BioPAX pathway converted from "Fatty acid metabolism" in the Reactome database. Fatty acid metabolism 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 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 Transport of Citrate from Mitochondrial Matrix to cytosol 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). Reactome DB_ID: 198498 1 cytosol GO 0005829 (S)-malate(2-) [ChEBI:15589] (S)-malate(2-) (S)-malate Reactome http://www.reactome.org ChEBI 15589 Reactome DB_ID: 29654 1 mitochondrial matrix GO 0005759 citric acid [ChEBI:30769] citric acid ChEBI 30769 Reactome DB_ID: 113544 1 Reactome DB_ID: 76190 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 372445 mitochondrial inner membrane GO 0005743 UniProt:P53007 SLC25A1 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 Chain Coordinates 14 EQUAL 311 EQUAL GO 0015142 GO molecular function 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 2.3.3.8 ACLY tetramer transforms CIT to Ac-CoA 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 Reactome DB_ID: 76194 1 coenzyme A(4-) [ChEBI:57287] coenzyme A(4-) CoA 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-({3-oxo-3-[(2-sulfanylethyl)amino]propyl}amino)butyl] diphosphate} ChEBI 57287 Reactome DB_ID: 76190 1 Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 76213 1 oxaloacetate(2-) [ChEBI:16452] oxaloacetate(2-) oxaloacetate dianion oxobutanedioic acid, ion(2-) oxaloacetate oxosuccinate oxobutanedioate ChEBI 16452 Reactome DB_ID: 29372 1 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 Reactome DB_ID: 76183 1 acetyl-CoA(4-) [ChEBI:57288] acetyl-CoA(4-) 3'-phosphonatoadenosine 5'-(3-{(3R)-4-[(3-{[2-(acetylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-3-hydroxy-2,2-dimethyl-4-oxobutyl} diphosphate) acetyl-CoA acetyl-CoA tetraanion acetyl-coenzyme A(4-) AcCoA(4-) ChEBI 57288 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 76188 ACLY tetramer [cytosol] ACLY tetramer Citrate lyase homotetramer Reactome DB_ID: 76187 4 UniProt:P53396 ACLY 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 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 GO 0003878 GO molecular function 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 Reactome DB_ID: 8933313 UniProt:Q9Y6X9 MORC2 MORC2 KIAA0852 MORC2 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 6.2.1.3 SLC27A2 ligates CoA to bempedoic acid to form ETC-1002-CoA 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 Reactome DB_ID: 9734538 1 bempedoic acid [Guide to Pharmacology:8321] bempedoic acid Nexletol&reg; Nilemdo&reg; ETC-1002 ESP-55016 Guide to Pharmacology 8321 Reactome DB_ID: 76194 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 111294 1 diphosphate(3-) [ChEBI:33019] diphosphate(3-) ChEBI 33019 Reactome DB_ID: 9734541 1 Reactome DB_ID: 76577 1 adenosine 5'-monophosphate(2-) [ChEBI:456215] adenosine 5'-monophosphate(2-) Adenosine-5-monophosphate(2-) AMP 5'-O-phosphonatoadenosine AMP dianion AMP(2-) Adenosine-5-monophosphate dianion ChEBI 456215 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 193386 endoplasmic reticulum membrane GO 0005789 UniProt:O14975 SLC27A2 SLC27A2 FATP2 VLACS FACVL1 ACSVL1 SLC27A2 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 GO 0004467 GO molecular function 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 6.4.1.2 acetyl-CoA + bicarbonate + ATP => malonyl-CoA + H2O + ADP + orthophosphate acetyl-CoA + bicarbonate + ATP => malonyl-CoA + H2O + ADP + orthophosphate Formation of Malonyl-CoA from Acetyl-CoA (liver) 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 Reactome DB_ID: 76183 1 Reactome DB_ID: 111627 1 hydrogencarbonate [ChEBI:17544] hydrogencarbonate ChEBI 17544 Reactome DB_ID: 113592 1 Reactome DB_ID: 29508 1 malonyl-CoA(5-) [ChEBI:57384] malonyl-CoA(5-) 3'-phosphonatoadenosine 5'-{3-[(3R)-4-{[3-({2-[(3-carboxylatoacetyl)sulfanyl]ethyl}amino)-3-oxopropyl]amino}-3-hydroxy-2,2-dimethyl-4-oxobutyl] diphosphate} malonyl-CoA ChEBI 57384 Reactome DB_ID: 29372 1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2976730 UniProt:Q13085 ACACA ACACA ACAC ACACA 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 N6-biotinyl-L-lysine at 786 786 EQUAL N6-biotinyl-L-lysine [MOD:00126] 1 EQUAL 2346 EQUAL GO 0003989 GO molecular function 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 Reactome DB_ID: 76190 Formation of fatty acid synthase (FAS) dimer Formation of fatty acid synthase (FAS) dimer Association of cytosolic FAS into multimers is linked to increased catalytic activity (Locke et al. 2008). Reactome DB_ID: 54659 2 UniProt:P49327 FASN 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 O-phosphopantetheine-L-serine at 2156 2156 EQUAL O-phosphopantetheine-L-serine [MOD:00159] 1 EQUAL 2511 EQUAL Reactome DB_ID: 77380 1 FASN dimer [cytosol] FASN dimer FAS dimer Reactome DB_ID: 54659 2 O-phosphopantetheine-L-serine at 2156 2156 EQUAL 1 EQUAL 2511 EQUAL 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 2.3.1.85 acetyl-CoA + 7 malonyl-CoA + 14 NADHP + 14 H+ => palmitate + 7 CO2 + 14 NADP+ + 8 CoASH + 6 H2O acetyl-CoA + 7 malonyl-CoA + 14 NADHP + 14 H+ => palmitate + 7 CO2 + 14 NADP+ + 8 CoASH + 6 H2O Conversion of malonyl-CoA and acetyl-CoA to palmitate 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 Reactome DB_ID: 29508 7 Reactome DB_ID: 29364 14 NADPH(4-) [ChEBI:57783] NADPH(4-) NADPH 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH tetraanion ChEBI 57783 Reactome DB_ID: 76183 1 Reactome DB_ID: 70106 14 hydron [ChEBI:15378] hydron ChEBI 15378 Reactome DB_ID: 113528 7 carbon dioxide [ChEBI:16526] carbon dioxide ChEBI 16526 Reactome DB_ID: 3632881 1 hexadecanoic acid [ChEBI:15756] hexadecanoic acid ChEBI 15756 Reactome DB_ID: 29356 6 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 29366 14 NADP(3-) [ChEBI:58349] NADP(3-) NADP(+) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADP trianion ChEBI 58349 Reactome DB_ID: 76194 8 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 77380 GO 0004312 GO molecular function 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 3.1.2.14 OLAH hydrolyzes decanoyl-FASN dimer to DECA and FASN dimer OLAH hydrolyzes decanoyl-FASN dimer to DECA and FASN dimer decanoyl-FASN dimer + 2 H2O => 2 decanoate + 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 Reactome DB_ID: 29356 2 Reactome DB_ID: 5655943 1 decanoyl-FASN dimer [cytosol] decanoyl-FASN dimer Reactome DB_ID: 5655935 2 O-phosphopantetheine-L-serine (decanoyl group) at 2156 2156 EQUAL ChEBI 23574 modification 1 EQUAL 2511 EQUAL 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 Reactome DB_ID: 879620 2 decanoic acid [ChEBI:30813] decanoic acid ChEBI 30813 Reactome DB_ID: 77380 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5655938 UniProt:Q9NV23 OLAH 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 GO 0016297 GO molecular function 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 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 ACSBG1,2 ligates CoA-SH to VLCFA, forming VLCFA-CoA 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 Reactome DB_ID: 76194 1 Reactome DB_ID: 5695985 1 very long-chain fatty acid [ChEBI:27283] very long-chain fatty acid higher fatty acid VLCFAs VLCFA very long-chain fatty acids ChEBI 27283 Reactome DB_ID: 113592 1 Reactome DB_ID: 111294 1 Reactome DB_ID: 5695971 1 very long-chain fatty acyl-CoA [ChEBI:61910] very long-chain fatty acyl-CoA very long-chain fatty acyl-coenzyme A very long-chain fatty acyl-coenzyme As VLCFA-CoA VLCFA-CoAs VLCFA-coenzyme A very long-chain acyl-CoA VLCFA-coenzyme As very long-chain acyl-coenzyme A VLCA-coenzyme A ChEBI 61910 Reactome DB_ID: 76577 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5695958 ACSBG1,2 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ACSBG1 [cytosol] ACSBG2 [cytosol] UniProt Q96GR2 UniProt Q5FVE4 GO 0031957 GO molecular function 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 ACSF3 ligates CoA-SH to VLCFA 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 Reactome DB_ID: 113593 1 Reactome DB_ID: 5696008 1 Reactome DB_ID: 29374 1 Reactome DB_ID: 159448 1 Reactome DB_ID: 5696003 1 Reactome DB_ID: 159450 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5696011 UniProt:Q4G176 ACSF3 ACSF3 PSEC0197 ACSF3 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 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 SLC27A3 ligates CoA-SH to VLCFA 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 Reactome DB_ID: 113593 1 Reactome DB_ID: 5696008 1 Reactome DB_ID: 29374 1 Reactome DB_ID: 159448 1 Reactome DB_ID: 5696003 1 Reactome DB_ID: 159450 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5216184 UniProt:Q5K4L6 SLC27A3 SLC27A3 UNQ367/PRO703 FATP3 PSEC0067 SLC27A3 ACSVL3 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 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 6.2.1.3 ACSL1,3,5,6 ligate CoA to PALM to form PALM-CoA ACSL1,3,5,6 ligate CoA to PALM to form PALM-CoA palmitate + CoASH + ATP => palmitoyl-CoA + AMP + pyrophosphate + H2O Conversion of palmitic acid to palmitoyl-CoA 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 Reactome DB_ID: 3632881 1 Reactome DB_ID: 76194 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 111294 1 Reactome DB_ID: 200993 1 palmitoyl-CoA(4-) [ChEBI:57379] palmitoyl-CoA(4-) hexadecanoyl-CoA 3'-phosphonatoadenosine 5'-(3-{(3R)-4-[(3-{[2-(hexadecanoylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-3-hydroxy-2,2-dimethyl-4-oxobutyl} diphosphate) ChEBI 57379 Reactome DB_ID: 76577 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 3878115 ACSL1,3,5,6 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ACSL5 [endoplasmic reticulum membrane] ACSL1 [endoplasmic reticulum membrane] ACSL6 [endoplasmic reticulum membrane] ACSL3 [endoplasmic reticulum membrane] UniProt Q9ULC5 UniProt P33121 UniProt Q9UKU0 UniProt O95573 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 6.2.1.3 ACSL3,4 ligate CoA to AA to form AA-CoA 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 Reactome DB_ID: 29768 1 arachidonate [ChEBI:32395] arachidonate (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (20:4n6) (5Z,8Z,11Z,14Z)-eicosatetraenoate ChEBI 32395 Reactome DB_ID: 76194 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 111294 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 548819 1 arachidonoyl-CoA(4-) [ChEBI:57368] arachidonoyl-CoA(4-) cis-Delta(5,8,11,14)-eicosatetraenoyl-CoA(4-) arachidonoyl-coenzyme A(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} C20:4-CoA(4-) (5Z,8Z,11Z,14Z)-eicosatetraenoyl-CoA (5Z,8Z,11Z,14Z)-5,8,11,14-eicosatetraenoyl-CoA(4-) cis-Delta(5,8,11,14)-eicosatetraenoyl-coenzyme A(4-) arachidonyl-coenzyme A(4-) S-[(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoyl]-coenzyme A(4-) ChEBI 57368 Reactome DB_ID: 76577 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2901793 ACSL3,4 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ACSL4 [endoplasmic reticulum membrane] UniProt O60488 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 ELOVL3,6,7 elongate PALM-CoA and Mal-CoA to 3OOD-CoA 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 Reactome DB_ID: 29508 1 Reactome DB_ID: 200993 1 Reactome DB_ID: 113528 1 Reactome DB_ID: 548812 1 3-oxooctadecanoyl-CoA(4-) [ChEBI:71407] 3-oxooctadecanoyl-CoA(4-) 3-ketooctadecanoyl-coenzyme A(4-) 3-oxostearoyl-CoA(4-) 3-oxooctadecanoyl-CoA 3-ketooctadecanoyl-CoA(4-) 3-oxostearoyl-coenzyme A(4-) 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-ketostearoyl-CoA(4-) 3-oxooctadecanoyl-coenzyme A(4-) 3-ketostearoyl-coenzyme A(4-) ChEBI 71407 Reactome DB_ID: 76194 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5676213 ELOVL3,6,7 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ELOVL6 [endoplasmic reticulum membrane] ELOVL3 [endoplasmic reticulum membrane] ELOVL7 [endoplasmic reticulum membrane] UniProt Q9H5J4 UniProt Q9HB03 UniProt A1L3X0 GO 0009922 GO molecular function 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 ELOVL1,4 elongate TCS-CoA and Mal-CoA to 3OHC-CoA 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 Reactome DB_ID: 29508 1 Reactome DB_ID: 548808 1 tetracosanoyl-CoA(4-) [ChEBI:65052] tetracosanoyl-CoA(4-) 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 tetracosanoyl-coenzyme A(4-) tetracosanoyl-CoA (4-) lignoceroyl-CoA(4-) C24:0-CoA(4-) C24:0-coenzyme A(4-) ChEBI 65052 Reactome DB_ID: 113528 1 Reactome DB_ID: 76194 1 Reactome DB_ID: 548797 1 3-oxohexacosanoyl-CoA(4-) [ChEBI:73980] 3-oxohexacosanoyl-CoA(4-) 3-oxohexacosanoyl-coenzyme A(4-) 3-ketohexacosanoyl-CoA(4-) 3-ketohexacosanoyl-coenzyme A(4-) 3-ketocerotoyl-CoA(4-) 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-oxohexacosanoyl-CoA 3-oxocerotoyl-CoA(4-) ChEBI 73980 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5676211 ELOVL1,4 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ELOVL4 [endoplasmic reticulum membrane] ELOVL1 [endoplasmic reticulum membrane] UniProt Q9GZR5 UniProt Q9BW60 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 ELOVL1,2,3,5 elongate AA-CoA and Mal-CoA to 3ODCT-CoA 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 Reactome DB_ID: 29508 1 Reactome DB_ID: 548819 1 Reactome DB_ID: 113528 1 Reactome DB_ID: 76194 1 Reactome DB_ID: 548816 1 (7Z,10Z,13Z,16Z)-3-oxodocosatetraenoyl-CoA [ChEBI:63821] (7Z,10Z,13Z,16Z)-3-oxodocosatetraenoyl-CoA all-cis-7,10,13,16-3-oxodocosatetraenoyl-CoA 3-oxo-(7Z,10Z,13Z,16Z)-docosatetraenoyl-CoA ChEBI 63821 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5676214 ELOVL1,2,3,5 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ELOVL5 [endoplasmic reticulum membrane] ELOVL1 [endoplasmic reticulum membrane] ELOVL3 [endoplasmic reticulum membrane] ELOVL2 [endoplasmic reticulum membrane] UniProt Q9NYP7 UniProt Q9NXB9 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 ELOVL7 elongates ICS-CoA and Mal-CoA to 3ODC-CoA 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 Reactome DB_ID: 29508 1 Reactome DB_ID: 548794 1 icosanoyl-CoA(4-) [ChEBI:57380] icosanoyl-CoA(4-) 3'-phosphonatoadenosine 5'-(3-{(3R)-3-hydroxy-4-[(3-{[2-(icosanoylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-2,2-dimethyl-4-oxobutyl} diphosphate) eicosanoyl-CoA eicosanoyl-CoA(4-) ChEBI 57380 Reactome DB_ID: 113528 1 Reactome DB_ID: 548829 1 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-ketodocosanoyl-coenzyme A(4-) 3-oxodocosanoyl-CoA ChEBI 71451 Reactome DB_ID: 76194 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 548661 UniProt:A1L3X0 ELOVL7 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. 1 EQUAL 281 EQUAL 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 1.1.1.211 HSD17B3,12 hydrogenates 3OOD-CoA to 3HODC-CoA 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 Reactome DB_ID: 29364 1 Reactome DB_ID: 548812 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 29366 1 Reactome DB_ID: 548836 1 3-hydroxyoctadecanoyl-CoA [ChEBI:50583] 3-hydroxyoctadecanoyl-CoA ChEBI 50583 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 3907274 HSD17B3,12 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity HSD17B12 [endoplasmic reticulum membrane] UniProt Q53GQ0 GO 0016509 GO molecular function 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 PTPLs dehydrate VLC3HA-CoA to VLCTDA-CoA 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 Reactome DB_ID: 5676631 1 (R)-3-hydroxyacyl-CoA [ChEBI:15456] (R)-3-hydroxyacyl-CoA (3R)-3-Hydroxyacyl-CoA ChEBI 15456 Reactome DB_ID: 29356 1 Reactome DB_ID: 5676634 1 trans-2-enoyl-CoA [ChEBI:50998] trans-2-enoyl-CoA ChEBI 50998 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5676630 PTPLs [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PTPLA [endoplasmic reticulum membrane] PTPLB [endoplasmic reticulum membrane] UniProt B0YJ81 UniProt Q6Y1H2 GO 0080023 GO molecular function 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 1.3.99 TECR,TECRL dehydrogenate TOD-CoA to ST-CoA 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 Reactome DB_ID: 29364 1 Reactome DB_ID: 548809 1 trans-2-octadecenoyl-CoA [ChEBI:50570] trans-2-octadecenoyl-CoA ChEBI 50570 Reactome DB_ID: 70106 1 Reactome DB_ID: 428139 1 stearoyl-CoA(4-) [ChEBI:57394] stearoyl-CoA(4-) stearoyl-coenzyme A tetraanion stearoyl-CoA tetraanion octadecanoyl-CoA stearoyl-coenzyme A(4-) 3'-phosphonatoadenosine 5'-(3-{(3R)-3-hydroxy-2,2-dimethyl-4-[(3-{[2-(octadecanoylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-4-oxobutyl} diphosphate) ChEBI 57394 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 4127425 TECR,TECRL [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TECR [endoplasmic reticulum membrane] UniProt Q9NZ01 GO 0017099 GO molecular function 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 GO 0035338 GO biological process 1.14.19.1 SCD desaturates ST-CoA to OLE-CoA 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 Reactome DB_ID: 428139 1 Reactome DB_ID: 29368 1 dioxygen [ChEBI:15379] dioxygen ChEBI 15379 Reactome DB_ID: 70106 2 Reactome DB_ID: 4085415 2 ferrocytochrome b5 [ChEBI:16518] ferrocytochrome b5 ChEBI 16518 Reactome DB_ID: 29356 2 Reactome DB_ID: 4085425 2 ferricytochrome b5 [ChEBI:18097] ferricytochrome b5 ChEBI 18097 Reactome DB_ID: 5690558 1 oleoyl-CoA [ChEBI:15534] oleoyl-CoA ChEBI 15534 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 8854942 SCD dimer [endoplasmic reticulum membrane] SCD dimer Reactome DB_ID: 400117 2 UniProt:O00767 SCD SCD FADS5 SCD SCDOS SCD1 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 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 GO 0004768 GO molecular function 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 1.14.19.1 SCD5 desaturates ST-CoA to OLE-CoA 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 Reactome DB_ID: 428139 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 70106 2 Reactome DB_ID: 4085415 2 Reactome DB_ID: 29356 2 Reactome DB_ID: 4085425 2 Reactome DB_ID: 5690558 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 8847584 SCD5 dimer [endoplasmic reticulum membrane] SCD5 dimer Reactome DB_ID: 8847580 2 UniProt:Q86SK9 SCD5 SCD5 SCD4 SCD5 SCD2 ACOD4 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 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 3.1.2.22 PPT1 hydrolyses palmitoylated proteins 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 Reactome DB_ID: 1605715 1 lysosomal lumen GO 0043202 Reactome DB_ID: 5690533 1 PALM:protein [lysosomal lumen] PALM:protein Reactome DB_ID: 6785219 1 protein [ChEBI:36080] protein [protein] ChEBI 36080 Reactome DB_ID: 5690516 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 Reactome DB_ID: 6785219 1 Reactome DB_ID: 5690516 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5690068 UniProt:P50897 PPT1 PPT1 CLN1 PPT PPT1 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 GO 0008474 GO molecular function 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 PPT2 hydrolyses PALMCoA to PALM 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 Reactome DB_ID: 1605715 1 Reactome DB_ID: 5690537 1 Reactome DB_ID: 5690516 1 Reactome DB_ID: 1678675 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5690039 UniProt:Q9UMR5 PPT2 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 GO 0098599 GO molecular function 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 1.1.1.100 2xHSD17B8:2xCBR4 reduces 3OA-ACP to 3HA-ACP 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 Reactome DB_ID: 113529 1 Reactome DB_ID: 8862377 1 3-oxoacyl-[acyl-carrier-protein] [ChEBI:84646] 3-oxoacyl-[acyl-carrier-protein] ChEBI 84646 Reactome DB_ID: 113600 1 NADPH [ChEBI:16474] NADPH TPNH ChEBI 16474 Reactome DB_ID: 8862371 1 (3R)-3-hydroxyacyl-[acyl-carrier-protein] [ChEBI:84648] (3R)-3-hydroxyacyl-[acyl-carrier-protein] ChEBI 84648 Reactome DB_ID: 113563 1 NADP(+) [ChEBI:18009] NADP(+) ChEBI 18009 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 8862181 2xHSD17B8:2xCBR4 [mitochondrial matrix] 2xHSD17B8:2xCBR4 Reactome DB_ID: 8862105 2 UniProt:Q92506 HSD17B8 HSD17B8 FABGL HKE6 SDR30C1 RING2 HSD17B8 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 DB_ID: 8862102 2 UniProt:Q8N4T8 CBR4 CBR4 SDR45C1 CBR4 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 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 GO 0004316 GO molecular function 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 4.2.1 RPP14 (HTD2) dehydrates 3HA-CoA to t2E-CoA 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 Reactome DB_ID: 8957387 1 Reactome DB_ID: 113521 1 Reactome DB_ID: 8957386 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 8933306 UniProt:P86397 HTD2 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 GO 0018812 GO molecular function 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 GO 0046949 GO biological process Arachidonic acid metabolism 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 Hydrolysis of phosphatidylcholine 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 Reactome DB_ID: 426925 1 1,2-diacyl-sn-glycero-3-phosphocholine [ChEBI:57643] 1,2-diacyl-sn-glycero-3-phosphocholine 1,2-diacyl-sn-glycero-3-phosphocholine betaine PC 1,2-diacyl-sn-glycero-3-phosphocholines 3-sn-phosphatidylcholine Diacyl PC Phosphatidylcholine 3-sn-phosphatidylcholines lecithin a 1,2-diacyl-sn-glycero-3-phosphocholine ChEBI 57643 Reactome DB_ID: 29356 1 Reactome DB_ID: 140356 1 endoplasmic reticulum lumen GO 0005788 Reactome DB_ID: 428981 1 1-O-acyl-sn-glycero-3-phosphocholine(1+) [ChEBI:17504] 1-O-acyl-sn-glycero-3-phosphocholine(1+) ChEBI 17504 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 111860 Active PLA2:phosphatidylcholine [endoplasmic reticulum membrane] Active PLA2:phosphatidylcholine Reactome DB_ID: 426925 1 Reactome DB_ID: 111859 1 UniProt:P47712 PLA2G4A PLA2G4A CPLA2 PLA2G4A 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 O-phospho-L-serine at 505 505 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 727 727 EQUAL 1 EQUAL 749 EQUAL Reactome DB_ID: 74016 1 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI 29108 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 GO 0047498 GO molecular function 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 Arachidonate diffuses across the ER membrane 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 DB_ID: 140356 1 Reactome DB_ID: 29768 1 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 2.3.1.75 AWAT1 transfers acyl group from acyl-CoA to ARACOH, forming wax esters 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 Reactome DB_ID: 5696426 1 icosan-1-ol [ChEBI:75627] icosan-1-ol arachidyl alcohol eicosyl alcohol eicosan-1-ol arachidic alcohol 1-eicosanol ChEBI 75627 Reactome DB_ID: 192172 1 acyl-CoA [ChEBI:17984] acyl-CoA ChEBI 17984 Reactome DB_ID: 5696412 1 wax ester [ChEBI:10036] wax ester Wax esters ChEBI 10036 Reactome DB_ID: 162743 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5696425 UniProt:Q58HT5 AWAT1 AWAT1 AWAT1 DGAT2L3 DGA2 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 GO 0047196 GO molecular function 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 FAAH hydrolyses AEA to AA and ETA 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 Reactome DB_ID: 5693754 1 anandamide [ChEBI:2700] anandamide ChEBI 2700 Reactome DB_ID: 29356 1 Reactome DB_ID: 29768 1 Reactome DB_ID: 1498751 1 ethanolamine [ChEBI:16000] ethanolamine ChEBI 16000 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5693746 UniProt:O00519 FAAH 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 GO 0017064 GO molecular function 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 FAAH2 hydrolyses AEA to AA and ETA 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 Reactome DB_ID: 5693752 1 lipid droplet GO 0005811 Reactome DB_ID: 5693747 1 Reactome DB_ID: 5693733 1 Reactome DB_ID: 5693736 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5693745 UniProt:Q6GMR7 FAAH2 FAAH2 AMDD FAAH2 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 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) 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 PTGS2 dimer binds PTGS2 inhibitors 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 Reactome DB_ID: 140491 1 PTGS2 dimer [endoplasmic reticulum membrane] PTGS2 dimer PGHS2 dimer Reactome DB_ID: 2311355 1 heme b [ChEBI:26355] heme b protoheme heme [3,7,12,17-tetramethyl-8,13-divinylporphyrin-2,18-dipropanoato(2-)]iron haem b PROTOPORPHYRIN IX CONTAINING FE protoheme IX (7,12-diethenyl-3,8,13,17-tetramethylporphyrin-2,18-dipropanoato)iron ChEBI 26355 Reactome DB_ID: 61605 2 UniProt:P35354 PTGS2 PTGS2 COX2 PTGS2 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 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 Reactome DB_ID: 9716714 1 PTGS2 inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity carprofen [cytosol] lumiracoxib [cytosol] rofecoxib [cytosol] etoricoxib [cytosol] celecoxib [cytosol] valdecoxib [cytosol] etodolac [cytosol] benzquinamide [cytosol] Guide to Pharmacology 7141 Guide to Pharmacology 2897 Guide to Pharmacology 2893 Guide to Pharmacology 2896 Guide to Pharmacology 2892 Guide to Pharmacology 2894 Guide to Pharmacology 7185 Guide to Pharmacology 7124 Reactome DB_ID: 2309778 1 PTGS2 dimer:PTGS2 inhibitors [endoplasmic reticulum membrane] PTGS2 dimer:PTGS2 inhibitors Reactome DB_ID: 140491 1 Converted from EntitySet in Reactome Reactome DB_ID: 9716714 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 ASA- acetylates PTGS1 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 Reactome DB_ID: 428986 1 PTGS1 dimer [endoplasmic reticulum membrane] PTGS1 dimer PGHS1 homodimer COX1 Reactome DB_ID: 2311355 1 Reactome DB_ID: 428931 2 UniProt:P23219 PTGS1 PTGS1 COX1 PTGS1 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 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 Reactome DB_ID: 2314693 1 acetylsalicylate [ChEBI:13719] acetylsalicylate ChEBI 13719 Reactome DB_ID: 2314695 1 Ac-PTGS1 dimer [endoplasmic reticulum membrane] Ac-PTGS1 dimer Reactome DB_ID: 2311355 1 Reactome DB_ID: 428931 1 24 EQUAL 599 EQUAL Reactome DB_ID: 2314694 1 O-acetyl-L-serine at 529 529 EQUAL O-acetyl-L-serine 24 EQUAL 599 EQUAL 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 Reactome DB_ID: 2314690 1 salicylate [ChEBI:30762] salicylate o-hydroxybenzoate 2-hydroxybenzoic acid ion(1-) sal ChEBI 30762 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 ASA- acetylates PTGS2 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 Reactome DB_ID: 140491 1 Reactome DB_ID: 2314693 1 Reactome DB_ID: 2314687 1 Ac-PTGS2 dimer [endoplasmic reticulum membrane] Ac-PTGS2 dimer Reactome DB_ID: 2311355 1 Reactome DB_ID: 2161824 1 O-acetyl-L-serine at 516 516 EQUAL 18 EQUAL 604 EQUAL Reactome DB_ID: 61605 1 18 EQUAL 604 EQUAL 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 DB_ID: 2314690 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 1.14.99.1 Arachidonic acid is oxidised to PGG2 by PTGS1 Arachidonic acid is oxidised to PGG2 by PTGS1 Arachidonic acid oxidised to PGG2 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 Reactome DB_ID: 113534 2 Reactome DB_ID: 140356 1 Reactome DB_ID: 140357 1 prostaglandin G2 [ChEBI:27647] prostaglandin G2 ChEBI 27647 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 428986 GO 0004666 GO molecular function 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 PTGS1 dimer binds PTGS1 Inhibitors 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 Reactome DB_ID: 9677343 1 PTGS1 Inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity bromfenac [cytosol] APAP [cytosol] meloxicam [cytosol] indomethacin [cytosol] nimesulide [cytosol] fenoprofen [cytosol] Guide to Pharmacology 7131 Guide to Pharmacology 5239 Guide to Pharmacology 7220 Guide to Pharmacology 1909 Guide to Pharmacology 7401 Guide to Pharmacology 4820 Reactome DB_ID: 428986 1 Reactome DB_ID: 9677354 1 PTGS1 dimer:PTGS1 Inhibitors [endoplasmic reticulum membrane] PTGS1 dimer:PTGS1 Inhibitors Converted from EntitySet in Reactome Reactome DB_ID: 9677343 1 Reactome DB_ID: 428986 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 1.14.99.1 Arachidonic acid is oxidised to PGG2 by PTGS2 Arachidonic acid is oxidised to PGG2 by PTGS2 Arachidonic acid oxidised to PGG2 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 Reactome DB_ID: 113534 2 Reactome DB_ID: 140356 1 Reactome DB_ID: 140357 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 140491 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 1.11.1.7 PGG2 is reduced to PGH2 by PTGS1 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 Reactome DB_ID: 156540 2 Reactome DB_ID: 140357 1 Reactome DB_ID: 76342 2 electron [ChEBI:10545] electron ChEBI 10545 Reactome DB_ID: 30138 1 prostaglandin H2 [ChEBI:15554] prostaglandin H2 ChEBI 15554 Reactome DB_ID: 113519 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 428986 GO 0004601 GO molecular function 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 1.11.1.7 PGG2 is reduced to PGH2 by PTGS2 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 Reactome DB_ID: 156540 2 Reactome DB_ID: 140357 1 Reactome DB_ID: 76342 2 Reactome DB_ID: 30138 1 Reactome DB_ID: 113519 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 140491 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 Reactome DB_ID: 2309778 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 Reactome DB_ID: 549282 1-methylnicotinamide [ChEBI:16797] 1-methylnicotinamide ChEBI 16797 PGH2 diffuses from the endoplasmic reticulum lumen to the cytosol 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 Reactome DB_ID: 30138 1 Reactome DB_ID: 265283 1 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 PGH2 is reduced to PGF2a by AKR1C3 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 Reactome DB_ID: 29364 1 Reactome DB_ID: 265283 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 879535 1 prostaglandin F2alpha [ChEBI:15553] prostaglandin F2alpha ChEBI 15553 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142714 UniProt:P42330 AKR1C3 AKR1C3 PGFS KIAA0119 DDH1 AKR1C3 HSD17B5 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 GO 0036130 GO molecular function 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 1.11.1 PGH2 is reduced to PGF2a by FAM213B 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 Reactome DB_ID: 265283 1 Reactome DB_ID: 2142774 1 thioredoxin dithiol [ChEBI:15967] thioredoxin dithiol ChEBI 15967 Reactome DB_ID: 879535 1 Reactome DB_ID: 2142833 1 thioredoxin disulfide [ChEBI:18191] thioredoxin disulfide ChEBI 18191 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142703 UniProt:Q8TBF2 PRXL2B PRXL2B FAM213B PRXL2B C1orf93 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 GO 0008379 GO molecular function 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 5.3.99.3 PGH2 is isomerised to PGE2 by PTGES 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 Reactome DB_ID: 265283 1 Reactome DB_ID: 265287 1 prostaglandin E2 [ChEBI:15551] prostaglandin E2 ChEBI 15551 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142686 PTGES trimer [endoplasmic reticulum membrane] PTGES trimer Prostaglandin E synthase homotrimer Reactome DB_ID: 2239524 3 glutathione [ChEBI:16856] glutathione ChEBI 16856 Reactome DB_ID: 2142717 3 UniProt:O14684 PTGES PTGES PGES MPGES1 PIG12 MGST1L1 PTGES 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 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 GO 0050220 GO molecular function 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 5.3.99.3 Prostaglandin E synthase isomerizes PGH2 to PGE2 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 Reactome DB_ID: 265283 1 Reactome DB_ID: 265287 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 8864254 PTGES2(88-377), PTGES3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PTGES2(88-377) [cytosol] PTGES3 [cytosol] UniProt Q9H7Z7 UniProt Q15185 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 1.1.1.189 PGE2 is converted to PGF2a by CBR1 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 Reactome DB_ID: 29364 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 265287 1 Reactome DB_ID: 879535 1 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142784 UniProt:P16152 CBR1 CBR1 CBR1 CBR SDR21C1 CRN 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 GO 0050221 GO molecular function 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 PGE2 is dehydrated to PGA2 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 Reactome DB_ID: 265287 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 2299726 1 prostaglandin A2 [ChEBI:27820] prostaglandin A2 ChEBI 27820 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 PGA2 is isomerised to PGC2 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 Reactome DB_ID: 2299726 1 Reactome DB_ID: 2299724 1 prostaglandin C2 [ChEBI:27555] prostaglandin C2 ChEBI 27555 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 PGC2 is isomerised to PGB2 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 Reactome DB_ID: 2299724 1 Reactome DB_ID: 2299721 1 prostaglandin B2 [ChEBI:28099] prostaglandin B2 ChEBI 28099 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 PGA2 is dehydrated to 15d-PGA2 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 Reactome DB_ID: 2299726 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 2299722 1 15-deoxy-Delta(12,14)-prostaglandin A2 [ChEBI:63975] 15-deoxy-Delta(12,14)-prostaglandin A2 ChEBI 63975 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 5.3.99.2 PGH2 is isomerised to PGD2 by PTGDS 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 Reactome DB_ID: 30138 1 Reactome DB_ID: 2161634 1 prostaglandin D2 [ChEBI:15555] prostaglandin D2 ChEBI 15555 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142814 UniProt:P41222 PTGDS 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 GO 0004667 GO molecular function 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 5.3.99.2 PGH2 is isomerised to PGD2 by HPGDS 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 Reactome DB_ID: 265283 1 Reactome DB_ID: 879629 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142683 HPGDS dimer [cytosol] HPGDS dimer Reactome DB_ID: 2142706 2 UniProt:O60760 HPGDS HPGDS HPGDS PGDS PTGDS2 GSTS 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 DB_ID: 29450 2 glutathionate(1-) [ChEBI:57925] glutathionate(1-) glutathionate anion glutathionate ion glutathione glutathionate ChEBI 57925 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 PGD2 is dehydrated to PGJ2 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 Reactome DB_ID: 2161634 1 Reactome DB_ID: 113519 1 Reactome DB_ID: 2142674 1 prostaglandin J2 [ChEBI:27485] prostaglandin J2 ChEBI 27485 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 PGJ2 is isomerised to delta12-PGJ2 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 Reactome DB_ID: 2142674 1 Reactome DB_ID: 2142821 1 13,14-dihydro-Delta(12)-prostaglandin J2 [ChEBI:28130] 13,14-dihydro-Delta(12)-prostaglandin J2 ChEBI 28130 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 Delta12-PGJ2 is dehydrated to 15d-PGJ2 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 Reactome DB_ID: 2142821 1 Reactome DB_ID: 2142702 1 15-deoxy-Delta(12,14)-prostaglandin J2 [ChEBI:34159] 15-deoxy-Delta(12,14)-prostaglandin J2 15-Deoxy-delta-12,14-PGJ2 15-Deoxy-delta-12,14-prostaglandin J2 15-Deoxy-PGJ2 ChEBI 34159 Reactome DB_ID: 113519 1 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 PGD2 is dehydrated to 15d-PGD2 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 Reactome DB_ID: 2161634 1 Reactome DB_ID: 2142817 1 15-deoxy-Delta(12,14)-prostaglandin D2 [ChEBI:63999] 15-deoxy-Delta(12,14)-prostaglandin D2 ChEBI 63999 Reactome DB_ID: 113519 1 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 1.1.1.188 PGD2 is reduced to 11-epi-PGF2a by AKRIC3 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 Reactome DB_ID: 29364 1 Reactome DB_ID: 879629 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 2142710 1 11-epi-prostaglandin F2alpha [ChEBI:27595] 11-epi-prostaglandin F2alpha ChEBI 27595 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142714 1 EQUAL 323 EQUAL GO 0036131 GO molecular function 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 1.1.1.141 PGD2/E2/F2a is oxidised to 15k-PGD2/E2/F2a by HPGD 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 Reactome DB_ID: 29360 1 NAD(1-) [ChEBI:57540] NAD(1-) NAD(+) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD anion ChEBI 57540 Converted from EntitySet in Reactome Reactome DB_ID: 2161661 1 PGD2/E2/F2a [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PGD2 [cytosol] PGF2a [cytosol] PGE2 [cytosol] Reactome DB_ID: 73473 1 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 57945 Reactome DB_ID: 70106 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161597 1 15k-PGD2,15k-PGE2,15k-PGF2a [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 15k-PGF2a [cytosol] 15k-PGD2 [cytosol] 15k-PGE2 [cytosol] ChEBI 28442 ChEBI 15557 ChEBI 15547 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142778 HPGD dimer [cytosol] HPGD dimer Reactome DB_ID: 2142677 2 UniProt:P15428 HPGD HPGD HPGD SDR36C1 PGDH1 FUNCTION Catalyzes the NAD-dependent dehydrogenation (oxidation) of a broad array of hydroxylated polyunsaturated fatty acids (mainly eicosanoids and docosanoids, including prostaglandins, lipoxins and resolvins), yielding their corresponding keto (oxo) metabolites (PubMed:8086429, PubMed:10837478, PubMed:16828555, PubMed:16757471, PubMed:21916491, PubMed:25586183). Decreases the levels of the pro-proliferative prostaglandins such as prostaglandin E2 (whose activity is increased in cancer because of an increase in the expression of cyclooxygenase 2) and generates oxo-fatty acid products that can profoundly influence cell function by abrogating pro-inflammatory cytokine expression (PubMed:25586183, PubMed:15574495). Converts resolvins E1, D1 and D2 to their oxo products, which represents a mode of resolvin inactivation. Resolvin E1 plays important roles during the resolution phase of acute inflammation, while resolvins D1 and D2 have a unique role in obesity-induced adipose inflammation (PubMed:16757471, PubMed:22844113).SUBUNIT Homodimer.TISSUE SPECIFICITY Detected in colon epithelium (at protein level).INDUCTION Down-regulated by cortisol, dexamethasone and betamethasone. Down-regulated in colon cancer. Up-regulated by TGFB1.SIMILARITY Belongs to the short-chain dehydrogenases/reductases (SDR) family. UniProt P15428 1 EQUAL 266 EQUAL Reactome Database ID Release 82 2142778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142778 Reactome R-HSA-2142778 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-2142778.1 GO 0016404 GO molecular function Reactome Database ID Release 82 2161623 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161623 Reactome Database ID Release 82 2161662 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161662 Reactome R-HSA-2161662 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-2161662.2 16828555 Pubmed 2006 Role of glutamine 148 of human 15-hydroxyprostaglandin dehydrogenase in catalytic oxidation of prostaglandin E2 Cho, H Huang, L Hamza, A Gao, D Zhan, CG Tai, HH Bioorg Med Chem 14:6486-91 3954355 Pubmed 1986 Isolation and properties of lung 15-hydroxyprostaglandin dehydrogenase from pregnant rabbits Bergholte, JM Okita, RT Arch Biochem Biophys 245:308-15 1.3.1.48 15k-PGE2/F2a is reduced to dhk-PGE2/F2a by PTGR1 15k-PGE2/F2a is reduced to dhk-PGE2/F2a by PTGR1 Prostaglandin reductase 2 (PTGR2) is a 13-prostaglandin reductase which metabolises eicosanoids by catalysing NADH/NADPH-dependant double bond reduction in 15-keto-prostaglandin E2 (15k-PGE2) and F2alpha (15k-PGF2a) to produce 13,14-dihydro-15-keto-prostaglandin E2 (dhk-PGE2) and F2alpha (dhk-PGF2a) respectively (Wu et al. 2008). This has been inferred from the reaction event in mice involving prostaglandin reductase 2 (Ptgr2) (Chou et al. 2007). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29364 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161650 1 15k-PGE2,15k-PGF2a [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 15k-PGF2a [cytosol] 15k-PGE2 [cytosol] Reactome DB_ID: 70106 1 Reactome DB_ID: 29366 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161684 1 dhk-PGE2,dhk-PGF2a [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity dhk-PGF2a [cytosol] dhk-PGE2 [cytosol] ChEBI 63976 ChEBI 15550 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 8940670 UniProt:Q8N8N7 PTGR2 PTGR2 ZADH1 PTGR2 FUNCTION Functions as 15-oxo-prostaglandin 13-reductase and acts on 15-keto-PGE1, 15-keto-PGE2, 15-keto-PGE1-alpha and 15-keto-PGE2-alpha with highest activity towards 15-keto-PGE2 (PubMed:19000823). Overexpression represses transcriptional activity of PPARG and inhibits adipocyte differentiation (By similarity).SUBUNIT Monomer.TISSUE SPECIFICITY Widely expressed.SIMILARITY Belongs to the NADP-dependent oxidoreductase L4BD family. UniProt Q8N8N7 1 EQUAL 351 EQUAL GO 0036132 GO molecular function Reactome Database ID Release 82 2161566 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161566 Reactome Database ID Release 82 2161692 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161692 Reactome R-HSA-2161692 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-2161692.2 17449869 Pubmed 2007 Identification of a novel prostaglandin reductase reveals the involvement of prostaglandin E2 catabolism in regulation of peroxisome proliferator-activated receptor gamma activation Chou, WL Chuang, LM Chou, CC Wang, AH Lawson, JA FitzGerald, GA Chang, ZF J Biol Chem 282:18162-72 19000823 Pubmed 2008 Structural basis for catalytic and inhibitory mechanisms of human prostaglandin reductase PTGR2 Wu, Yu-Hauh Ko, Tzu-Ping Guo, Rey-Ting Hu, Su-Ming Chuang, Lee-Ming Wang, Andrew H-J Structure 16:1714-23 5.3.99.4 PTGIS, CYP8A1 isomerise PGH2 to PGI2 PTGIS, CYP8A1 isomerise PGH2 to PGI2 Prostacyclin synthase (CYP8A1) mediates the isomerization of prostaglandin H2 to prostaglandin I2 Prostacyclin synthase (PTGIS) aka CYP8A1 mediates the isomerisation of prostaglandin H2 (PGH2) to prostaglandin I2 (PGI2) aka prostacyclin (Wada et al. 2004). This reaction is not coupled with any P450 reductase proteins nor consumes NADPH. Experiments on rats with thrombolytic models suggest endogenous MNA could be a stimulator of the COX2/PGI2 pathway and thus regulate an anti-thrombotic effect (Chlopicki et al. 2007). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 Reactome DB_ID: 30138 1 Reactome DB_ID: 31593 1 prostaglandin I2 [ChEBI:15552] prostaglandin I2 ChEBI 15552 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 3222410 PTGIS,CYP8B1 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PTGIS [endoplasmic reticulum membrane] UniProt Q16647 GO 0008116 GO molecular function Reactome Database ID Release 82 76495 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76495 Reactome Database ID Release 82 76496 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76496 Reactome R-HSA-76496 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-76496.2 15115769 Pubmed 2004 Purification and characterization of recombinant human prostacyclin synthase Wada, M Yokoyama, C Hatae, T Shimonishi, M Nakamura, M Imai, Y Ullrich, V Tanabe, T J Biochem 135:455-63 17641676 Pubmed 2007 1-Methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathway Chlopicki, S Swies, J Mogielnicki, A Buczko, W Bartus, M Lomnicka, M Adamus, J Gebicki, J Br. J. Pharmacol. 152:230-9 PGI2 is hydrolysed to 6k-PGF1a PGI2 is hydrolysed to 6k-PGF1a The ring in prostaglandin I2 (PGI2) aka prostacyclin is highly labile and rapidly hydolyses to form the stable but biologically inactive 6-keto-prostaglandin F1alpha (6k-PGF1a) (Wada et al. 2004). PGI2 and 6k-PGF1a are often used interchangeably in the literature. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 31593 1 Reactome DB_ID: 113519 1 Reactome DB_ID: 2142786 1 6-oxoprostaglandin F1alpha [ChEBI:28158] 6-oxoprostaglandin F1alpha ChEBI 28158 Reactome Database ID Release 82 2161619 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161619 Reactome R-HSA-2161619 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-2161619.2 5.3.99.5 TBXAS1 isomerises PGH2 to TXA2 TBXAS1 isomerises PGH2 to TXA2 Thromboxane synthase (CYP5A1) mediates the isomerization of prostaglandin H2 to thromboxane A2 Thromboxane synthase (TBXAS1) aka CYP5A1 mediates the isomerisation of prostaglandin H2 (PGH2) to thromboxane A2 (TXA2) (Miyata et al. 2001, Chevalier et al. 2001). This reaction is not coupled with any P450 reductase proteins nor consumes NADPH. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 Reactome DB_ID: 30138 1 Reactome DB_ID: 32879 1 thromboxane A2 [ChEBI:15627] thromboxane A2 ChEBI 15627 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 65976 UniProt:P24557 TBXAS1 TBXAS1 TXAS CYP5 TBXAS1 CYP5A1 FUNCTION Catalyzes the conversion of prostaglandin H2 (PGH2) to thromboxane A2 (TXA2), a potent inducer of blood vessel constriction and platelet aggregation (PubMed:8436233, PubMed:11297515, PubMed:9873013, PubMed:11097184, PubMed:24009185, PubMed:22735388). Cleaves also PGH2 to 12-hydroxy-heptadecatrienoicacid (12-HHT) and malondialdehyde, which is known to act as a mediator of DNA damage. 12-HHT and malondialdehyde are formed stoichiometrically in the same amounts as TXA2 (PubMed:11297515, PubMed:9873013, PubMed:22735388). Additionally, displays dehydratase activity, toward (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (15(S)-HPETE) producing 15-KETE and 15-HETE (PubMed:17459323).PATHWAY Lipid metabolism; fatty acid metabolism.SUBUNIT Monomer.TISSUE SPECIFICITY Platelets, lung, kidney, spleen, macrophages and lung fibroblasts.DISEASE Thromboxane synthetase deficiency has been detected in some patients with a bleeding disorder due to platelet dysfunction.SIMILARITY Belongs to the cytochrome P450 family.CAUTION It is uncertain whether Met-1 is the initiator. An alternative upstream Met is found in primates, but not in other mammals. UniProt P24557 1 EQUAL 533 EQUAL GO 0004796 GO molecular function Reactome Database ID Release 82 76499 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76499 Reactome Database ID Release 82 76500 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76500 Reactome R-HSA-76500 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-76500.1 7925341 Pubmed 1994 Characterization of the human gene (TBXAS1) encoding thromboxane synthase Miyata, A Yokoyama, C Ihara, H Bandoh, S Takeda, O Takahashi, E Tanabe, T Eur J Biochem 224:273-9 11465543 Pubmed 2001 Identification of genetic variants in the human thromboxane synthase gene (CYP5A1) Chevalier, D Lo-Guidice, JM Sergent, E Allorge, D Debuysère, H Ferrari, N Libersa, C Lhermitte, M Broly, F Mutat Res 432:61-7 TXA2 is hydrolysed to TXB2 TXA2 is hydrolysed to TXB2 Thromboxane A2 degenerates to thromboxane B2 Thromboxane A2 (TXA2) contains an unstable ether linkage that is rapidly hydrolysed under aqueous conditions to form the biologically inert thromboxane B2 (TXB2) (Wang et al. 2001, Hamberg et al. 1975), which is excreted. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 32879 1 Reactome DB_ID: 113519 1 Reactome DB_ID: 443890 1 thromboxane B2 [ChEBI:28728] thromboxane B2 ChEBI 28728 Reactome Database ID Release 82 443894 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=443894 Reactome R-HSA-443894 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-443894.2 1059088 Pubmed 1975 Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides Hamberg, M Svensson, J Samuelsson, B Proc Natl Acad Sci U S A 72:2994-8 11297515 Pubmed 2001 Substrate binding is the rate-limiting step in thromboxane synthase catalysis Wang, LH Tsai, AL Hsu, PY J Biol Chem 276:14737-43 TXB2 is converted to 11dh-TXB2 by TXDH TXB2 is converted to 11dh-TXB2 by TXDH Thromboxane B2 (TXB2) undergoes dehydrogenation at C-11 to form 11-dehydro-thromboxane B2 (11dh-TXB2). The enzyme responsible for catalysis has been termed 11-dehydroxythromboxane B2 dehydrogenase (TXDH) (Kumlin & Granström 1986, Catella et al. 1986, Westlund et al. 1994). The human TXDH isoform has not been cloned but 11dh-TXB2 has been detected in various experiments. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 443890 1 Reactome DB_ID: 194653 1 Reactome DB_ID: 2142828 1 11-dehydro-thromboxane B2 [ChEBI:28667] 11-dehydro-thromboxane B2 ChEBI 28667 Reactome DB_ID: 156540 1 Reactome DB_ID: 194697 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2161595 TXDH [endoplasmic reticulum lumen] TXDH 11-dehydroxythromboxane B2 dehydrogenase 11-Hydroxythromboxane B2 reductase GO 0036133 GO molecular function Reactome Database ID Release 82 2161726 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161726 Reactome Database ID Release 82 2161732 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161732 Reactome R-HSA-2161732 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-2161732.2 3461463 Pubmed 1986 11-Dehydrothromboxane B2: a quantitative index of thromboxane A2 formation in the human circulation Catella, F Healy, D Lawson, JA FitzGerald, GA Proc Natl Acad Sci U S A 83:5861-5 8200461 Pubmed 1994 11-Hydroxythromboxane B2 dehydrogenase is identical to cytosolic aldehyde dehydrogenase Westlund, P Fylling, AC Cederlund, E Jörnvall, H FEBS Lett 345:99-103 3823488 Pubmed 1986 Radioimmunoassay for 11-dehydro-TXB2: a method for monitoring thromboxane production in vivo Kumlin, M Granström, E Prostaglandins 32:741-67 PGH2 is degraded to 12S-HHT and MDA by TBXAS1 PGH2 is degraded to 12S-HHT and MDA by TBXAS1 Thromboxane synthase (TBXAS1) aka CYP5A1 facilitates rearrangement of the PGH2 endoperoxide bridge by a complementary mechanism to prostacyclin synthase, interacting with the C-9 oxygen to promote endoperoxide bond cleavage. The C-11 oxygen radical initiates intramolecular rearrangement, resulting in either the formation of thromboxane A2 (TXA2) or 12-hydroxyheptadecatrienoic acid (12S-HHT) and malonaldehyde (MDA) (Wang et al. 2001). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 30138 1 Reactome DB_ID: 2161562 1 malonaldehyde [ChEBI:566274] malonaldehyde 1,3-Propanedialdehyde Malonodialdehyde 1,3-Propanedione Malonic dialdehyde MDA Malonyldialdehyde MDD Malondialdehyde 1,3-Propanedial Malonic aldehyde ChEBI 566274 Reactome DB_ID: 2142797 1 12S-HHTrE [ChEBI:63977] 12S-HHTrE ChEBI 63977 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 65976 1 EQUAL 533 EQUAL GO 0036134 GO molecular function Reactome Database ID Release 82 2161594 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161594 Reactome Database ID Release 82 2161613 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161613 Reactome R-HSA-2161613 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-2161613.2 Reactome Database ID Release 82 2162123 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162123 Reactome R-HSA-2162123 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-2162123.3 20655950 Pubmed 2011 Old and new generation lipid mediators in acute inflammation and resolution Stables, Melanie J Gilroy, Derek W Prog. Lipid Res. 50:35-51 19244215 Pubmed 2009 Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology Buczynski, MW Dumlao, DS Dennis, EA J Lipid Res 50:1015-38 978-0-444-53219-0 ISBN 2008 The eicosanoids: cyclooxygenase, lipoxygenase, and epoxygenase pathways Smith, William L Murphy, RC Biochemistry of Lipids, Lipoproteins and Membranes, 5th Edition (Book): 331-362 GO 0019371 GO biological process Synthesis of Leukotrienes (LT) and Eoxins (EX) Synthesis of Leukotrienes (LT) and Eoxins (EX) Leukotrienes (LTs) are biologically active molecules formed in response to inflammatory stimuli. They cause contraction of bronchial smooth muscles, stimulation of vascular permeability, and attraction and activation of leukocytes. LTs were discovered in 1938 and were termed the "slow release substance" (SRS) until their structures were determined in 1979 and they were then renamed to leukotrienes. LTs are derived from arachidonic acid through action by arachidonate 5-lipoxygenase (ALOX5). Cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are generated as products derived from leukotriene A4 (LTA4). Eoxins are generated from leukotrienes (LTs) and resemble cysteinyl leukotrienes but have a different three-dimensional structure (Murphy & Gijon 2007, Hammarstrom 1983, MA.Claesson 2009, Vance & Vance 2008, Buczynski et al. 2009). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 2.7.11.1 ALOX5 is phosphorylated by MAPKAP2 ALOX5 is phosphorylated by MAPKAP2 Arachidonate 5-lipoxygenase (ALOX5) catalyzes the first step in leukotriene biosynthesis and has a key role in inflammatory processes. ALOX5 is phosphorylated by MAPKAPK2; MAPKAPK2 is stimulated by arachidonic acid. Authored: Jupe, S, 2009-07-14 Reviewed: Rush, MG, 2012-11-10 Edited: Jupe, S, 2010-05-06 Reactome DB_ID: 2237880 1 ALOX5:Ca2+:Fe2+ [cytosol] ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 71067 1 iron(2+) [ChEBI:29033] iron(2+) FE (II) ION Fe(2+) Fe(II) Ferrous ion Fe2+ iron ion(2+) ChEBI 29033 Reactome DB_ID: 429010 1 UniProt:P09917 ALOX5 ALOX5 LOG5 ALOX5 FUNCTION Catalyzes the oxygenation of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) to 5-hydroperoxyeicosatetraenoate (5-HPETE) followed by the dehydration to 5,6- epoxyeicosatetraenoate (Leukotriene A4/LTA4), the first two steps in the biosynthesis of leukotrienes, which are potent mediators of inflammation (PubMed:8631361, PubMed:21233389, PubMed:22516296, PubMed:24282679, PubMed:19022417, PubMed:23246375, PubMed:8615788, PubMed:24893149, PubMed:31664810). Also catalyzes the oxygenation of arachidonate into 8-hydroperoxyicosatetraenoate (8-HPETE) and 12-hydroperoxyicosatetraenoate (12-HPETE) (PubMed:23246375). Displays lipoxin synthase activity being able to convert (15S)-HETE into a conjugate tetraene (PubMed:31664810). Although arachidonate is the preferred substrate, this enzyme can also metabolize oxidized fatty acids derived from arachidonate such as (15S)-HETE, eicosapentaenoate (EPA) such as (18R)- and (18S)-HEPE or docosahexaenoate (DHA) which lead to the formation of specialized pro-resolving mediators (SPM) lipoxin and resolvins E and D respectively, therefore it participates in anti-inflammatory responses (PubMed:21206090, PubMed:31664810, PubMed:8615788, PubMed:17114001, PubMed:32404334). Oxidation of DHA directly inhibits endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor gamma (PPARgamma) (By similarity). It does not catalyze the oxygenation of linoleic acid and does not convert (5S)-HETE to lipoxin isomers (PubMed:31664810). In addition to inflammatory processes, it participates in dendritic cell migration, wound healing through an antioxidant mechanism based on heme oxygenase-1 (HO-1) regulation expression, monocyte adhesion to the endothelium via ITGAM expression on monocytes (By similarity). Moreover, it helps establish an adaptive humoral immunity by regulating primary resting B cells and follicular helper T cells and participates in the CD40-induced production of reactive oxygen species (ROS) after CD40 ligation in B cells through interaction with PIK3R1 that bridges ALOX5 with CD40 (PubMed:21200133). May also play a role in glucose homeostasis, regulation of insulin secretion and palmitic acid-induced insulin resistance via AMPK (By similarity). Can regulate bone mineralization and fat cell differentiation increases in induced pluripotent stem cells (By similarity).ACTIVITY REGULATION Undergoes a sequential loss of the oxygenase and pseudoperoxidase activities which is dependent on the structural characteristics of the substrate for the reaction, on oxygen concentration and on exposure to phospholipids and calcium (PubMed:8631361). 15-HETE and other 15-mono-hydroxyeicosanoids exhibit the highest inhibitory potencies in their capability of suppressing 5-lipoxygenation of arachidonic acid, whereas the other HETEs, (5S,15S)-dihydroxy-(6E,8Z,11Z,13E)-eicosatetraenoic acid (5,15-diHETE) as well as octadecanoids, are modest or poor inhibitors (PubMed:8615788). The formation of (5S)-hydroperoxy-(15S)-hydroxy-(6E,8Z,11Z,13E)-eicosatetraenoate is strongly stimulated by either hydroperoxypolyenoic fatty acids or arachidonic acid (PubMed:8615788). Arachidonate 5-lipoxygenase and leukotriene A4 synthase activities are allosterically increased by ATP (PubMed:24893149).PATHWAY Lipid metabolism; leukotriene A4 biosynthesis.SUBUNIT Homodimer (PubMed:22516296, PubMed:21233389). Interacts with ALOX5AP and LTC4S (PubMed:19233132). Interacts with COTL1, the interaction is required for stability and efficient catalytic activity (PubMed:19807693). Interacts with PIK3R1; this interaction bridges ALOX5 with CD40 after CD40 ligation in B cells and leads to the production of reactive oxygen species (ROS) (PubMed:21200133). Interacts (via PLAT domain) with DICER1 (via Dicer dsRNA-binding fold domain); this interaction enhances arachidonate 5-lipoxygenase activity and modifies the miRNA precursor processing activity of DICER1 (PubMed:19022417).PTM Serine phosphorylation by MAPKAPK2 is stimulated by arachidonic acid (PubMed:11844797, PubMed:18978352). Phosphorylation on Ser-524 by PKA has an inhibitory effect (PubMed:15280375). Phosphorylation on Ser-272 prevents export from the nucleus (PubMed:11844797, PubMed:18978352). Phosphorylation at Ser-524 is stimulated by 8-bromo-3',5'-cyclic AMP or prostaglandin E2 (PubMed:26210919).SIMILARITY Belongs to the lipoxygenase family. UniProt P09917 2 EQUAL 674 EQUAL Reactome DB_ID: 74016 2 Reactome Database ID Release 82 2237880 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2237880 Reactome R-HSA-2237880 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-2237880.1 Reactome DB_ID: 113592 1 Reactome DB_ID: 265277 1 p-S272-ALOX5:Ca2+:Fe2+ [cytosol] p-S272-ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 71067 1 Reactome DB_ID: 265276 1 O-phospho-L-serine at 272 272 EQUAL 2 EQUAL 674 EQUAL Reactome DB_ID: 74016 2 Reactome Database ID Release 82 265277 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265277 Reactome R-HSA-265277 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-265277.1 Reactome DB_ID: 29370 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 187760 UniProt:P49137 MAPKAPK2 MAPKAPK2 MAPKAPK2 FUNCTION Stress-activated serine/threonine-protein kinase involved in cytokine production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, CEP131, ELAVL1, HNRNPA0, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Phosphorylates HSF1; leading to the interaction with HSP90 proteins and inhibiting HSF1 homotrimerization, DNA-binding and transactivation activities (PubMed:16278218). Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to the dissociation of HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impairment of their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to the regulation of the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity, leading to inhibition of dependent degradation of ARE-containing transcripts. Phosphorylates CEP131 in response to cellular stress induced by ultraviolet irradiation which promotes binding of CEP131 to 14-3-3 proteins and inhibits formation of novel centriolar satellites (PubMed:26616734). Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilization of GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3.ACTIVITY REGULATION Activated following phosphorylation by p38-alpha/MAPK14 following various stresses. Inhibited following sumoylation. Specifically inhibited by pyrrolopyridine inhibitors.SUBUNIT Heterodimer with p38-alpha/MAPK14; this heterodimer forms a stable complex: molecules are positioned 'face to face' so that the ATP-binding sites of both kinases are at the heterodimer interface (PubMed:12171911, PubMed:17576063, PubMed:17255097, PubMed:17480064, PubMed:17449059, PubMed:17395714). Interacts with PHC2 (PubMed:15094067). Interacts with HSF1 (PubMed:16278218).TISSUE SPECIFICITY Expressed in all tissues examined.PTM Sumoylation inhibits the protein kinase activity.PTM Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at Thr-222, Ser-272 and Thr-334.SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. UniProt P49137 O-phospho-L-threonine at 222 222 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-serine at 272 272 EQUAL O-phospho-L-threonine at 334 334 EQUAL 1 EQUAL 400 EQUAL GO 0004674 GO molecular function Reactome Database ID Release 82 429015 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=429015 Reactome Database ID Release 82 429016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=429016 Reactome R-HSA-429016 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-429016.2 10779545 Pubmed 2000 5-lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases Werz, O Klemm, J Samuelsson, B Rådmark, O Proc Natl Acad Sci U S A 97:5261-6 11844797 Pubmed 2002 Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2) Werz, O Szellas, D Steinhilber, D Rådmark, O J Biol Chem 277:14793-800 1.13.11.34 Arachidonic acid is oxidised to 5S-HpETE by ALOX5 Arachidonic acid is oxidised to 5S-HpETE by ALOX5 Oxidation of arachidonic acid to 5-HpETE Arachidonate 5-lipoxygenase (ALOX5) catalyzes the formation of leukotriene A4 (LTA4) from arachidonic acid in a two-step process. First, arachidonic acid AA is oxidized to form 5S-hydroperoxyeicosatetranoic acid (5S-HpETE) (Rouzer et al. 1988, Rouzer & Samuelsson 1987, Rouzer et al. 1986). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 29368 1 Reactome DB_ID: 29768 1 Reactome DB_ID: 266010 1 5(S)-HPETE [ChEBI:15632] 5(S)-HPETE ChEBI 15632 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318764 nuclear envelope GO 0005635 ALOX5:ALOX5AP:LTC4S [nuclear envelope] ALOX5:ALOX5AP:LTC4S ALOX5:FLAP:LTC4S Reactome DB_ID: 2318770 1 ALOX5AP trimer [nuclear envelope] ALOX5AP trimer FLAP trimer Reactome DB_ID: 2318768 3 UniProt:P20292 ALOX5AP ALOX5AP FLAP ALOX5AP FUNCTION Required for leukotriene biosynthesis by ALOX5 (5-lipoxygenase). Anchors ALOX5 to the membrane. Binds arachidonic acid, and could play an essential role in the transfer of arachidonic acid to ALOX5. Binds to MK-886, a compound that blocks the biosynthesis of leukotrienes.SUBUNIT Homotrimer. Interacts with LTC4S and ALOX5.DOMAIN The C-terminal part after residue 140 is mostly unstructured.DISEASE Genetic variations in ALOX5AP may be associated with susceptibility to myocardial infarction. Involvement in myocardial infarction is however unclear: according to some authors (PubMed:14770184), a 4-SNP haplotype in ALOX5AP confers risk of myocardial infarction, while according to other (PubMed:17304054) ALOX5AP is not implicated in this condition.SIMILARITY Belongs to the MAPEG family. UniProt P20292 1 EQUAL 161 EQUAL Reactome Database ID Release 82 2318770 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318770 Reactome R-HSA-2318770 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-2318770.1 Reactome DB_ID: 2318769 1 p-S272-ALOX5:Ca2+:Fe2+ [nuclear envelope] p-S272-ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 2318767 2 Reactome DB_ID: 2318766 1 Reactome DB_ID: 2318765 1 O-phospho-L-serine at 272 272 EQUAL 2 EQUAL 674 EQUAL Reactome Database ID Release 82 2318769 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318769 Reactome R-HSA-2318769 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-2318769.1 Reactome DB_ID: 2142729 1 LTC4S trimer [nuclear envelope] LTC4S trimer LTC4 synthase homotrimer Reactome DB_ID: 266025 3 UniProt:Q16873 LTC4S LTC4S LTC4S FUNCTION Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4 with high specificity (PubMed:7937884, PubMed:27791009, PubMed:27365393, PubMed:9153254, PubMed:23409838). Can also catalyze the transfer of a glutathionyl group from glutathione (GSH) to 13(S),14(S)-epoxy-docosahexaenoic acid to form maresin conjugate in tissue regeneration 1 (MCTR1), a bioactive lipid mediator that possess potent anti-inflammatory and proresolving actions (PubMed:27791009).ACTIVITY REGULATION Inhibited by MK886.PATHWAY Lipid metabolism; leukotriene C4 biosynthesis.SUBUNIT Homotrimer (PubMed:17632548, PubMed:17632546). Interacts with ALOX5AP and ALOX5 (PubMed:19233132).TISSUE SPECIFICITY Detected in lung, platelets and the myelogenous leukemia cell line KG-1 (at protein level). LTC4S activity is present in eosinophils, basophils, mast cells, certain phagocytic mononuclear cells, endothelial cells, vascular smooth muscle cells and platelets.PTM Phosphorylation at Ser-36 by RPS6KB1 inhibits the leukotriene-C4 synthase activity.DISEASE LTC4 synthase deficiency is associated with a neurometabolic developmental disorder characterized by muscular hypotonia, psychomotor retardation, failure to thrive, and microcephaly.SIMILARITY Belongs to the MAPEG family. UniProt Q16873 1 EQUAL 150 EQUAL Reactome Database ID Release 82 2142729 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142729 Reactome R-HSA-2142729 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-2142729.1 Reactome Database ID Release 82 2318764 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318764 Reactome R-HSA-2318764 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-2318764.1 GO 0004051 GO molecular function Reactome Database ID Release 82 265275 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265275 Reactome Database ID Release 82 265296 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265296 Reactome R-HSA-265296 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-265296.1 3164719 Pubmed 1988 Characterization of cloned human leukocyte 5-lipoxygenase expressed in mammalian cells Rouzer, CA Rands, E Kargman, S Jones, RE Register, RB Dixon, RA J Biol Chem 263:10135-40 3006030 Pubmed 1986 Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activities Rouzer, CA Matsumoto, T Samuelsson, B Proc Natl Acad Sci U S A 83:857-61 3118366 Pubmed 1987 Reversible, calcium-dependent membrane association of human leukocyte 5-lipoxygenase Rouzer, CA Samuelsson, B Proc Natl Acad Sci U S A 84:7393-7 ALOX5 binds ALOX5 inhibitors ALOX5 binds ALOX5 inhibitors 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 (AA) that is released from membrane phospholipids. Once released, AA can be acted on by various enzymes to form different eicosanoids. Arachidonate lipoxygenase 5 (ALOX)5 form leukotrienes (LTs) and eicosatetraenoic acids (ETEs) from AA. LTs and ETEs are biologically active molecules formed in response to inflammatory stimuli. They cause contraction of bronchial smooth muscles, stimulation of vascular permeability, and attraction and activation of leukocytes. When produced in excess, these molecules may contribute to a wide range of pathological inflammatory responses.<br><br>ALOX5 inhibitors are compounds that slow or stop the action of the ALOX5 enzyme, which is responsible for the production of inflammatory LTs and ETEs. Zileuton blocks the activity of ALOX5 (Carter et al. 1991). Zileuton is used in the treatment of acne vulgaris (Zouboulis 2005, Zouboulis et al. 2009) and for the prophylaxis and chronic treatment of allergic asthma (Bruno et al. 2018, Morina et al. 2016). Meclofenamic acid is a non-steroidal anti-inflammatory drug (NSAID) used for the relief of mild to moderate pain, for the treatment of primary dysmenorrhea and for the treatment of idiopathic heavy menstrual blood loss. It is also used for relief of the signs and symptoms of acute and chronic rheumatoid arthritis and osteoarthritis. In vitro meclofenamic acid was found to be an inhibitor of human ALOX5 activity (Boctor et al. 1986). Balsalazide, olsalazine and sulfasalazine are all pro-drugs that are enzymatically cleaved in the colon to produce the anti-inflammatory agent mesalazine (5-aminosalicylic acid, 5-ASA, mesalazine (Klotz 1985, Selby et al. 1985, Sharon et al. 1978, Hawkey et al. 1985, Neilsen et al. 1987). Once metabolised, 5-ASA acts locally in the colon to reduce inflammation in conditions such as inflammatory bowel disease and ulcerative colitis (Wiggins & Rajapakse 2009, Rask-Madsen et al. 1992, Singer et al. 2006, Hoult 1986, Feagan & Macdonald 2012). Authored: Jassal, Bijay, 2021-03-25 Reviewed: Huddart, Rachel, 2022-03-01 Edited: Jassal, Bijay, 2021-10-27 Edited: Matthews, Lisa, 2022-05-10 Reactome DB_ID: 2318764 1 Converted from EntitySet in Reactome Reactome DB_ID: 9707237 1 ALOX5 inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity balsalazide [cytosol] olsalazine [cytosol] zileuton [cytosol] sulfasalazine [cytosol] meclofenamic acid [cytosol] Guide to Pharmacology 11569 Guide to Pharmacology 11578 Guide to Pharmacology 5297 Guide to Pharmacology 4840 Guide to Pharmacology 7219 Reactome DB_ID: 9707188 1 ALOX5:ALOX5 inhibitors [nuclear envelope] ALOX5:ALOX5 inhibitors Reactome DB_ID: 2318764 1 Converted from EntitySet in Reactome Reactome DB_ID: 9707237 1 Reactome Database ID Release 82 9707188 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9707188 Reactome R-HSA-9707188 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-9707188.1 Reactome Database ID Release 82 9707186 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9707186 Reactome R-HSA-9707186 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-9707186.1 20436887 Pubmed 2009 Zileuton, a new efficient and safe systemic anti-acne drug Zouboulis, Christos C Dermatoendocrinol 1:188-92 2866075 Pubmed 1985 Modulation of human colonic arachidonic acid metabolism by sulfasalazine Hawkey, C J Boughton-Smith, N K Whittle, B J Dig Dis Sci 30:1161-5 2877850 Pubmed 1986 Pharmacological and biochemical actions of sulphasalazine Hoult, J R Drugs 32:18-26 29133059 Pubmed 2018 Recent advances in the search for novel 5-lipoxygenase inhibitors for the treatment of asthma Bruno, Ferdinando Spaziano, Giuseppe Liparulo, Angela Roviezzo, Fiorentina Nabavi, Seyed Mohammed Sureda, Antoni Filosa, Rosanna D'Agostino, Bruno Eur J Med Chem 153:65-72 23076889 Pubmed 2012 Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis Feagan, Brian G Macdonald, John K Cochrane Database Syst Rev 10:CD000543 1848634 Pubmed 1991 5-lipoxygenase inhibitory activity of zileuton Carter, G W Young, P R Albert, D H Bouska, J Dyer, R Bell, R L Summers, J B Brooks, D W J Pharmacol Exp Ther 256:929-37 3933675 Pubmed 1985 Olsalazine in active ulcerative colitis Selby, W S Barr, G D Ireland, A Mason, C H Jewell, D P Br Med J (Clin Res Ed) 291:1373-5 27046942 Pubmed 2016 Maximum Time of the Effect of Antileukotriene - Zileuton in Treatment of Patients with Bronchial Asthma Morina, Naim Boçari, Gëzim Iljazi, Ali Hyseini, Kadir Halac, Gunay Acta Inform Med 24:16-9 3020588 Pubmed 1986 Meclofenamate sodium is an inhibitor of both the 5-lipoxygenase and cyclooxygenase pathways of the arachidonic acid cascade in vitro Boctor, A M Eickholt, M Pugsley, T A Prostaglandins Leukot Med 23:229-38 16795963 Pubmed 2006 Efficacy and tolerability of olsalazine (dipentum) in the treatment of patients with ulcerative colitis--results of a field study Singer, M V Schmausser, H Schönfeld, G Hepatogastroenterology 53:317-21 2882965 Pubmed 1987 Inhibition of 5-lipoxygenase pathway of arachidonic acid metabolism in human neutrophils by sulfasalazine and 5-aminosalicylic acid Nielsen, O H Bukhave, K Elmgreen, J Ahnfelt-Rønne, I Dig Dis Sci 32:577-82 2864155 Pubmed 1985 Clinical pharmacokinetics of sulphasalazine, its metabolites and other prodrugs of 5-aminosalicylic acid Klotz, U Clin Pharmacokinet 10:285-302 15604543 Pubmed 2005 Zileuton, an oral 5-lipoxygenase inhibitor, directly reduces sebum production Zouboulis, Ch C Saborowski, A Boschnakow, A Dermatology 210:36-8 1359745 Pubmed 1992 5-Lipoxygenase inhibitors for the treatment of inflammatory bowel disease Rask-Madsen, J Bukhave, K Laursen, L S Lauritsen, K Agents ActionsC37-46 30669 Pubmed 1978 Role of prostaglandins in ulcerative colitis. Enhanced production during active disease and inhibition by sulfasalazine Sharon, P Ligumsky, M Rachmilewitz, D Zor, U Gastroenterology 75:638-40 19743890 Pubmed 2009 Balsalazide: a novel 5-aminosalicylate prodrug for the treatment of active ulcerative colitis Wiggins, Jon Brendan Rajapakse, Ramona Expert Opin Drug Metab Toxicol 5:1279-84 1.13.11.34 5S-HpETE is dehydrated to LTA4 by ALOX5 5S-HpETE is dehydrated to LTA4 by ALOX5 Dehydration of 5-HpETE to leukotriene A4 In the second step of the formation of leukotriene A4 (LTA4) from arachidonic acid, arachidonate 5-lipoxygenase (ALOX5) converts 5S-hydroperoxyeicosatetranoic acid (5S-HpETE) to an allylic epoxide, leukotriene A4 (LTA4) (Rouzer et al. 1988, Rouzer & Samuelsson 1987, Rouzer et al. 1986). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Reviewed: Hansen, Trond Vidar, 2018-02-21 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 266010 1 Reactome DB_ID: 265281 1 leukotriene A4 [ChEBI:15651] leukotriene A4 ChEBI 15651 Reactome DB_ID: 29356 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318764 Reactome Database ID Release 82 266051 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266051 Reactome R-HSA-266051 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-266051.2 3.3.2.6 LTA4 is hydolysed to LTB4 by LTA4H LTA4 is hydolysed to LTB4 by LTA4H LTA4 is hydrolyzed to LTB4 Leukotriene A4 hydrolase (LTA4H) is a monomeric, soluble enzyme that catalyzes the hydrolysis of the allylic epoxide leukotriene A4 (LTA4) to the dihydroxy acid leukotriene B4 (LTB4) (Radmark et al. 1984, McGee & Fitzpatrick 1985). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 265281 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 266056 1 leukotriene B4 [ChEBI:15647] leukotriene B4 ChEBI 15647 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 266038 LTA4H:Zn2+ [cytosol] LTA4H:Zn2+ LTA4 hydrolase (Zinc cofactor) Reactome DB_ID: 29426 1 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 Reactome DB_ID: 266022 1 UniProt:P09960 LTA4H LTA4H LTA4 LTA4H FUNCTION Bifunctional zinc metalloenzyme that comprises both epoxide hydrolase (EH) and aminopeptidase activities. Acts as an epoxide hydrolase to catalyze the conversion of LTA4 to the pro-inflammatory mediator leukotriene B4 (LTB4) (PubMed:11917124, PubMed:12207002, PubMed:15078870, PubMed:18804029, PubMed:1897988, PubMed:1975494, PubMed:2244921). Has also aminopeptidase activity, with high affinity for N-terminal arginines of various synthetic tripeptides (PubMed:20813919, PubMed:18804029). In addition to its pro-inflammatory EH activity, may also counteract inflammation by its aminopeptidase activity, which inactivates by cleavage another neutrophil attractant, the tripeptide Pro-Gly-Pro (PGP), a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP9) and prolylendopeptidase (PREPL) (PubMed:20813919, PubMed:24591641). Involved also in the biosynthesis of resolvin E1 and 18S-resolvin E1 from eicosapentaenoic acid, two lipid mediators that show potent anti-inflammatory and pro-resolving actions (PubMed:21206090).ACTIVITY REGULATION Inhibited by bestatin (PubMed:11175901). The epoxide hydrolase activity is restrained by suicide inactivation that involves binding of LTA4 to Tyr-379 (PubMed:7667299). 4-(4-benzylphenyl)thiazol-2-amine (ARM1) selectively inhibits the epoxide hydrolase activity (PubMed:24591641).PATHWAY Lipid metabolism; leukotriene B4 biosynthesis.SUBUNIT Monomer.TISSUE SPECIFICITY Isoform 1 and isoform 2 are expressed in monocytes, lymphocytes, neutrophils, reticulocytes, platelets and fibroblasts.PTM Phosphorylation at Ser-416 inhibits leukotriene-A4 hydrolase activity.SIMILARITY Belongs to the peptidase M1 family. UniProt P09960 2 EQUAL 611 EQUAL Reactome Database ID Release 82 266038 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266038 Reactome R-HSA-266038 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-266038.1 GO 0004463 GO molecular function Reactome Database ID Release 82 266024 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266024 Reactome Database ID Release 82 266072 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266072 Reactome R-HSA-266072 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-266072.1 2995393 Pubmed 1985 Enzymatic hydration of leukotriene A4. Purification and characterization of a novel epoxide hydrolase from human erythrocytes McGee, J Fitzpatrick, F J Biol Chem 260:12832-7 6490615 Pubmed 1984 Leukotriene A4 hydrolase in human leukocytes. Purification and properties Rådmark, O Shimizu, T Jörnvall, H Samuelsson, B J Biol Chem 259:12339-45 LTB4 is oxidised to 12-oxoLTB4 by PTGR1 LTB4 is oxidised to 12-oxoLTB4 by PTGR1 Prostaglandin reductase 1 (PTGR1) aka LTB4DH metabolizes eicosanoids by catalysing the oxidation of leukotriene B4 (LTB4) to form 12-oxo-Leukotriene B4 (12-oxoLTB4) aka 12-Keto-LTB4. The gene was originally cloned as leukotriene B4 12-hydroxydehydrogenase (LTB4DH) but was later discovered to have dual functionality as a prostaglandin reductase (Yokomizo et al. 1996). This reaction has been inferred from a reaction in pigs (Yokomizo et al. 1993, Ensor et al. 1998). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 266056 1 Reactome DB_ID: 29366 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 2142810 1 12-dehydro-leukotriene B4 [ChEBI:27814] 12-dehydro-leukotriene B4 ChEBI 27814 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142671 UniProt:Q14914 PTGR1 PTGR1 LTB4DH PTGR1 FUNCTION NAD(P)H-dependent oxidoreductase involved in metabolic inactivation of pro- and anti-inflammatory eicosanoids: prostaglandins (PG), leukotrienes (LT) and lipoxins (LX) (PubMed:25619643). Catalyzes with high efficiency the reduction of the 13,14 double bond of 15-oxoPGs, including 15-oxo-PGE1, 15-oxo-PGE2, 15-oxo-PGF1-alpha and 15-oxo-PGF2-alpha (PubMed:25619643). Catalyzes with lower efficiency the oxidation of the hydroxyl group at C12 of LTB4 and its derivatives, converting them into biologically less active 12-oxo-LTB4 metabolites (PubMed:25619643) (By similarity). Reduces 15-oxo-LXA4 to 13,14 dihydro-15-oxo-LXA4, enhancing neutrophil recruitment at the inflammatory site (By similarity). May play a role in metabolic detoxification of alkenals and ketones. Reduces alpha,beta-unsaturated alkenals and ketones, particularly those with medium-chain length, showing highest affinity toward (2E)-decenal and (3E)-3-nonen-2-one (PubMed:25619643). May inactivate 4-hydroxy-2-nonenal, a cytotoxic lipid constituent of oxidized low-density lipoprotein particles (By similarity).SUBUNIT Monomer or homodimer.TISSUE SPECIFICITY High expression in the kidney, liver, and intestine but not in leukocytes.SIMILARITY Belongs to the NADP-dependent oxidoreductase L4BD family. UniProt Q14914 1 EQUAL 329 EQUAL GO 0097257 GO molecular function Reactome Database ID Release 82 2161632 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161632 Reactome Database ID Release 82 2161567 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161567 Reactome R-HSA-2161567 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-2161567.2 9461497 Pubmed 1998 Purification, cDNA cloning and expression of 15-oxoprostaglandin 13-reductase from pig lung Ensor, CM Zhang, H Tai, HH Biochem J 330:103-8 8394361 Pubmed 1993 Enzymatic inactivation of leukotriene B4 by a novel enzyme found in the porcine kidney. Purification and properties of leukotriene B4 12-hydroxydehydrogenase Yokomizo, T Izumi, T Takahashi, T Kasama, T Kobayashi, Y Sato, F Taketani, Y Shimizu, T J Biol Chem 268:18128-35 8576264 Pubmed 1996 cDNA cloning, expression, and mutagenesis study of leukotriene B4 12-hydroxydehydrogenase Yokomizo, T Ogawa, Y Uozumi, N Kume, K Izumi, T Shimizu, T J Biol Chem 271:2844-50 1.14.14.94 CYP4F2, 4F3 20-hydroxylate LTB4 CYP4F2, 4F3 20-hydroxylate LTB4 CYP4F2 omega-hydroxylates leukotriene B4, thus inactivating it Leukotriene B4 (LTB4) is formed from arachidonic acid and is a potent inflammatory mediator. LTB4's activity is terminated by formation of its omega hydroxylated metabolite, 20-hydroxyleukotriene B4 (20OH-LTB4), catalysed by CYP4F2 primarily in human liver (Jin et al. 1998) and also by CYP4F3 (Kikuta et al. 1998). Authored: Jassal, Bijay, 2008-05-19 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 Reactome DB_ID: 29364 1 Reactome DB_ID: 266056 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 2161636 1 20-hydroxy-leukotriene B4 [ChEBI:15646] 20-hydroxy-leukotriene B4 ChEBI 15646 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161611 Cytochrome P450 (CYP4F2/4F3 based) [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP4F2 [endoplasmic reticulum membrane] CYP4F3 [endoplasmic reticulum membrane] UniProt P78329 UniProt Q08477 GO 0050051 GO molecular function Reactome Database ID Release 82 2162138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162138 Reactome Database ID Release 82 211873 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211873 Reactome R-HSA-211873 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-211873.1 9539102 Pubmed 1998 Human leukotriene B4 omega-hydroxylase (CYP4F3) gene: molecular cloning and chromosomal localization Kikuta, Y Kato, M Yamashita, Y Miyauchi, Y Tanaka, K Kamada, N Kusunose, M DNA Cell Biol 17:221-30 9799565 Pubmed 1998 Role of human CYP4F2 in hepatic catabolism of the proinflammatory agent leukotriene B4 Jin, R Koop, DR Raucy, JL Lasker, JM Arch Biochem Biophys 359:89-98 20oh-LTB4 is oxidised to 20cho-LTB4 by CYP4F2/4F3 20oh-LTB4 is oxidised to 20cho-LTB4 by CYP4F2/4F3 The cytochrome P450s 4F2 (CYP4F2) and F3 (CYP4F3) oxidise the omega hydroxylated metabolite, 20-hydroxyleukotriene B4 (20oh-LTB4) to form 20-aldehyde leukotriene B4 (20cho-LTB4) (Soberman et al. 1988). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29364 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 2161636 1 Reactome DB_ID: 2142740 1 20-oxoleukotriene B4 [ChEBI:63979] 20-oxoleukotriene B4 ChEBI 63979 Reactome DB_ID: 29356 2 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161611 GO 0097258 GO molecular function Reactome Database ID Release 82 2161740 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161740 Reactome Database ID Release 82 2161745 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161745 Reactome R-HSA-2161745 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-2161745.2 2836406 Pubmed 1988 The identification and formation of 20-aldehyde leukotriene B4 Soberman, RJ Sutyak, JP Okita, RT Wendelborn, DF Roberts LJ, 2nd Austen, KF J Biol Chem 263:7996-8002 20cho-LTB4 is oxidised to 20cooh-LTB4 by CYP4F2/4F3 20cho-LTB4 is oxidised to 20cooh-LTB4 by CYP4F2/4F3 The cytochrome P450s 4F2 (CYP4F2) and F3 (CYP4F3) oxidise 20-aldehyde leukotriene B4 (20cho-LTB4) to form 20-carboxy leukotriene B4 (20cooh-LTB4) (Soberman et al. 1988). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29364 1 Reactome DB_ID: 2142740 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 2161582 1 20-hydroxy-20-oxoleukotriene B4 [ChEBI:27562] 20-hydroxy-20-oxoleukotriene B4 ChEBI 27562 Reactome DB_ID: 29356 1 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161611 GO 0097259 GO molecular function Reactome Database ID Release 82 2161602 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161602 Reactome Database ID Release 82 2161792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161792 Reactome R-HSA-2161792 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-2161792.2 20cho-LTB4 is oxidised to 20cooh-LTB4 by ALDH 20cho-LTB4 is oxidised to 20cooh-LTB4 by ALDH An aldehyde dehydrogenase (ALDH) yet to be cloned in humans has been observed to oxidise 20-aldehyde leukotriene B4 (20cho-LTB4) to form 20-carboxy leukotriene B4 (20cooh-LTB4) (Sutyak et al. 1989). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29364 1 Reactome DB_ID: 2142740 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 2161582 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2161598 ALDH [cytosol] ALDH Aldehyde dehydrogenase Reactome Database ID Release 82 2161683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161683 Reactome Database ID Release 82 2161979 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161979 Reactome R-HSA-2161979 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-2161979.2 2549038 Pubmed 1989 Identification of an aldehyde dehydrogenase in the microsomes of human polymorphonuclear leukocytes that metabolizes 20-aldehyde leukotriene B4 Sutyak, J Austen, KF Soberman, RJ J Biol Chem 264:14818-23 20cooh-LTB4 is converted to 18cooh-LTB4 20cooh-LTB4 is converted to 18cooh-LTB4 Once omega-oxidation has occurred, 20-carboxy leukotriene B4 (20cooh-LTB4) can be further metabolized by beta-oxidation at its omega end into 18-carboxy-LTB4 (18cooh-LTB4) (Berry et al. 2003, Wheelan et al. 1999). The actual human enzyme or enzymes involved have yet to be identified. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2161582 1 Reactome DB_ID: 2142676 1 18-hydroxy-18-oxo-dinorleukotriene B4 [ChEBI:63980] 18-hydroxy-18-oxo-dinorleukotriene B4 ChEBI 63980 Reactome Database ID Release 82 2161790 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161790 Reactome R-HSA-2161790 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-2161790.2 9862787 Pubmed 1999 Metabolic transformations of leukotriene B4 in primary cultures of human hepatocytes Wheelan, P Hankin, JA Bilir, B Guenette, D Murphy, RC J Pharmacol Exp Ther 288:326-34 12709426 Pubmed 2003 Urinary metabolites of leukotriene B4 in the human subject Berry, KA Borgeat, P Gosselin, J Flamand, L Murphy, RC J Biol Chem 278:24449-60 4.4.1.20 LTA4 is converted to LTC4 by LTC4S LTA4 is converted to LTC4 by LTC4S LTA4 conjugates with glutathione to form LTC4 Leukotriene A4 conjugates with reduced glutathione (GSH) to produce leukotriene C4 (LTC4). This conjugation is mediated by the homodimeric, perinuclear membrane-bound enzyme leukotriene C4 synthase (LTC4S) (Lam et al. 1994, Welsch et al. 1994). LTC4S differs from cytosolic and microsomal GSH-S-transferases by having a very narrow substrate specificity and the inability to conjugate xenobiotics. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 265281 1 Reactome DB_ID: 29450 1 Reactome DB_ID: 266066 1 leukotriene C4 [ChEBI:16978] leukotriene C4 ChEBI 16978 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318764 GO 0004464 GO molecular function Reactome Database ID Release 82 266055 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266055 Reactome Database ID Release 82 266050 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266050 Reactome R-HSA-266050 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-266050.1 8052639 Pubmed 1994 Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4 Lam, Bing K Penrose, JF Freeman, GJ Austen, KF Proc Natl Acad Sci U S A 91:7663-7 7937884 Pubmed 1994 Molecular cloning and expression of human leukotriene-C4 synthase Welsch, DJ Creely, DP Hauser, SD Mathis, KJ Krivi, GG Isakson, PC Proc Natl Acad Sci U S A 91:9745-9 LTC4 is exported from the cytosol by ABCC1 LTC4 is exported from the cytosol by ABCC1 ABCC1 mediates LTC4 export from the cell On formation, leukotriene C4 (LTC4) is exported to the extracellular region by the ABCC1 transporter (Sjolinder et al. 1999, Lam et al. 1989) and processed further by cleavage reactions. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 266066 1 Reactome DB_ID: 266013 1 extracellular region GO 0005576 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 266068 plasma membrane GO 0005886 UniProt:P33527 ABCC1 ABCC1 ABCC1 MRP1 MRP FUNCTION Mediates export of organic anions and drugs from the cytoplasm (PubMed:7961706, PubMed:16230346, PubMed:9281595, PubMed:10064732, PubMed:11114332). Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics (PubMed:7961706, PubMed:16230346, PubMed:9281595, PubMed:10064732, PubMed:11114332). Confers resistance to anticancer drugs by decreasing accumulation of drug in cells, and by mediating ATP- and GSH-dependent drug export (PubMed:9281595). Hydrolyzes ATP with low efficiency (PubMed:16230346). Catalyzes the export of sphingosine 1-phosphate from mast cells independently of their degranulation (PubMed:17050692). Participates in inflammatory response by allowing export of leukotriene C4 from leukotriene C4-synthezing cells (By similarity).ACTIVITY REGULATION MK 571 inhibits sphingosine 1-phosphate and leukotriene C4 export.TISSUE SPECIFICITY Lung, testis and peripheral blood mononuclear cells.SIMILARITY Belongs to the ABC transporter superfamily. ABCC family. Conjugate transporter (TC 3.A.1.208) subfamily. UniProt P33527 1 EQUAL 1531 EQUAL GO 0140359 GO molecular function Reactome Database ID Release 82 266058 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266058 Reactome Database ID Release 82 266070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266070 Reactome R-HSA-266070 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-266070.1 10064732 Pubmed 1999 Characterization of a leukotriene C4 export mechanism in human platelets: possible involvement of multidrug resistance-associated protein 1 Sjölinder, Mikael Tornhamre, S Claesson, HE Hydman, J Lindgren, J J Lipid Res 40:439-46 2753893 Pubmed 1989 The identification of a distinct export step following the biosynthesis of leukotriene C4 by human eosinophils Lam, Bing K Owen WF, Jr Austen, KF Soberman, RJ J Biol Chem 264:12885-9 3.4.19.13 GGT1, 5 dimers hydrolyse LTC4 to LTD4 GGT1, 5 dimers hydrolyse LTC4 to LTD4 Cleavage of the gamma-glutamyl bond of LTC4 forms LTD4 The reversible conversion of leukotriene C4 (LTC4) to leukotriene D4 (LTD4) is catalysed by gamma-glutamyl transferases 1 (GGT1) and 5 (GGT5). GGTs are present on the outer surface of plasma membranes and are a heterodimer of a heavy and a light chain. Its action involves the hydrolysis of the gamma-glutamyl peptide bond of glutathione and glutathione conjugates, releasing glutamate. In this example, LTC4 is a glutathione conjugate that is hydrolysed to LTD4 (Anderson et al. 1982, Wickham et al. 2011). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 266013 1 Reactome DB_ID: 109276 1 Reactome DB_ID: 210382 1 L-glutamate(1-) [ChEBI:29985] L-glutamate(1-) C5H8NO4 WHUUTDBJXJRKMK-VKHMYHEASA-M (2S)-2-ammoniopentanedioate 146.12136 L-glutamate hydrogen L-glutamate InChI=1S/C5H9NO4/c6-3(5(9)10)1-2-4(7)8/h3H,1-2,6H2,(H,7,8)(H,9,10)/p-1/t3-/m0/s1 L-glutamic acid, ion(1-) [NH3+][C@@H](CCC([O-])=O)C([O-])=O L-glutamic acid monoanion ChEBI 29985 Reactome DB_ID: 266074 1 leukotriene D4 [ChEBI:28666] leukotriene D4 ChEBI 28666 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2162130 GGT1, 5 dimers [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0036374 GO molecular function Reactome Database ID Release 82 266030 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266030 Reactome Database ID Release 82 266046 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266046 Reactome R-HSA-266046 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-266046.4 21447318 Pubmed 2011 Gamma-glutamyl compounds: substrate specificity of gamma-glutamyl transpeptidase enzymes Wickham, S West, MB Cook, PF Hanigan, MH Anal Biochem 414:208-14 6122208 Pubmed 1982 Interconversion of leukotrienes catalyzed by purified gamma-glutamyl transpeptidase: concomitant formation of leukotriene D4 and gamma-glutamyl amino acids Anderson, ME Allison, RD Meister, Alton Proc Natl Acad Sci U S A 79:1088-91 3.4.13.21 3.4.13.18 LTD4 is converted to LTE4 by DPEP1/2 LTD4 is converted to LTE4 by DPEP1/2 Further cleavage of LTD4 forms LTE4 Another outer surface membrane-bound, homodimeric enzyme, dipeptidase, existing in two forms DPEP1 (Adachi et al. 1989) and DPEP2 (Lee et al. 1983, Raulf et al. 1987), further hydrolyses leukotriene D4 (LTD4) to leukotriene E4 (LTE4), cleaving a glycine residue in the process. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 109276 1 Reactome DB_ID: 266074 1 Reactome DB_ID: 266033 1 leukotriene E4 [ChEBI:15650] leukotriene E4 ChEBI 15650