:27647 Reactome Database ID Release 82 140357 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140357 Reactome R-ALL-140357 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-140357.3 ACTIVATION GENE ONTOLOGY GO:0004666 Reactome Database ID Release 82 140354 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140354 Reactome Database ID Release 82 140355 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140355 Reactome R-HSA-140355 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-140355.1 4776443 Pubmed 1973 Isolation and properties of intermediates in prostaglandin biosynthesis Nugteren, DH Hazelhof, E Biochim Biophys Acta 326:448-61 4521806 Pubmed 1974 Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation Hamberg, M Svensson, J Wakabayashi, T Samuelsson, B Proc Natl Acad Sci U S A 71:345-9 LEFT-TO-RIGHT PTGS1 dimer binds PTGS1 Inhibitors Prostaglandins are involved in physiological functions such as protecting the stomach mucosa, platelet aggregation and regulating kidney function. They also play pathological roles in inflammation, fever and pain (Ricciotti & FitzGerald 2011). Cyclooxygenase enzymes mediate the production of protaglandins. Prostaglandin G/H synthase 1 (PTGS1, cyclooxygenase 1, COX1) is a mainly constitutively expressed enzyme that acts in a 'housekeeping' fashion producing prostaglandins for physiological functions whereas prostaglandin G/H synthase 2 (PTGS2, cyclooxygenase 2, COX2) is an inducible form which mediates protaglandin production for inflammation.<br><br>In 1971, John R Vane showed that the pharmacological actions of aspirin and similar nonsteroid anti-inflammatory drugs (NSAIDs) were due to the inhibition of cyclooxygenase (Vane 1971). Thus, aspirin-like drugs exert their anti-inflammatory, antipyretic and analgesic effects by the inhibition of cyclooxygenase (Vane & Botting 1997, Botting 2006). The beneficial actions of NSAIDs can be associated with inhibition of COX2 whereas their harmful side effects are associated with inhibition of COX1 therefore developing drugs with a high COX2 specificity is advantageous (Cryer & Feldman 1998, Warner et al. 1999, García-Rayado et al. 2018, Saad & Matthew 2020).<br><br>Most NSAIDs possess some or all of antipyretic, analgesic and anti-inflammatory properties and are used to treat rheumatic and osteoarthritic conditions, pain, inflammation and fever (Botting 2006, Crofford 2013). Authored: Jassal, Bijay, 2020-03-05 Reviewed: Huddart, Rachel, 2022-03-01 Edited: Jassal, Bijay, 2020-03-05 Edited: Matthews, Lisa, 2022-05-10 Converted from EntitySet in Reactome PTGS1 Inhibitors Reactome DB_ID: 9677343 meloxicam Mobic&reg; UHAC-62XX Reactome DB_ID: 9677371 meloxicam [Guide to Pharmacology:7220] meloxicam Mobic&reg; UHAC-62XX Guide to Pharmacology 7220 Reactome Database ID Release 82 9677371 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677371 Reactome R-ALL-9677371 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677371.1 indomethacin Indocid&reg; Indocin&reg; Reactome DB_ID: 9677460 indomethacin [Guide to Pharmacology:1909] indomethacin Indocid&reg; Indocin&reg; Guide to Pharmacology 1909 Reactome Database ID Release 82 9677460 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677460 Reactome R-ALL-9677460 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677460.1 R-805 nimesulide Reactome DB_ID: 9677334 nimesulide [Guide to Pharmacology:7401] nimesulide R-805 Guide to Pharmacology 7401 Reactome Database ID Release 82 9677334 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677334 Reactome R-ALL-9677334 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677334.1 APAP paracetamol acetaminophen Panadol&reg; Tylenol&reg; Reactome DB_ID: 9677362 paracetamol [Guide to Pharmacology:5239] paracetamol acetaminophen Panadol&reg; Tylenol&reg; Guide to Pharmacology 5239 Reactome Database ID Release 82 9677362 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677362 Reactome R-ALL-9677362 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677362.1 ChEBI 46195 bromfenac Reactome DB_ID: 9677640 bromfenac [Guide to Pharmacology:7131] bromfenac AHR-10282B Bromday&reg; Prolensa&reg; Xibrom&reg; Guide to Pharmacology 7131 Reactome Database ID Release 82 9677640 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677640 Reactome R-ALL-9677640 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677640.1 fenoprofen Reactome DB_ID: 9677638 fenoprofen [Guide to Pharmacology:4820] fenoprofen fenoprofen calcium Nalfon&reg; Guide to Pharmacology 4820 Reactome Database ID Release 82 9677638 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677638 Reactome R-ALL-9677638 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677638.1 Reactome Database ID Release 82 9677343 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677343 Reactome R-ALL-9677343 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677343.1 PTGS1 dimer:PTGS1 Inhibitors Reactome DB_ID: 9677354 1 1 Reactome Database ID Release 82 9677354 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677354 Reactome R-HSA-9677354 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9677354.1 Reactome Database ID Release 82 9677320 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677320 Reactome R-HSA-9677320 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9677320.1 9219313 Pubmed 1997 Mechanism of action of aspirin-like drugs Vane, J R Botting, R M Semin. Arthritis Rheum. 26:2-10 9626023 Pubmed 1998 Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs Cryer, B Feldman, M Am. J. Med. 104:413-21 30252262 Pubmed 2020 Nonsteroidal Anti-Inflammatory Drugs (NSAID) Toxicity Saad, Jennifer Mathew, Dana 10377455 Pubmed 1999 Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis Warner, T D Giuliano, F Vojnovic, I Bukasa, A Mitchell, J A Vane, J R Proc. Natl. Acad. Sci. U.S.A. 96:7563-8 5284360 Pubmed 1971 Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs Vane, J R Nature New Biol. 231:232-5 21508345 Pubmed 2011 Prostaglandins and inflammation Ricciotti, Emanuela FitzGerald, Garret A Arterioscler. Thromb. Vasc. Biol. 31:986-1000 30139288 Pubmed 2018 NSAID induced gastrointestinal damage and designing GI-sparing NSAIDs García-Rayado, Guillermo Navarro, Mercedes Lanas, Angel Expert Rev Clin Pharmacol 11:1031-1043 17218763 Pubmed 2006 Inhibitors of cyclooxygenases: mechanisms, selectivity and uses Botting, R M J. Physiol. Pharmacol. 57:113-24 24267197 Pubmed 2013 Use of NSAIDs in treating patients with arthritis Crofford, Leslie J Arthritis Res. Ther. 15:S2 LEFT-TO-RIGHT 1.14.99.1 Arachidonic acid oxidised to PGG2 Arachidonic acid is oxidised to PGG2 by PTGS2 Prostaglandin G/H synthase PTGS2 exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The cyclooxygenase function catalyzes the initial conversion of arachidonic acid to an intermediate, prostaglandin G2 (PGG2) (Hamberg et al. 1974, Nugteren 1973). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-05-28 09:06:10 Edited: Jassal, Bijay, 2008-05-19 2 ACTIVATION Reactome Database ID Release 82 2309772 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309772 Reactome Database ID Release 82 2309787 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309787 Reactome R-HSA-2309787 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2309787.1 LEFT-TO-RIGHT 1.11.1.7 PGG2 is reduced to PGH2 by PTGS1 Peroxidative reduction of PGG2 to PGH2 Prostaglandin G/H synthase 1 (PTGS1) exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The peroxidase function converts prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) via a two-electron reduction (Hamberg et al. 1973, Hla & Neilson 1992, Swinney et al. 1997, Barnett et al. 1994). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 H+ hydron Reactome DB_ID: 156540 Reactome Database ID Release 82 156540 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=156540 Reactome R-ALL-156540 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-156540.3 COMPOUND C00080 2 e- electron Reactome DB_ID: 76342 electron [ChEBI:10545] electron ChEBI CHEBI:10545 Reactome Database ID Release 82 76342 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76342 Reactome R-ALL-76342 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-76342.3 2 PGH2 (5Z,13E)-(15S)-9alpha,11alpha-Epidioxy-15-hydroxyprosta-5,13-dienoate prostaglandin H2 Reactome DB_ID: 30138 prostaglandin H2 [ChEBI:15554] prostaglandin H2 ChEBI CHEBI:15554 Reactome Database ID Release 82 30138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=30138 Reactome R-ALL-30138 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-30138.3 COMPOUND C00427 H2O water Reactome DB_ID: 113519 Reactome Database ID Release 82 113519 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113519 Reactome R-ALL-113519 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113519.3 COMPOUND C00001 ACTIVATION GENE ONTOLOGY GO:0004601 Reactome Database ID Release 82 140358 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140358 Reactome Database ID Release 82 140359 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140359 Reactome R-HSA-140359 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-140359.1 7947975 Pubmed 1994 Purification, characterization and selective inhibition of human prostaglandin G/H synthase 1 and 2 expressed in the baculovirus system Barnett, J Chow, J Ives, D Chiou, M Mackenzie, R Osen, E Nguyen, B Tsing, S Bach, C Freire, J Biochim Biophys Acta 1209:130-9 4514999 Pubmed 1973 Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesis Hamberg, M Samuelsson, B Proc Natl Acad Sci U S A 70:899-903 9139685 Pubmed 1997 Differential allosteric regulation of prostaglandin H synthase 1 and 2 by arachidonic acid Swinney, DC Mak, AY Barnett, J Ramesha, CS J Biol Chem 272:12393-8 1380156 Pubmed 1992 Human cyclooxygenase-2 cDNA Hla, T Neilson, K Proc Natl Acad Sci U S A 89:7384-8 LEFT-TO-RIGHT 1.11.1.7 PGG2 is reduced to PGH2 by PTGS2 Peroxidative reduction of PGG2 to PGH2 Prostaglandin G/H synthase 2 (PTGS2) exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The peroxidase function converts prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) via a two-electron reduction (Hamberg et al. 1973, Hla & Neilson 1992, Swinney et al. 1997, Barnett et al. 1994). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 2 2 ACTIVATION Reactome Database ID Release 82 2309777 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309777 Reactome Database ID Release 82 2309773 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309773 Reactome R-HSA-2309773 6 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2309773.6 INHIBITION Reactome Database ID Release 82 9677534 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677534 ACTIVATION Reactome Database ID Release 82 5362144 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5362144 Reactome R-HSA-5362144 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5362144.1 MNA N1MNA 1-methylnicotinamide N-1-methylnicotinamide NMN Reactome DB_ID: 549282 1-methylnicotinamide [ChEBI:16797] 1-methylnicotinamide ChEBI CHEBI:16797 Reactome Database ID Release 82 549282 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=549282 Reactome R-ALL-549282 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-549282.3 LEFT-TO-RIGHT PGH2 diffuses from the endoplasmic reticulum lumen to the cytosol PGH2 moves from the endoplasmic reticulum to the cytosol. The mechanism of this movement has not been determined and could could simply be diffusion through the ER membrane. Authored: D'Eustachio, P, 2012-06-04 Reviewed: Rush, MG, 2012-11-10 PGH2 (5Z,13E)-(15S)-9alpha,11alpha-Epidioxy-15-hydroxyprosta-5,13-dienoate prostaglandin H2 Reactome DB_ID: 265283 Reactome Database ID Release 82 265283 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265283 Reactome R-ALL-265283 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-265283.3 COMPOUND C00427 Reactome Database ID Release 82 2299725 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2299725 Reactome R-HSA-2299725 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2299725.3 20346915 Pubmed 2010 The prostaglandin transporter PGT transports PGH(2) Chi, Yuling Schuster, Victor L Biochem. Biophys. Res. Commun. 395:168-72 LEFT-TO-RIGHT PGH2 is reduced to PGF2a by AKR1C3 Aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS is responsible for the reduction of prostaglandin H2 (PGH2) to prostaglandin F2alpha (PGF2a) (Suzuki-Yamamoto et al. 1999, Komoto et al. 2004, Komoto et al. 2006). There is an additional way of achieving this reaction involving the prostamide/prostaglandin F synthase, FAM213B and thioredoxin (TRX). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGF2a prostaglandin F2alpha Reactome DB_ID: 879535 prostaglandin F2alpha [ChEBI:15553] prostaglandin F2alpha ChEBI CHEBI:15553 Reactome Database ID Release 82 879535 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879535 Reactome R-ALL-879535 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-879535.3 ACTIVATION AKR1C3 Aldo-keto reductase family 1 member C3 AK1C3_HUMAN Reactome DB_ID: 2142714 UniProt:P42330 AKR1C3 AKR1C3 DDH1 HSD17B5 KIAA0119 PGFS FUNCTION Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids. Acts as a NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductase on the steroid nucleus and side chain and regulates the metabolism of androgens, estrogens and progesterone (PubMed:10622721, PubMed:11165022, PubMed:7650035, PubMed:9415401, PubMed:9927279). Displays the ability to catalyze both oxidation and reduction in vitro, but most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentration of NADPH (PubMed:14672942, PubMed:11165022). Acts preferentially as a 17-ketosteroid reductase and has the highest catalytic efficiency of the AKR1C enzyme for the reduction of delta4-androstenedione to form testosterone (PubMed:20036328). Reduces prostaglandin (PG) D2 to 11beta-prostaglandin F2, progesterone to 20alpha-hydroxyprogesterone and estrone to 17beta-estradiol (PubMed:15047184, PubMed:20036328, PubMed:10622721, PubMed:11165022, PubMed:10998348, PubMed:19010934). Catalyzes the transformation of the potent androgen dihydrotestosterone (DHT) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol) (PubMed:10998348, PubMed:14672942, PubMed:11165022, PubMed:7650035, PubMed:9415401, PubMed:10557352). Also displays retinaldehyde reductase activity toward 9-cis-retinal (PubMed:21851338).ACTIVITY REGULATION Strongly inhibited by nonsteroidal anti-inflammatory drugs (NSAID) including flufenamic acid and indomethacin. Also inhibited by the flavinoid, rutin, and by selective serotonin inhibitors (SSRIs) (PubMed:14979715, PubMed:14996743, PubMed:10557352). The oxidation reaction is inhibited by low micromolar concentrations of NADPH (PubMed:14672942).PATHWAY Steroid metabolism.TISSUE SPECIFICITY Expressed in many tissues including adrenal gland, brain, kidney, liver, lung, mammary gland, placenta, small intestine, colon, spleen, prostate and testis. High expression in prostate and mammary gland. In the prostate, higher levels in epithelial cells than in stromal cells. In the brain, expressed in medulla, spinal cord, frontotemporal lobes, thalamus, subthalamic nuclei and amygdala. Weaker expression in the hippocampus, substantia nigra and caudate.SIMILARITY Belongs to the aldo/keto reductase family. UniProt P42330 1 EQUAL 323 EQUAL Reactome Database ID Release 82 2142714 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142714 Reactome R-HSA-2142714 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142714.1 GENE ONTOLOGY GO:0036130 Reactome Database ID Release 82 2161558 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161558 Reactome Database ID Release 82 2161549 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161549 Reactome R-HSA-2161549 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161549.2 10622721 Pubmed 1999 cDNA cloning, expression and characterization of human prostaglandin F synthase Suzuki-Yamamoto, T Nishizawa, M Fukui, M Okuda-Ashitaka, E Nakajima, T Ito, S Watanabe, K FEBS Lett 462:335-40 14979715 Pubmed 2004 Crystal structure of human prostaglandin F synthase (AKR1C3) Komoto, J Yamada, T Watanabe, K Takusagawa, F Biochemistry 43:2188-98 16475787 Pubmed 2006 Prostaglandin F2alpha formation from prostaglandin H2 by prostaglandin F synthase (PGFS): crystal structure of PGFS containing bimatoprost Komoto, J Yamada, T Watanabe, K Woodward, DF Takusagawa, F Biochemistry 45:1987-96 LEFT-TO-RIGHT 1.11.1 PGH2 is reduced to PGF2a by FAM213B Prostamide/prostaglandin F synthase, FAM213B and thioredoxin (TXN) are the proteins involved in the reduction of prostaglandin H2 (PGH2) to prostaglandin F2alpha (PGF2a) (Moriuchi et al. 2008, Yoshikawa et al. 2011). This reaction has been inferred from an event in mice. An additional way of achieving this reaction involves the protein aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 TXN-S2H2 Thioredoxin thioredoxin dithiol Reduced thioredoxin Reactome DB_ID: 2142774 thioredoxin dithiol [ChEBI:15967] thioredoxin dithiol ChEBI CHEBI:15967 Reactome Database ID Release 82 2142774 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142774 Reactome R-ALL-2142774 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142774.3 TXN-S2 Thioredoxin disulphide thioredoxin disulfide Oxidised thioredoxin Reactome DB_ID: 2142833 thioredoxin disulfide [ChEBI:18191] thioredoxin disulfide ChEBI CHEBI:18191 Reactome Database ID Release 82 2142833 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142833 Reactome R-ALL-2142833 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142833.3 ACTIVATION FAM213B Prostamide/prostaglandin F synthase C1orf93 PGFS_HUMAN Reactome DB_ID: 2142703 UniProt:Q8TBF2 PRXL2B PRXL2B C1orf93 FAM213B FUNCTION Catalyzes the reduction of prostaglandin-ethanolamide H(2) (prostamide H(2)) to prostamide F(2alpha) with NADPH as proton donor. Also able to reduce prostaglandin H(2) to prostaglandin F(2alpha) (By similarity).SIMILARITY Belongs to the peroxiredoxin-like PRXL2 family. Prostamide/prostaglandin F synthase subfamily. UniProt Q8TBF2 1 EQUAL 198 EQUAL Reactome Database ID Release 82 2142703 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142703 Reactome R-HSA-2142703 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142703.1 GENE ONTOLOGY GO:0008379 Reactome Database ID Release 82 2161731 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161731 Reactome Database ID Release 82 2161612 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161612 Reactome R-HSA-2161612 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161612.2 20950588 Pubmed 2011 Preferential localization of prostamide/prostaglandin F synthase in myelin sheaths of the central nervous system Yoshikawa, K Takei, S Hasegawa-Ishii, S Chiba, Y Furukawa, A Kawamura, N Hosokawa, M Woodward, DF Watanabe, K Shimada, A Brain Res 1367:22-32 18006499 Pubmed 2008 Molecular characterization of a novel type of prostamide/prostaglandin F synthase, belonging to the thioredoxin-like superfamily Moriuchi, H Koda, N Okuda-Ashitaka, E Daiyasu, H Ogasawara, K Toh, H Ito, S Woodward, DF Watanabe, K J Biol Chem 283:792-801 LEFT-TO-RIGHT 5.3.99.3 PGH2 is isomerised to PGE2 by PTGES Prostaglandin E synthase (PTGES) requires glutathione (GSH) as an essential cofactor for its enzymatic activity, and together they isomerise prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2) (Jegerschold et al. 2008). After PGH2 has been produced by the prostaglandin G/H synthases (PTGS1 and 2) on the lumenal side of the endoplasmic reticulum, it diffuses through the membrane to the active site of PTGES located on the cytoplasmic side. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGE2 prostaglandin E2 Reactome DB_ID: 265287 prostaglandin E2 [ChEBI:15551] prostaglandin E2 ChEBI CHEBI:15551 Reactome Database ID Release 82 265287 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265287 Reactome R-ALL-265287 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-265287.3 ACTIVATION PTGES trimer Prostaglandin E synthase homotrimer Reactome DB_ID: 2142686 GSH Reduced glutathione glutathione 5-L-Glutamyl-L-cysteinylglycine N-(N-gamma-L-Glutamyl-L-cysteinyl)glycine gamma-L-Glutamyl-L-cysteinyl-glycine Reactome DB_ID: 2239524 glutathione [ChEBI:16856] glutathione ChEBI CHEBI:16856 Reactome Database ID Release 82 2239524 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2239524 Reactome R-ALL-2239524 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2239524.3 COMPOUND C00051 3 PTGES Prostaglandin E synthase PTGES_HUMAN Reactome DB_ID: 2142717 UniProt:O14684 PTGES PTGES MGST1L1 MPGES1 PGES PIG12 FUNCTION Terminal enzyme of the cyclooxygenase (COX)-2-mediated prostaglandin E2 (PGE2) biosynthetic pathway. Catalyzes the glutathione-dependent oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2) in response to inflammatory stimuli (PubMed:18682561, PubMed:10377395, PubMed:12672824, PubMed:12460774, PubMed:10869354, PubMed:12244105). Plays a key role in inflammation response, fever and pain (By similarity). Catalyzes also the oxidoreduction of endocannabinoids into prostaglandin glycerol esters and PGG2 into 15-hydroperoxy-PGE2 (PubMed:12244105, PubMed:12672824). In addition, displays low glutathione transferase and glutathione-dependent peroxidase activities, toward 1-chloro-2,4-dinitrobenzene and 5-hydroperoxyicosatetraenoic acid (5-HPETE), respectively (PubMed:12672824).ACTIVITY REGULATION Induced by interleukin IL1B.PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Homotrimer.INDUCTION Induced by the interleukin IL1B (PubMed:10377395, PubMed:10760517). Induced By p53/TP53 (PubMed:9305847).SIMILARITY Belongs to the MAPEG family. UniProt O14684 1 EQUAL 152 EQUAL Reactome Database ID Release 82 2142717 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142717 Reactome R-HSA-2142717 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142717.1 3 Reactome Database ID Release 82 2142686 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142686 Reactome R-HSA-2142686 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142686.1 GENE ONTOLOGY GO:0050220 Reactome Database ID Release 82 2161577 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161577 Reactome Database ID Release 82 2161660 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161660 Reactome R-HSA-2161660 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161660.3 18682561 Pubmed 2008 Structural basis for induced formation of the inflammatory mediator prostaglandin E2 Jegerschöld, C Pawelzik, SC Purhonen, P Bhakat, P Gheorghe, KR Gyobu, N Mitsuoka, K Morgenstern, R Jakobsson, PJ Hebert, H Proc Natl Acad Sci U S A 105:11110-5 LEFT-TO-RIGHT 5.3.99.3 Prostaglandin E synthase isomerizes PGH2 to PGE2 Prostaglandin E2 (PGE2) is the most abundant prostanoid in the body and is a major mediator of inflammation in diseases such as osteoarthritis and rheumatoid arthritis. The product of arachidonic acid, prostaglandin H2 (PGH2) serves as the substrate for the isomerization to PGE2. The conversion is carried out by prostaglandin E synthases. Of the three forms, two are predominanly cytosolic. Prostaglandin E synthase 3 (PTGES3) is also called cytosolic prostaglandin E2 synthase (cPGES). Prostaglandin E synthase 2 (mPGES-2, PTGES2) is synthesized as a Golgi membrane-associated protein which undergoes a spontaneous cleavage of the N-terminal hydrophobic domain leading to a truncated mature cytosolic protein. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 ACTIVATION Converted from EntitySet in Reactome PTGES2(88-377), PTGES3 Reactome DB_ID: 8864254 PGES2_HUMAN PTGES2(88-377) Prostaglandin E synthase 2 ecNumber4.1.2.-/ecNumber ecNumber5.3.99.3/ecNumber Reactome DB_ID: 5423596 UniProt:Q9H7Z7 PTGES2 PTGES2 C9orf15 PGES2 FUNCTION Isomerase that catalyzes the conversion of PGH2 into the more stable prostaglandin E2 (PGE2) (in vitro) (PubMed:12804604, PubMed:18198127, PubMed:17585783). The biological function and the GSH-dependent property of PTGES2 is still under debate (PubMed:18198127, PubMed:17585783). In vivo, PTGES2 could form a complex with GSH and heme and would not participate in PGE2 synthesis but would catalyze the degradation of prostaglandin E2 H2 (PGH2) to 12(S)-hydroxy-5(Z),8(E),10(E)-heptadecatrienoic acid (HHT) and malondialdehyde (MDA) (PubMed:17585783) (By similarity).ACTIVITY REGULATION Isomerase activity is increased by sulfhydril compounds. Dithiothreitol (DTT) is most effective, followed by dihydrolipoic acid, glutathione (GSH) and 2-mercaptoethanol.PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Homodimer. May interact with CEBPB (By similarity). Interacts with EXOSC10.TISSUE SPECIFICITY Widely expressed. Expressed in the heart, including apex, inter-ventricular septum, both atria and ventricles, but not in the aorta. Also expressed in fetal heart. Detected in various regions of the brain: cerebellum; occipital, frontal and parietal lobes. Also expressed in the lymph nodes, skeletal muscle, kidney and trachea, but not in the thymus or lung. Overexpressed in colorectal cancer.PTM Synthesized as a Golgi membrane-associated protein, and the proteolytic removal of the N-terminal hydrophobic domain leads to the formation of a mature cytosolic enzyme.SIMILARITY Belongs to the GST superfamily.CAUTION It is not known if heme and GST are required for prostaglandin synthase activity. The protein copurifies with heme and GST when DTT is omitted during the purification procedure. The GSH-heme complex-bound enzyme has been proposed to act as a lyase and catalyze the degradation of prostaglandin E2 H2 (PGH2) to 12(S)-hydroxy-5(Z),8(E),10(E)-heptadecatrienoic acid (HHT) and malondialdehyde (MDA). According to PubMed:18198127, boiling the enzyme leads to loss of prostaglandin synthase activity, but does not eliminate the lyase activity. Besides, free heme can catalyze the formation of 12L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) (PubMed:18198127). A more recent study demonstrates the GSH-dependent property of PTGES2, DTT dissociates the bound heme to produce active PGE2 synthase in vitro (By similarity). PTGES2 can only catalyzes PGE2 synthesis in the free state as an enzyme, while in vivo it forms a complex with heme and does not participate in PGE2 synthesis (By similarity). In agreement with this study, the in vivo evidence from PTGES2 deficient mice do not show that this protein is responsible for the PGE2 production under basal or pathophysiological conditions (By similarity). UniProt Q9H7Z7 88 EQUAL 377 EQUAL Reactome Database ID Release 82 5423596 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5423596 Reactome R-HSA-5423596 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5423596.2 cPGES PTGES3 Prostaglandin E synthase 3 Reactome DB_ID: 265269 UniProt:Q15185 PTGES3 PTGES3 P23 TEBP FUNCTION Cytosolic prostaglandin synthase that catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2) (PubMed:10922363). Molecular chaperone that localizes to genomic response elements in a hormone-dependent manner and disrupts receptor-mediated transcriptional activation, by promoting disassembly of transcriptional regulatory complexes (PubMed:11274138, PubMed:12077419). Facilitates HIF alpha proteins hydroxylation via interaction with EGLN1/PHD2, leading to recruit EGLN1/PHD2 to the HSP90 pathway (PubMed:24711448).PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Binds to the progesterone receptor (PubMed:8114727). Interacts with TERT; the interaction, together with HSP90AA1, is required for correct assembly and stabilization of the telomerase holoenzyme complex (PubMed:11274138). Interacts (via PXLE motif) with EGLN1/PHD2, recruiting EGLN1/PHD2 to the HSP90 pathway to facilitate HIF alpha proteins hydroxylation (PubMed:24711448). Interacts with HSP90AA1, FLCN, FNIP1 and FNIP2 (PubMed:27353360).DOMAIN The PXLE motif mediates interaction with EGLN1/PHD2.SIMILARITY Belongs to the p23/wos2 family. UniProt Q15185 1 EQUAL 160 EQUAL Reactome Database ID Release 82 265269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265269 Reactome R-HSA-265269 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265269.1 Reactome Database ID Release 82 8864254 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8864254 Reactome R-HSA-8864254 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8864254.2 Reactome Database ID Release 82 265290 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265290 Reactome Database ID Release 82 265295 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265295 Reactome R-HSA-265295 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265295.2 10922363 Pubmed 2000 Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis Tanioka, T Nakatani, Y Semmyo, N Murakami, M Kudo, I J Biol Chem 275:32775-82 12835322 Pubmed 2003 Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2 Murakami, Makoto Nakashima, Karin Kamei, Daisuke Masuda, Seiko Ishikawa, Yukio Ishii, Toshiharu Ohmiya, Yoshihiro Watanabe, Kikuko Kudo, Ichiro J. Biol. Chem. 278:37937-47 LEFT-TO-RIGHT 1.1.1.189 PGE2 is converted to PGF2a by CBR1 Carbonyl reductase (CBR1) aka prostaglandin 9-keto reductase inactivates prostaglandin E2 (PGE2) by converting it to prostaglandin F2alpha (PGF2a) (Wermuth 1981, Miura et al. 2008). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 ACTIVATION CBR1 Carbonyl reductase (NADPH)1 CBR1_HUMAN Reactome DB_ID: 2142784 UniProt:P16152 CBR1 CBR1 CBR CRN SDR21C1 FUNCTION NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol (PubMed:18449627, PubMed:15799708, PubMed:17912391, PubMed:7005231, PubMed:1921984, PubMed:17344335, PubMed:18826943). Can convert prostaglandin E to prostaglandin F2-alpha (By similarity). Can bind glutathione, which explains its higher affinity for glutathione-conjugated substrates. Catalyzes the reduction of S-nitrosoglutathione (PubMed:18826943, PubMed:17344335). In addition, participates in the glucocorticoid metabolism by catalyzing the NADPH-dependent cortisol/corticosterone into 20beta-dihydrocortisol (20b-DHF) or 20beta-corticosterone (20b-DHB), which are weak agonists of NR3C1 and NR3C2 in adipose tissue (PubMed:28878267).ACTIVITY REGULATION Inhibited by quercetin, rutenin and its derivatives.SUBUNIT Monomer.TISSUE SPECIFICITY Expressed in kidney (at protein level).SIMILARITY Belongs to the short-chain dehydrogenases/reductases (SDR) family. UniProt P16152 2 EQUAL 277 EQUAL Reactome Database ID Release 82 2142784 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142784 Reactome R-HSA-2142784 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142784.1 GENE ONTOLOGY GO:0050221 Reactome Database ID Release 82 2161655 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161655 Reactome Database ID Release 82 2161651 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161651 Reactome R-HSA-2161651 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161651.2 7005231 Pubmed 1981 Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductase Wermuth, B J Biol Chem 256:1206-13 18493841 Pubmed 2008 Different functions between human monomeric carbonyl reductase 3 and carbonyl reductase 1 Miura, T Nishinaka, T Terada, T Mol Cell Biochem 315:113-21 LEFT-TO-RIGHT PGE2 is dehydrated to PGA2 Cyclopentenone prostaglandins comprise a family of molecules that are formed by dehydration of hydroxyl moieties in prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Dehydration of PGE2 leads to prostaglandin A2 (PGA2) (Hamberg & Samuelsson B 1966, Amin 1989). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGA2 prostaglandin A2 Reactome DB_ID: 2299726 prostaglandin A2 [ChEBI:27820] prostaglandin A2 ChEBI CHEBI:27820 Reactome Database ID Release 82 2299726 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2299726 Reactome R-ALL-2299726 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2299726.3 Reactome Database ID Release 82 2161659 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161659 Reactome R-HSA-2161659 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161659.2 5903721 Pubmed 1966 Prostaglandins in human seminal plasma. Prostaglandins and related factors 46 Hamberg, M Samuelsson, B J Biol Chem 241:257-63 2717650 Pubmed 1989 Simultaneous determination of prostaglandins (PG) E2, A2 and B2 and stability studies of PGE2 in pharmaceutical preparations by ion-pair reversed phase HPLC Amin, M Pharm Acta Helv 64:45-50 LEFT-TO-RIGHT PGA2 is isomerised to PGC2 Dehydration in the cyclopentane ring of prostaglandin E2 (PGE2) yields prostaglandin A2 (PGA2) followed by isomerization of the double bond to yield the unstable compound prostaglandin C2 (PGC2) (Straus & Glass, 2001). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGC2 prostaglandin C2 Reactome DB_ID: 2299724 prostaglandin C2 [ChEBI:27555] prostaglandin C2 ChEBI CHEBI:27555 Reactome Database ID Release 82 2299724 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2299724 Reactome R-ALL-2299724 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2299724.3 Reactome Database ID Release 82 2161666 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161666 Reactome R-HSA-2161666 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161666.2 11301410 Pubmed 2001 Cyclopentenone prostaglandins: new insights on biological activities and cellular targets Straus, DS Glass, CK Med Res Rev 21:185-210 LEFT-TO-RIGHT PGC2 is isomerised to PGB2 Isomerization of the double bond in prostaglandin A2 (PGA2) forms prostaglandin C2 (PGC2). This is an unstable compound which undergoes a second isomerization to yield prostaglandin B2 (PGB2) (Straus & Glass, 2001). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGB2 prostaglandin B2 Reactome DB_ID: 2299721 prostaglandin B2 [ChEBI:28099] prostaglandin B2 ChEBI CHEBI:28099 Reactome Database ID Release 82 2299721 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2299721 Reactome R-ALL-2299721 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2299721.3 Reactome Database ID Release 82 2161735 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161735 Reactome R-HSA-2161735 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161735.2 LEFT-TO-RIGHT PGA2 is dehydrated to 15d-PGA2 The non-enzymatic dehydration of prostaglandin A2 (PGA2) into 15-deoxy prostaglandin A2 (15d-PGA2) which occurs in mice (Petrova et al. 1999) is inferred in humans. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 15d-PGA2 15-deoxy-Delta(12,14)-prostaglandin A2 Reactome DB_ID: 2299722 15-deoxy-Delta(12,14)-prostaglandin A2 [ChEBI:63975] 15-deoxy-Delta(12,14)-prostaglandin A2 ChEBI CHEBI:63975 Reactome Database ID Release 82 2299722 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2299722 Reactome R-ALL-2299722 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2299722.3 Reactome Database ID Release 82 2161668 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161668 Reactome R-HSA-2161668 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161668.2 10200320 Pubmed 1999 Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta12,14-prostaglandin J2 Petrova, TV Akama, KT Van Eldik, LJ Proc Natl Acad Sci U S A 96:4668-73 LEFT-TO-RIGHT 5.3.99.2 PGH2 is isomerised to PGD2 by PTGDS Prostaglandin D2 (PGD2) is a structural isomer of prostaglandin E2 (PGE2). There is a 9-keto and 11-hydroxy group on PGE2 with these substituents reversed on PGD2. PGD2 is formed by two evolutionarily distinct, but functionally convergent, prostaglandin D synthases: lipocalin-type prostaglandin-D synthase aka Prostaglandin-H2 D-isomerase (PTDGS) and hematopoietic prostaglandin D synthase (HPGDS). One of the main differences between these two proteins is that HPGDS requires glutathione (GSH) for catalysis while PTDGS can function without this cofactor. Here, PTDGS promotes the isomerisation of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2) (Zhou et al. 2010). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGD2 prostaglandin D2 Reactome DB_ID: 2161634 prostaglandin D2 [ChEBI:15555] prostaglandin D2 ChEBI CHEBI:15555 Reactome Database ID Release 82 2161634 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161634 Reactome R-ALL-2161634 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2161634.3 COMPOUND C00696 ACTIVATION PTGDS Prostaglandin-H2 D-isomerase PTGDS_HUMAN Reactome DB_ID: 2142814 UniProt:P41222 PTGDS PTGDS PDS FUNCTION Catalyzes the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation (PubMed:20667974). Involved in a variety of CNS functions, such as sedation, NREM sleep and PGE2-induced allodynia, and may have an anti-apoptotic role in oligodendrocytes. Binds small non-substrate lipophilic molecules, including biliverdin, bilirubin, retinal, retinoic acid and thyroid hormone, and may act as a scavenger for harmful hydrophobic molecules and as a secretory retinoid and thyroid hormone transporter. Possibly involved in development and maintenance of the blood-brain, blood-retina, blood-aqueous humor and blood-testis barrier. It is likely to play important roles in both maturation and maintenance of the central nervous system and male reproductive system (PubMed:20667974, PubMed:9475419). Involved in PLA2G3-dependent maturation of mast cells. PLA2G3 is secreted by immature mast cells and acts on nearby fibroblasts upstream to PTDGS to synthesize PGD2, which in turn promotes mast cell maturation and degranulation via PTGDR (By similarity).SUBUNIT Monomer.TISSUE SPECIFICITY Abundant in the brain and CNS, where it is expressed in tissues of the blood-brain barrier and secreted into the cerebro-spinal fluid. Abundantly expressed in the heart. In the male reproductive system, it is expressed in the testis, epididymis and prostate, and is secreted into the seminal fluid. Expressed in the eye and secreted into the aqueous humor. Lower levels detected in various tissue fluids such as serum, normal urine, ascitic fluid and tear fluid. Also found in a number of other organs including ovary, fimbriae of the fallopian tubes, kidney, leukocytes.DEVELOPMENTAL STAGE Expression in the amniotic fluid increases dramatically during weeks 12 to 25 of pregnancy. Levels decrease slowly after 25 weeks.INDUCTION By IL1B/interleukin-1 beta and thyroid hormone. Probably induced by dexamethasone, dihydrotestosterone (DHT), progesterone, retinoic acid and retinal. Repressed by the Notch-Hes signaling pathway.DOMAIN Forms a beta-barrel structure that accommodates hydrophobic ligands in its interior.PTM N- and O-glycosylated. Both N-glycosylation recognition sites are almost quantitatively occupied by N-glycans of the biantennary complex type, with a considerable proportion of structures bearing a bisecting GlcNAc. N-glycan at Asn-78: dHex1Hex5HexNAc4. Agalacto structure as well as sialylated and nonsialylated oligosaccharides bearing alpha2-3- and/or alpha2-6-linked NeuNAc are present.MISCELLANEOUS It has been proposed that the urinary and serum levels may provide a sensitive indicator of renal damage in diabetes mellitus and hypertension. Elevated levels in the coronary circulation may also be associated with angina. Changes in charge and molecular weight microheterogeneity, due to modification of the N-linked oligosaccharides, may be associated with neurodegenerative disease and multiple sclerosis. Detected in meningioma but not in other brain tumors and may be considered a specific cell marker for meningioma. Expression levels in amniotic fluid are altered in abnormal pregnancies. Levels are lower in pregnancies with trisomic fetuses and fetuses with renal abnormalities.SIMILARITY Belongs to the calycin superfamily. Lipocalin family. UniProt P41222 23 EQUAL 190 EQUAL Reactome Database ID Release 82 2142814 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142814 Reactome R-HSA-2142814 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142814.1 GENE ONTOLOGY GO:0004667 Reactome Database ID Release 82 2161647 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161647 Reactome Database ID Release 82 2161620 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161620 Reactome R-HSA-2161620 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161620.2 20667974 Pubmed 2010 Structure-function analysis of human l-prostaglandin D synthase bound with fatty acid molecules Zhou, Y Shaw, N Li, Y Zhao, Y Zhang, R Liu, ZJ FASEB J 24:4668-77 LEFT-TO-RIGHT 5.3.99.2 PGH2 is isomerised to PGD2 by HPGDS Prostaglandin D2 (PGD2) is a structural isomer of prostaglandin E2 (PGE2). There is a 9-keto and 11-hydroxy group on PGE2 with these substituents reversed on PGD2. PGD2 is formed by two evolutionarily distinct, but functionally convergent, prostaglandin D synthases: lipocalin-type prostaglandin-D synthase aka Prostaglandin-H2 D-isomerase (PTDGS) and hematopoietic prostaglandin D synthase (HPGDS). One of the main differences between these two proteins is that HPGDS requires glutathione (GSH) for catalysis while PTDGS can function without this cofactor. Here, HPGDS with GSH promotes the isomerisation of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2) (Jowsey et al. 2001, Inoue et al. 2003). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGD2 prostaglandin D2 Reactome DB_ID: 879629 Reactome Database ID Release 82 879629 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879629 Reactome R-ALL-879629 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-879629.3 COMPOUND C00696 ACTIVATION HPGDS dimer Reactome DB_ID: 2142683 HPGDS Hematopoietic prostaglandin D synthase HPGDS_HUMAN Reactome DB_ID: 2142706 UniProt:O60760 HPGDS HPGDS GSTS PGDS PTGDS2 FUNCTION Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide.ACTIVITY REGULATION Prostaglandin PGD2 synthesis is stimulated by calcium and magnesium ions. One calcium or magnesium ion is bound between the subunits of the homodimer. The interactions with the protein are for the most part mediated via water molecules. Magnesium increases the affinity for glutathione, while calcium has no effect on the affinity for glutathione.SUBUNIT Homodimer.TISSUE SPECIFICITY Expressed in a number of megakaryocytic cell lines but not in platelets. Highly expressed in adipose tissue, macrophages and placenta. Also expressed at lower levels in lung, heart, lymph nodes, appendix, bone marrow and fetal liver.DEVELOPMENTAL STAGE Highest levels in immature megakaryocytic cells. Disappears after final differentiation to platelets.INDUCTION By 12-O-tetradecanoylphorbol-13-acetate (TPA).SIMILARITY Belongs to the GST superfamily. Sigma family. UniProt O60760 2 EQUAL 199 EQUAL Reactome Database ID Release 82 2142706 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142706 Reactome R-HSA-2142706 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142706.1 2 GSH Reduced glutathione glutathione 5-L-Glutamyl-L-cysteinylglycine N-(N-gamma-L-Glutamyl-L-cysteinyl)glycine gamma-L-Glutamyl-L-cysteinyl-glycine glutathionate(1-) Reactome DB_ID: 29450 glutathionate(1-) [ChEBI:57925] glutathionate(1-) glutathionate ion glutathionate anion glutathionate glutathione ChEBI CHEBI:57925 Reactome Database ID Release 82 29450 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29450 Reactome R-ALL-29450 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29450.4 COMPOUND C00051 2 Reactome Database ID Release 82 2142683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142683 Reactome R-HSA-2142683 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142683.1 Reactome Database ID Release 82 2161729 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161729 Reactome Database ID Release 82 2161701 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161701 Reactome R-HSA-2161701 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161701.3 12627223 Pubmed 2003 Mechanism of metal activation of human hematopoietic prostaglandin D synthase Inoue, T Irikura, Daisuke Okazaki, N Kinugasa, S Matsumura, H Uodome, N Yamamoto, M Kumasaka, T Miyano, M Kai, Y Urade, Y Nat Struct Biol 10:291-6 11672424 Pubmed 2001 Mammalian class Sigma glutathione S-transferases: catalytic properties and tissue-specific expression of human and rat GSH-dependent prostaglandin D2 synthases Jowsey, IR Thomson, AM Flanagan, JU Murdock, PR Moore, GB Meyer, DJ Murphy, GJ Smith, SA Hayes, JD Biochem J 359:507-16 LEFT-TO-RIGHT PGD2 is dehydrated to PGJ2 Analogous to prostaglandin E2 (PGE2), dehydration of the prostaglandin D2 (PGD2) prostane ring forms prostaglandin J2 (PGJ2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGJ2 prostaglandin J2 Reactome DB_ID: 2142674 prostaglandin J2 [ChEBI:27485] prostaglandin J2 ChEBI CHEBI:27485 Reactome Database ID Release 82 2142674 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142674 Reactome R-ALL-2142674 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142674.3 Reactome Database ID Release 82 2161733 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161733 Reactome R-HSA-2161733 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161733.2 11907120 Pubmed 2002 15-Deoxy-delta 12,14-prostaglandins D2 and J2 are potent activators of human eosinophils Monneret, G Li, H Vasilescu, J Rokach, J Powell, WS J Immunol 168:3563-9 LEFT-TO-RIGHT PGJ2 is isomerised to delta12-PGJ2 Delta-12-prostaglandin J2 (delta12-PGJ2) is an isomerisation product of prostaglandin J2 (PGJ2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 delta12-PGJ2 13,14-dihydro-Delta(12)-prostaglandin J2 Reactome DB_ID: 2142821 13,14-dihydro-Delta(12)-prostaglandin J2 [ChEBI:28130] 13,14-dihydro-Delta(12)-prostaglandin J2 ChEBI CHEBI:28130 Reactome Database ID Release 82 2142821 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142821 Reactome R-ALL-2142821 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142821.3 Reactome Database ID Release 82 2161563 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161563 Reactome R-HSA-2161563 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161563.2 LEFT-TO-RIGHT Delta12-PGJ2 is dehydrated to 15d-PGJ2 15-Deoxy-delta(12,14)-PDJ2 (15d-PGJ2) is a dehydration product of delta-12-prostaglandin J2 (delta12-PGJ2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 15d-PGJ2 15-deoxy-Delta(12,14)-prostaglandin J2 Reactome DB_ID: 2142702 15-deoxy-Delta(12,14)-prostaglandin J2 [ChEBI:34159] 15-deoxy-Delta(12,14)-prostaglandin J2 15-Deoxy-PGJ2 15-Deoxy-delta-12,14-prostaglandin J2 15-Deoxy-delta-12,14-PGJ2 ChEBI CHEBI:34159 Reactome Database ID Release 82 2142702 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142702 Reactome R-ALL-2142702 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142702.3 Reactome Database ID Release 82 2161588 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161588 Reactome R-HSA-2161588 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161588.2 LEFT-TO-RIGHT PGD2 is dehydrated to 15d-PGD2 15-Deoxy-delta 12,14-prostaglandins D2 (15d-PGD2) is a dehydrated form of prostaglandin D2 (PGD2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 15d-PGD2 15-deoxy-Delta(12,14)-prostaglandin D2 Reactome DB_ID: 2142817 15-deoxy-Delta(12,14)-prostaglandin D2 [ChEBI:63999] 15-deoxy-Delta(12,14)-prostaglandin D2 ChEBI CHEBI:63999 Reactome Database ID Release 82 2142817 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142817 Reactome R-ALL-2142817 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142817.3 Reactome Database ID Release 82 2161673 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161673 Reactome R-HSA-2161673 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161673.2 LEFT-TO-RIGHT 1.1.1.188 PGD2 is reduced to 11-epi-PGF2a by AKRIC3 Aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS is the enzyme involved in NADPH-dependent prostaglandin D2 11-keto reductase activity of reducing prostaglandin D2 (PGD2) to 11-epi-Prostaglandin F2alpha (11-epi-PGF2a) (Liston & Roberts 1985, Koda et al. 2004). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 11epi-PGF2a 11-epi-prostaglandin F2alpha Reactome DB_ID: 2142710 11-epi-prostaglandin F2alpha [ChEBI:27595] 11-epi-prostaglandin F2alpha ChEBI CHEBI:27595 Reactome Database ID Release 82 2142710 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142710 Reactome R-ALL-2142710 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142710.3 ACTIVATION GENE ONTOLOGY GO:0036131 Reactome Database ID Release 82 2161608 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161608 Reactome Database ID Release 82 2161614 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161614 Reactome R-HSA-2161614 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161614.2 15047184 Pubmed 2004 Synthesis of prostaglandin F ethanolamide by prostaglandin F synthase and identification of Bimatoprost as a potent inhibitor of the enzyme: new enzyme assay method using LC/ESI/MS Koda, N Tsutsui, Y Niwa, H Ito, S Woodward, DF Watanabe, K Arch Biochem Biophys 424:128-36 3862115 Pubmed 1985 Transformation of prostaglandin D2 to 9 alpha, 11 beta-(15S)-trihydroxyprosta-(5Z,13E)-dien-1-oic acid (9 alpha, 11 beta-prostaglandin F2): a unique biologically active prostaglandin produced enzymatically in vivo in humans Liston, TE Roberts LJ, 2nd Proc Natl Acad Sci U S A 82:6030-4 LEFT-TO-RIGHT 1.1.1.141 PGD2/E2/F2a is oxidised to 15k-PGD2/E2/F2a by HPGD 15-Hydroxyprostaglandin dehydrogenase (HPGD) oxidises prostaglandins D2 (PGD2), E2 (PGE2), and F2alpha (PGF2a) to 15-keto-prostaglandin D2 (15k-PGD2), E2 (15k-PGE2), and F2alpha (15k-PGF2a) respectively (Cho et al. 2006). This reaction is inferred from rabbits (Bergholte & Okita 1986). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 NAD NAD+ NAD(+) Nicotinamide adenine dinucleotide DPN Diphosphopyridine nucleotide Reactome DB_ID: 29360 NAD(1-) [ChEBI:57540] NAD(1-) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD(+) NAD anion ChEBI CHEBI:57540 Reactome Database ID Release 82 29360 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29360 Reactome R-ALL-29360 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29360.5 COMPOUND C00003 Converted from EntitySet in Reactome PGD2/E2/F2a Reactome DB_ID: 2161661 Reactome Database ID Release 82 2161661 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161661 Reactome R-ALL-2161661 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2161661.1 NADH Reactome DB_ID: 73473 NADH(2-) [ChEBI:57945] NADH(2-) NADH dianion adenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADH ChEBI CHEBI:57945 Reactome Database ID Release 82 73473 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73473 Reactome R-ALL-73473 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-73473.4 COMPOUND C00004 Converted from EntitySet in Reactome 15k-PGD2,15k-PGE2,15k-PGF2a Reactome DB_ID: 2161597 15k-PGD2 15-dehydro-prostaglandin D2 Reactome DB_ID: 2142752 15-dehydro-prostaglandin D2 [ChEBI:15557] 15-dehydro-prostaglandin D2 ChEBI CHEBI:15557 Reactome Database ID Release 82 2142752 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142752 Reactome R-ALL-2142752 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142752.3 15k-PGE2 15-dehydro-prostaglandin E2 Reactome DB_ID: 2142721 15-dehydro-prostaglandin E2 [ChEBI:15547] 15-dehydro-prostaglandin E2 ChEBI CHEBI:15547 Reactome Database ID Release 82 2142721 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142721 Reactome R-ALL-2142721 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142721.3