BioPAX pathway converted from "Arachidonic acid metabolism" in the Reactome database. Arachidonic acid metabolism Eicosanoids, oxygenated, 20-carbon fatty acids, are autocrine and paracrine signaling molecules that modulate physiological processes including pain, fever, inflammation, blood clot formation, smooth muscle contraction and relaxation, and the release of gastric acid. Eicosanoids are synthesized in humans primarily from arachidonic acid (all-cis 5,8,11,14-eicosatetraenoic acid) that is released from membrane phospholipids. Once released, arachidonic acid is acted on by prostaglandin G/H synthases (PTGS, also known as cyclooxygenases (COX)) to form prostaglandins and thromboxanes, by arachidonate lipoxygenases (ALOX) to form leukotrienes, epoxygenases (cytochrome P450s and epoxide hydrolase) to form epoxides such as 15-eicosatetraenoic acids, and omega-hydrolases (cytochrome P450s) to form hydroxyeicosatetraenoic acids (Buczynski et al. 2009, Vance & Vance 2008).<br>Levels of free arachidonic acid in the cell are normally very low so the rate of synthesis of eicosanoids is determined primarily by the activity of phospholipase A2, which mediates phospholipid cleavage to generate free arachidonic acid. The enzymes involved in arachidonic acid metabolism are typically constitutively expressed so the subset of these enzymes expressed by a cell determines the range of eicosanoids it can synthesize.<br>Eicosanoids are unstable, undergoing conversion to inactive forms with half-times under physiological conditions of seconds or minutes. Many of these reactions appear to be spontaneous. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 LEFT-TO-RIGHT Hydrolysis of phosphatidylcholine Once bound to the membrane, cPLA2 hydrolyzes phosphatidylcholine to produce arachidonic acid (AA), a precursor to inflammatory mediators. While several phospholipases can catalyze this reaction in cells overexpressing the enzymes, PLA2G4A is the major enzyme that catalyzes this reaction in vivo (Reed et al. 2011). At the same time, possible physiological roles have been described for soluble phospholipases (sPLA) in the mobilization of arachidonic acid in some cell types or under some physiological conditions (Murakami et al. 2011). Here, the major role of PLA2G4A has been annotated. Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-11-06 PC Phosphatidyl choline 1,2-diacyl-sn-glycero-3-phosphocholine Reactome DB_ID: 426925 endoplasmic reticulum membrane GENE ONTOLOGY GO:0005789 1,2-diacyl-sn-glycero-3-phosphocholine [ChEBI:57643] 1,2-diacyl-sn-glycero-3-phosphocholine a 1,2-diacyl-sn-glycero-3-phosphocholine PC 1,2-diacyl-sn-glycero-3-phosphocholine betaine 3-sn-phosphatidylcholine 1,2-diacyl-sn-glycero-3-phosphocholines Phosphatidylcholine Diacyl PC lecithin 3-sn-phosphatidylcholines ChEBI CHEBI:57643 Reactome Database ID Release 81 426925 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426925 Reactome R-ALL-426925 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-426925.4 Reactome http://www.reactome.org COMPOUND C00157 additional information MI MI:0361 H2O water Reactome DB_ID: 29356 cytosol GENE ONTOLOGY GO:0005829 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 81 29356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29356 Reactome R-ALL-29356 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29356.5 COMPOUND C00001 LPC 2-Lysophosphatidylcholine 1-Acyl-sn-glycero-3-phosphocholine 1-O-acyl-sn-glycero-3-phosphocholine(1+) 1-Acyl-sn-glycerol-3-phosphocholine 1-Acylglycero-3-phosphocholine Reactome DB_ID: 428981 1-O-acyl-sn-glycero-3-phosphocholine(1+) [ChEBI:17504] 1-O-acyl-sn-glycero-3-phosphocholine(1+) ChEBI CHEBI:17504 Reactome Database ID Release 81 428981 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428981 Reactome R-ALL-428981 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-428981.4 AA arachidonic acid Reactome DB_ID: 140356 endoplasmic reticulum lumen GENE ONTOLOGY GO:0005788 arachidonate [ChEBI:32395] arachidonate (20:4n6) (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (5Z,8Z,11Z,14Z)-eicosatetraenoate ChEBI CHEBI:32395 Reactome Database ID Release 81 140356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140356 Reactome R-ALL-140356 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-140356.4 ACTIVATION Active PLA2:phosphatidylcholine Reactome DB_ID: 111860 1 phospho-cPLA2 p-S505,S727-PLA2G4A Phosphatidylcholine 2-acylhydrolase Phospholipase A2 group IVA Reactome DB_ID: 111859 UniProt:P47712 PLA2G4A PLA2G4A CPLA2 PLA2G4 FUNCTION Has primarily calcium-dependent phospholipase and lysophospholipase activities, with a major role in membrane lipid remodeling and biosynthesis of lipid mediators of the inflammatory response (PubMed:7794891, PubMed:8619991, PubMed:8702602, PubMed:9425121, PubMed:10358058, PubMed:14709560, PubMed:16617059, PubMed:17472963, PubMed:27642067, PubMed:18451993). Plays an important role in embryo implantation and parturition through its ability to trigger prostanoid production (By similarity). Preferentially hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) (PubMed:7794891, PubMed:8619991, PubMed:9425121, PubMed:10358058, PubMed:17472963, PubMed:18451993). Selectively hydrolyzes sn-2 arachidonoyl group from membrane phospholipids, providing the precursor for eicosanoid biosynthesis via the cyclooxygenase pathway (PubMed:18451993, PubMed:7794891, PubMed:9425121, PubMed:10358058, PubMed:17472963). In an alternative pathway of eicosanoid biosynthesis, hydrolyzes sn-2 fatty acyl chain of eicosanoid lysophopholipids to release free bioactive eicosanoids (PubMed:27642067). Hydrolyzes the ester bond of the fatty acyl group attached at sn-1 position of phospholipids (phospholipase A1 activity) only if an ether linkage rather than an ester linkage is present at the sn-2 position. This hydrolysis is not stereospecific (PubMed:7794891). Has calcium-independent phospholipase A2 and lysophospholipase activities in the presence of phosphoinositides (PubMed:12672805). Has O-acyltransferase activity. Catalyzes the transfer of fatty acyl chains from phospholipids to a primary hydroxyl group of glycerol (sn-1 or sn-3), potentially contributing to monoacylglycerol synthesis (PubMed:7794891).ACTIVITY REGULATION Activated by cytosolic calcium, which is necessary for binding to membrane lipids (PubMed:12672805). Activated by phosphorylation in response to mitogenic stimuli (PubMed:8381049). Activated by ceramide-1-phosphate. Binding (via C2 domain) to ceramide-1-phosphate increases the affinity for membrane lipids (PubMed:17472963). Can be activated by phosphoinositides in the absence of calcium (PubMed:12672805). Inhibited by ANXA5 in a calcium- and substrate-dependent way (PubMed:9425121).PATHWAY Membrane lipid metabolism; glycerophospholipid metabolism.PATHWAY Lipid metabolism; arachidonate metabolism.PATHWAY Lipid metabolism; prostaglandin biosynthesis.PATHWAY Lipid metabolism; leukotriene B4 biosynthesis.SUBUNIT Interacts with KAT5.TISSUE SPECIFICITY Expressed in various cells and tissues such as macrophages, neutrophils, fibroblasts and lung endothelium. Expressed in platelets (at protein level) (PubMed:25102815).DOMAIN The N-terminal C2 domain associates with lipid membranes upon calcium binding. It modulates enzyme activity by presenting the active site to its substrate in response to elevations of cytosolic calcium (PubMed:9430701, PubMed:9665851, PubMed:11375391). In the presence of phosphoinositides, regulates phospholipase A2 and lysophospholipase activities in a calcium-independent way (PubMed:12672805).PTM Phosphorylated at both Ser-505 and Ser-727 in response to mitogenic stimuli. Homo sapiens NCBI Taxonomy 9606 UniProt P47712 505 EQUAL O-phospho-L-serine MOD MOD:00046 727 EQUAL 1 EQUAL 749 EQUAL Reactome Database ID Release 81 111859 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111859 Reactome R-HSA-111859 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-111859.1 1 Ca2+ Calcium calcium(2+) Reactome DB_ID: 74016 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI CHEBI:29108 Reactome Database ID Release 81 74016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74016 Reactome R-ALL-74016 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-74016.3 COMPOUND C00076 1 Reactome Database ID Release 81 111860 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111860 Reactome R-HSA-111860 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-111860.1 GENE ONTOLOGY GO:0047498 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 81 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 81 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 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 21746768 Pubmed 2011 Secreted phospholipase A2 revisited Murakami, Makoto Taketomi, Yoshitaka Sato, Hiroyasu Yamamoto, Kei J. Biochem. 150:233-55 LEFT-TO-RIGHT Arachidonate diffuses across the ER membrane Arachidonate released by phospholipases diffuses within the membrane and out of the membrane into the ER lumen and cytosol. The relatively low level of arachidonate in the cytoplasm is probably due to reesterification into complex lipids by acyl transferases. Authored: Jupe, S, 2009-07-14 Reviewed: Rush, MG, 2012-11-10 Edited: Jupe, S, 2009-07-14 AA Arachidonate arachidonic acid cis-5,8,11,14-Eicosatetraenoic acid Reactome DB_ID: 29768 Reactome Database ID Release 81 29768 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29768 Reactome R-ALL-29768 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29768.4 COMPOUND C00219 Reactome Database ID Release 81 428990 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428990 Reactome R-HSA-428990 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428990.3 6810878 Pubmed 1982 How is the level of free arachidonic acid controlled in mammalian cells? Irvine, RF Biochem J 204:3-16 6146314 Pubmed 1984 Inositol trisphosphate and diacylglycerol as second messengers Berridge, MJ Biochem J 220:345-60 LEFT-TO-RIGHT 2.3.1.75 AWAT1 transfers acyl group from acyl-CoA to ARACOH, forming wax esters Arachidyl alcohol (ARACOH) is straight-chain fatty alcohol of C20 length used as an emollient in cosmetics. Esterification of alcohols with fatty acids represents the formation of both storage and cytoprotective molecules in the body. Overproduction of these esters is associated with several disease pathologies, including atherosclerosis and obesity. The ER membrane-associated acyl-CoA wax alcohol acyltransferase 1 (AWAT1) mediates the esterification of its preferred substrate ARACOH (Turkish et al. 2005). Authored: Jassal, Bijay, 2015-05-29 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-05-29 ARACOH arachidyl alcohol icosan-1-ol Reactome DB_ID: 5696426 icosan-1-ol [ChEBI:75627] icosan-1-ol arachidyl alcohol 1-eicosanol arachidic alcohol eicosan-1-ol eicosyl alcohol ChEBI CHEBI:75627 Reactome Database ID Release 81 5696426 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696426 Reactome R-ALL-5696426 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5696426.3 Acyl-CoA Acyl_minus_CoA Reactome DB_ID: 192172 acyl-CoA [ChEBI:17984] acyl-CoA ChEBI CHEBI:17984 Reactome Database ID Release 81 192172 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=192172 Reactome R-ALL-192172 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-192172.2 CoA-SH coenzyme A Reactome DB_ID: 162743 coenzyme A(4-) [ChEBI:57287] coenzyme A(4-) 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-({3-oxo-3-[(2-sulfanylethyl)amino]propyl}amino)butyl] diphosphate} CoA ChEBI CHEBI:57287 Reactome Database ID Release 81 162743 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=162743 Reactome R-ALL-162743 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-162743.5 COMPOUND C00010 wax ester arachidyl ester Reactome DB_ID: 5696412 wax ester [ChEBI:10036] wax ester Wax esters ChEBI CHEBI:10036 Reactome Database ID Release 81 5696412 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696412 Reactome R-ALL-5696412 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5696412.3 ACTIVATION AWAT1 Acyl-CoA wax alcohol acyltransferase 1 ecNumber2.3.1.75/ecNumber AWAT1_HUMAN Reactome DB_ID: 5696425 UniProt:Q58HT5 AWAT1 AWAT1 DGA2 DGAT2L3 FUNCTION Acyltransferase that catalyzes the formation of ester bonds between fatty alcohols and fatty acyl-CoAs to form wax monoesters (PubMed:15671038). Shows a strong preference for decyl alcohol (C10), with less activity towards C16 and C18 alcohols (PubMed:15671038). Shows a strong preference for saturated acyl-CoAs (PubMed:15671038).TISSUE SPECIFICITY Predominantly expressed in skin, where it is limited to the sebaceous gland. Expressed in more mature, centrally located cells just before their rupture and sebum release. Also expressed in all tissues except spleen. Expressed at higher level in thymus, prostate and testis.SIMILARITY Belongs to the diacylglycerol acyltransferase family. UniProt Q58HT5 1 EQUAL 328 EQUAL Reactome Database ID Release 81 5696425 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696425 Reactome R-HSA-5696425 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5696425.1 GENE ONTOLOGY GO:0047196 Reactome Database ID Release 81 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 81 5696424 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696424 Reactome R-HSA-5696424 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5696424.2 15671038 Pubmed 2005 Identification of two novel human acyl-CoA wax alcohol acyltransferases: members of the diacylglycerol acyltransferase 2 (DGAT2) gene superfamily Turkish, Aaron R Henneberry, Annette L Cromley, Debra Padamsee, Mahajabeen Oelkers, P Bazzi, Hisham Christiano, Angela M Billheimer, JT Sturley, Stephen L J. Biol. Chem. 280:14755-64 LEFT-TO-RIGHT FAAH hydrolyses AEA to AA and ETA Fatty acid amides are a class of lipid transmitters that include the endogenous cannabinoid anandamide (AEA) and the sleep-inducing chemical oleamide. The magnitude and duration of their signalling are controlled by enzymatic hydrolysis mediated by fatty-acid amide hydrolases 1 and 2 (FAAH, H2). Hydrolysis of AEA is described here (Wei et al. 2006). FAAH is localised to the ER membrane whereas FAAH2 is localised to lipid droplets (Kaczocha et al. 2010). Authored: Jassal, Bijay, 2015-05-18 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-05-18 AEA anandamide Reactome DB_ID: 5693754 anandamide [ChEBI:2700] anandamide ChEBI CHEBI:2700 Reactome Database ID Release 81 5693754 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693754 Reactome R-ALL-5693754 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5693754.3 ETA ethanolamine Reactome DB_ID: 1498751 ethanolamine [ChEBI:16000] ethanolamine ChEBI CHEBI:16000 Reactome Database ID Release 81 1498751 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1498751 Reactome R-ALL-1498751 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-1498751.3 ACTIVATION FAAH Fatty-acid amide hydrolase 1 ecNumber3.5.1.99/ecNumber FAAH1_HUMAN Reactome DB_ID: 5693746 UniProt:O00519 FAAH FAAH FAAH1 FUNCTION Catalyzes the hydrolysis of endogenous amidated lipids like the sleep-inducing lipid oleamide ((9Z)-octadecenamide), the endocannabinoid anandamide (N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine), as well as other fatty amides, to their corresponding fatty acids, thereby regulating the signaling functions of these molecules (PubMed:9122178, PubMed:17015445, PubMed:19926788). Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates (PubMed:9122178, PubMed:17015445). It can also catalyze the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol) (PubMed:21049984). FAAH cooperates with PM20D1 in the hydrolysis of amino acid-conjugated fatty acids such as N-fatty acyl glycine and N-fatty acyl-L-serine, thereby acting as a physiological regulator of specific subsets of intracellular, but not of extracellular, N-fatty acyl amino acids (By similarity).ACTIVITY REGULATION Inhibited by O-aryl carbamates and alpha-keto heterocycles (PubMed:17015445). Inhibited by trifluoromethyl ketone (PubMed:9122178).SUBUNIT Homodimer.TISSUE SPECIFICITY Highly expressed in the brain, small intestine, pancreas, skeletal muscle and testis. Also expressed in the kidney, liver, lung, placenta and prostate.POLYMORPHISM Genetic variations in FAAH can be associated with susceptibility to polysubstance abuse [MIM:606581]. At homozygosity, variant Thr-129 is strongly associated with drug and alcohol abuse, and methamphetamine dependence.SIMILARITY Belongs to the amidase family. UniProt O00519 1 EQUAL 579 EQUAL Reactome Database ID Release 81 5693746 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693746 Reactome R-HSA-5693746 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5693746.1 GENE ONTOLOGY GO:0017064 Reactome Database ID Release 81 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 81 5693742 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693742 Reactome R-HSA-5693742 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5693742.1 19926788 Pubmed 2010 Lipid droplets are novel sites of N-acylethanolamine inactivation by fatty acid amide hydrolase-2 Kaczocha, Martin Glaser, Sherrye T Chae, Janiper Brown, Deborah A Deutsch, Dale G J. Biol. Chem. 285:2796-806 17015445 Pubmed 2006 A second fatty acid amide hydrolase with variable distribution among placental mammals Wei, Binqing Q Mikkelsen, Tarjei S McKinney, Michele K Lander, Eric S Cravatt, BF J. Biol. Chem. 281:36569-78 LEFT-TO-RIGHT FAAH2 hydrolyses AEA to AA and ETA Fatty acid amides are a class of lipid transmitters that include the endogenous cannabinoid anandamide (AEA) and the sleep-inducing chemical oleamide. The magnitude and duration of their signalling are controlled by enzymatic hydrolysis mediated by fatty-acid amide hydrolases 1 and 2 (FAAH, H2). Hydrolysis of AEA is described here (Wei et al. 2006). FAAH is localised to the ER membrane whereas FAAH2 is localised to lipid droplets (Kaczocha et al. 2010). Authored: Jassal, Bijay, 2015-05-18 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-05-18 AEA anandamide Reactome DB_ID: 5693752 lipid droplet GENE ONTOLOGY GO:0005811 Reactome Database ID Release 81 5693752 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693752 Reactome R-ALL-5693752 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5693752.4 H2O water Reactome DB_ID: 5693747 Reactome Database ID Release 81 5693747 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693747 Reactome R-ALL-5693747 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5693747.4 COMPOUND C00001 ETA ethanolamine Reactome DB_ID: 5693736 Reactome Database ID Release 81 5693736 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693736 Reactome R-ALL-5693736 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5693736.4 AA Arachidonate arachidonic acid cis-5,8,11,14-Eicosatetraenoic acid Reactome DB_ID: 5693733 Reactome Database ID Release 81 5693733 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693733 Reactome R-ALL-5693733 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-5693733.5 COMPOUND C00219 ACTIVATION FAAH2 Fatty-acid amide hydrolase 2 ecNumber3.5.1.99/ecNumber FAAH2_HUMAN Reactome DB_ID: 5693745 UniProt:Q6GMR7 FAAH2 FAAH2 AMDD FUNCTION Catalyzes the hydrolysis of endogenous amidated lipids like the sleep-inducing lipid oleamide ((9Z)-octadecenamide), the endocannabinoid anandamide (N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine), as well as other fatty amides, to their corresponding fatty acids, thereby regulating the signaling functions of these molecules (PubMed:17015445, PubMed:19926788). Hydrolyzes monounsaturated substrate anandamide preferentially as compared to polyunsaturated substrates.ACTIVITY REGULATION Inhibited by O-aryl carbamates and alpha-keto heterocytes.SUBUNIT Homodimer.TISSUE SPECIFICITY Expressed in kidney, liver, lung, prostate, heart and ovary.SIMILARITY Belongs to the amidase family. UniProt Q6GMR7 1 EQUAL 532 EQUAL Reactome Database ID Release 81 5693745 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693745 Reactome R-HSA-5693745 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5693745.2 Reactome Database ID Release 81 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 81 5693751 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693751 Reactome R-HSA-5693751 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5693751.1 Synthesis of Prostaglandins (PG) and Thromboxanes (TX) The bioactive prostaglandin (PG) signalling molecules, including PGA2, PGE2, PGF2a, and PGI2 (prostacyclin) are synthesised from arachidonic acid and its products by various prostaglandin synthase type enzymes. Prostaglandin H2 (PGH2) is the starting point for the synthesis of Thromboxanes (TXs) (Buczynski et al. 2009, Vance & Vance 2008). PGs and TXs are collectively known as the prostanoids.<br>Two enzymes, PTGS1 and 2 (COX1 and 2) both catalyze the two-step conversion of arachidonic acid to PGH2. PTGS1 is constitutively expressed in many cell types while PTGS2 is induced in response to stress and mediates the syntheses of prostaglandins associated with pain, fever, and inflammation. Aspirin irreversibly inactivates both enzymes (though it acts more efficiently on PTGS1), explaining both its antiinflammatory effects and side effects like perturbed gastic acid secretion. Drugs like celecoxib, by specifically inhibiting PTGS2, have a strong anti-inflammatory effect with fewer side effects. These PTGS2-specific drugs, however, probably because of their effects on the balance of prostaglandin synthesis in platelets and endothelial cells, can also promote blood clot formation (Buczynski et al. 2009; Stables & Gilroy 2011). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 LEFT-TO-RIGHT PTGS2 dimer binds PTGS2 inhibitors While closely similar, PTGS1 and 2 differ sufficiently in the structures of their active sites so that the latter enzyme selectively binds and is inhibited by PTGS2 inhibitors (benzquinamide, carprofen, celecoxib, etodolac, etoricoxib, lumiracoxib, rofecoxib, valdecoxib) (Luong et al. 1996; Smith et al. 2000; Dong et al. 2011). Authored: D'Eustachio, P, 2012-06-05 Reviewed: Rush, MG, 2012-11-10 Edited: D'Eustachio, P, 2012-06-05 PTGS2 dimer PGHS2 dimer Reactome DB_ID: 140491 heme b Reactome DB_ID: 2311355 heme b [ChEBI:26355] heme b heme protoheme IX protoheme haem b (7,12-diethenyl-3,8,13,17-tetramethylporphyrin-2,18-dipropanoato)iron [3,7,12,17-tetramethyl-8,13-divinylporphyrin-2,18-dipropanoato(2-)]iron PROTOPORPHYRIN IX CONTAINING FE ChEBI CHEBI:26355 Reactome Database ID Release 81 2311355 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2311355 Reactome R-ALL-2311355 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2311355.2 1 PTGS2 Prostaglandin G/H synthase 2 precursor Cyclooxygenase -2 COX-2 Prostaglandin-endoperoxide synthase 2 Prostaglandin H2 synthase 2 PGH synthase 2 PGHS-2 PHS II Reactome DB_ID: 61605 UniProt:P35354 PTGS2 PTGS2 COX2 FUNCTION Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate, with a particular role in the inflammatory response (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593, PubMed:11939906, PubMed:19540099). The cyclooxygenase activity oxygenates arachidonate (AA, C20:4(n-6)) to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide PGH2, the precursor of all 2-series prostaglandins and thromboxanes (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593). This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593). Similarly catalyzes successive cyclooxygenation and peroxidation of dihomo-gamma-linoleate (DGLA, C20:3(n-6)) and eicosapentaenoate (EPA, C20:5(n-3)) to corresponding PGH1 and PGH3, the precursors of 1- and 3-series prostaglandins (PubMed:11939906, PubMed:19540099). In an alternative pathway of prostanoid biosynthesis, converts 2-arachidonoyl lysophopholipids to prostanoid lysophopholipids, which are then hydrolyzed by intracellular phospholipases to release free prostanoids (PubMed:27642067). Metabolizes 2-arachidonoyl glycerol yielding the glyceryl ester of PGH2, a process that can contribute to pain response (PubMed:22942274). Generates lipid mediators from n-3 and n-6 polyunsaturated fatty acids (PUFAs) via a lipoxygenase-type mechanism. Oxygenates PUFAs to hydroperoxy compounds and then reduces them to corresponding alcohols (PubMed:11034610, PubMed:11192938, PubMed:9048568, PubMed:9261177). Plays a role in the generation of resolution phase interaction products (resolvins) during both sterile and infectious inflammation (PubMed:12391014). Metabolizes docosahexaenoate (DHA, C22:6(n-3)) to 17R-HDHA, a precursor of the D-series resolvins (RvDs) (PubMed:12391014). As a component of the biosynthetic pathway of E-series resolvins (RvEs), converts eicosapentaenoate (EPA, C20:5(n-3)) primarily to 18S-HEPE that is further metabolized by ALOX5 and LTA4H to generate 18S-RvE1 and 18S-RvE2 (PubMed:21206090). In vascular endothelial cells, converts docosapentaenoate (DPA, C22:5(n-3)) to 13R-HDPA, a precursor for 13-series resolvins (RvTs) shown to activate macrophage phagocytosis during bacterial infection (PubMed:26236990). In activated leukocytes, contributes to oxygenation of hydroxyeicosatetraenoates (HETE) to diHETES (5,15-diHETE and 5,11-diHETE) (PubMed:22068350, PubMed:26282205). During neuroinflammation, plays a role in neuronal secretion of specialized preresolving mediators (SPMs) 15R-lipoxin A4 that regulates phagocytic microglia (By similarity).ACTIVITY REGULATION The cyclooxygenase activity is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, flurbiprofen, celecoxib, flufenamic, mefenamic and tolfenamic acids as well as by hydroperoxide scavenger erythrocyte glutathione peroxidase GPX1 (PubMed:26859324, PubMed:27226593, PubMed:7592599, PubMed:9048568). Aspirin triggers enzyme acetylation turning off its ability to generate proinflammatory 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 81 61605 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=61605 Reactome R-HSA-61605 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-61605.1 2 Reactome Database ID Release 81 140491 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140491 Reactome R-HSA-140491 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-140491.1 Converted from EntitySet in Reactome PTGS2 inhibitors COX-2 inhibitors Reactome DB_ID: 9716714 benzquinamide Reactome DB_ID: 9716734 benzquinamide [Guide to Pharmacology:7124] benzquinamide P-2647 Quantril&reg; Guide to Pharmacology 7124 Reactome Database ID Release 81 9716734 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716734 Reactome R-ALL-9716734 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716734.1 ChEBI 27662 carprofen Reactome DB_ID: 9716728 carprofen [Guide to Pharmacology:7141] carprofen Ro-205720000 Guide to Pharmacology 7141 Reactome Database ID Release 81 9716728 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716728 Reactome R-ALL-9716728 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716728.1 ChEBI 364453 celecoxib Reactome DB_ID: 9716723 celecoxib [Guide to Pharmacology:2892] celecoxib Celecox&reg; Onsenal&reg; SC-58635 SC58635 Guide to Pharmacology 2892 Reactome Database ID Release 81 9716723 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716723 Reactome R-ALL-9716723 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716723.1 ChEBI 41423 etodolac Reactome DB_ID: 9716725 etodolac [Guide to Pharmacology:7185] etodolac AY-24236 Lodine&reg; Guide to Pharmacology 7185 Reactome Database ID Release 81 9716725 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716725 Reactome R-ALL-9716725 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716725.1 ChEBI 60371 etoricoxib Reactome DB_ID: 9716732 etoricoxib [Guide to Pharmacology:2896] etoricoxib Arcoxia&reg; MK0663 MK 0663 MK-0663 Guide to Pharmacology 2896 Reactome Database ID Release 81 9716732 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716732 Reactome R-ALL-9716732 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716732.1 ChEBI 6339 lumiracoxib Reactome DB_ID: 9716731 lumiracoxib [Guide to Pharmacology:2897] lumiracoxib Prexige&reg; Guide to Pharmacology 2897 Reactome Database ID Release 81 9716731 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716731 Reactome R-ALL-9716731 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716731.1 ChEBI 73044 rofecoxib Reactome DB_ID: 9716716 rofecoxib [Guide to Pharmacology:2893] rofecoxib Ceoxx&reg; MK 966 Vioxx&reg; Guide to Pharmacology 2893 Reactome Database ID Release 81 9716716 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716716 Reactome R-ALL-9716716 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716716.1 ChEBI 8887 valdecoxib Reactome DB_ID: 9716713 valdecoxib [Guide to Pharmacology:2894] valdecoxib Bextra&reg; SC-65872 Guide to Pharmacology 2894 Reactome Database ID Release 81 9716713 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716713 Reactome R-ALL-9716713 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716713.1 ChEBI 63634 Reactome Database ID Release 81 9716714 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9716714 Reactome R-ALL-9716714 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9716714.1 PTGS2 dimer:PTGS2 inhibitors Reactome DB_ID: 2309778 1 1 Reactome Database ID Release 81 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 81 2309779 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309779 Reactome R-HSA-2309779 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2309779.4 10966456 Pubmed 2000 Cyclooxygenases: structural, cellular, and molecular biology Smith, William L DeWitt, David L Garavito, R Michael Annu Rev Biochem 69:145-82 8901870 Pubmed 1996 Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2 Luong, Christine Miller, Aaron Barnett, Jim Chow, Joan Ramesha, Chakk Browner, Michelle F Nat. Struct. Biol. 3:927-33 21467029 Pubmed 2011 Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer Dong, Liang Vecchio, Alex J Sharma, Narayan P Jurban, Brice J Malkowski, Michael G Smith, William L J. Biol. Chem. 286:19035-46 LEFT-TO-RIGHT ASA- acetylates PTGS1 The ionized form of aspirin, acetylsalicylate (ASA-) reacts spontaneously with one subunit of PTGS1 dimer to acetylate serine residue 516. The modified enzyme is no longer capable of catalyzing the conversion of arachidonic acid to PGH2. The identity of the acetylated residue is inferred from data for the humann PTGS2 enzyme (Lecomte et al. 1994) and the ovine PGHS1 enzyme (Loll et al. 1995). Authored: D'Eustachio, P, 2012-06-07 Reviewed: Rush, MG, 2012-11-10 Edited: D'Eustachio, P, 2012-06-07 COX1 PTGS1 dimer PGHS1 homodimer Reactome DB_ID: 428986 1 COX1 PTGS1 Prostaglandin G/H synthase 1 PGH1_HUMAN Cyclooxygenase-1 Reactome DB_ID: 428931 UniProt:P23219 PTGS1 PTGS1 COX1 FUNCTION Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate, with a particular role in the inflammatory response. The cyclooxygenase activity oxygenates arachidonate (AA, C20:4(n-6)) to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide PGH2, the precursor of all 2-series prostaglandins and thromboxanes. This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:7947975). Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells (Probable).ACTIVITY REGULATION The cyclooxygenase activity is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen, flurbiprofen, ketoprofen, naproxen, flurbiprofen, anirolac, fenclofenac and diclofenac.PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Homodimer.MISCELLANEOUS The conversion of arachidonate to prostaglandin H2 is a 2 step reaction: a cyclooxygenase (COX) reaction which converts arachidonate to prostaglandin G2 (PGG2) and a peroxidase reaction in which PGG2 is reduced to prostaglandin H2 (PGH2). The cyclooxygenase reaction occurs in a hydrophobic channel in the core of the enzyme. The peroxidase reaction occurs at a heme-containing active site located near the protein surface. The nonsteroidal anti-inflammatory drugs (NSAIDs) binding site corresponds to the cyclooxygenase active site.MISCELLANEOUS Conversion of arachidonate to prostaglandin H2 is mediated by 2 different isozymes: the constitutive PTGS1 and the inducible PTGS2. PTGS1 is expressed constitutively and generally produces prostanoids acutely in response to hormonal stimuli to fine-tune physiological processes requiring instantaneous, continuous regulation (e.g. hemostasis). PTGS2 is inducible and typically produces prostanoids that mediate responses to physiological stresses such as infection and inflammation.MISCELLANEOUS PTGS1 and PTGS2 are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin and ibuprofen. Aspirin is able to produce an irreversible inactivation of the enzyme through a serine acetylation. Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. PTGS2 is the principal isozyme responsible for production of inflammatory prostaglandins. New generation PTGSs inhibitors strive to be selective for PTGS2, to avoid side effects such as gastrointestinal complications and ulceration.SIMILARITY Belongs to the prostaglandin G/H synthase family. UniProt P23219 24 EQUAL 599 EQUAL Reactome Database ID Release 81 428931 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428931 Reactome R-HSA-428931 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428931.1 2 Reactome Database ID Release 81 428986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428986 Reactome R-HSA-428986 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428986.1 ASA- acetylsalicylate(1-) Reactome DB_ID: 2314693 acetylsalicylate [ChEBI:13719] acetylsalicylate ChEBI CHEBI:13719 Reactome Database ID Release 81 2314693 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314693 Reactome R-ALL-2314693 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2314693.4 Ac-PTGS1 dimer Reactome DB_ID: 2314695 1 1 Ac-PTGS1 O-acetyl-L-serine-PTGS1 Reactome DB_ID: 2314694 529 EQUAL O-acetyl-L-serine MOD MOD:00369 24 EQUAL 599 EQUAL Reactome Database ID Release 81 2314694 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314694 Reactome R-HSA-2314694 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314694.1 1 Reactome Database ID Release 81 2314695 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314695 Reactome R-HSA-2314695 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314695.1 ST salicylate Reactome DB_ID: 2314690 salicylate [ChEBI:30762] salicylate sal o-hydroxybenzoate 2-hydroxybenzoic acid ion(1-) ChEBI CHEBI:30762 Reactome Database ID Release 81 2314690 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314690 Reactome R-ALL-2314690 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2314690.3 Reactome Database ID Release 81 2314678 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314678 Reactome R-HSA-2314678 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314678.4 7552725 Pubmed 1995 The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase Loll, Patrick J Picot, Daniel Garavito, R Michael Nat. Struct. Biol. 2:637-43 8175750 Pubmed 1994 Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin Lecomte, Marc Laneuville, Odette Ji, Chuan DeWitt, David L Smith, William L J. Biol. Chem. 269:13207-15 LEFT-TO-RIGHT ASA- acetylates PTGS2 The ionized form of aspirin, acetylsalicylate (ASA-) reacts spontaneously with one subunit of PTGS2 dimer (Dong et al. 2011) to acetylate serine residue 516 (Lecomte et al. 1994). The modified enzyme is no longer capable of catalyzing the conversion of arachidonic acid to PGH2, but acquires the ability to convert it to 15R-HETE. Authored: D'Eustachio, P, 2012-06-07 Reviewed: Rush, MG, 2012-11-10 Edited: D'Eustachio, P, 2012-06-07 Ac-PTGS2 dimer Reactome DB_ID: 2314687 1 Ac-PTGS2 O-acetyl-L-serine-PTGS2 acetyl-PTGS2 Cyclooxygenase -2 Ac-COX-2 Ac-Prostaglandin-endoperoxide synthase 2 Ac-Prostaglandin H2 synthase 2 Ac-PGH synthase 2 Ac-PGHS-2 Ac-PHS II Reactome DB_ID: 2161824 516 EQUAL 18 EQUAL 604 EQUAL Reactome Database ID Release 81 2161824 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161824 Reactome R-HSA-2161824 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161824.1 1 1 Reactome Database ID Release 81 2314687 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314687 Reactome R-HSA-2314687 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314687.1 Reactome Database ID Release 81 2314686 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314686 Reactome R-HSA-2314686 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314686.3 LEFT-TO-RIGHT 1.14.99.1 Arachidonic acid oxidised to PGG2 Arachidonic acid is oxidised to PGG2 by PTGS1 Prostaglandin G/H synthase PTGS1 exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The cyclooxygenase function catalyzes the initial conversion of arachidonic acid to an intermediate, prostaglandin G2 (PGG2) (Hamberg et al. 1974, Nugteren 1973). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-05-28 09:06:10 Edited: Jassal, Bijay, 2008-05-19 O2 Oxygen dioxygen Reactome DB_ID: 113534 dioxygen [ChEBI:15379] dioxygen ChEBI CHEBI:15379 Reactome Database ID Release 81 113534 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113534 Reactome R-ALL-113534 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113534.3 COMPOUND C00007 2 PGG2 prostaglandin G2 Reactome DB_ID: 140357 prostaglandin G2 [ChEBI:27647] prostaglandin G2 ChEBI CHEBI:27647 Reactome Database ID Release 81 140357 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140357 Reactome R-ALL-140357 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-140357.3 ACTIVATION GENE ONTOLOGY GO:0004666 Reactome Database ID Release 81 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 81 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 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 4776443 Pubmed 1973 Isolation and properties of intermediates in prostaglandin biosynthesis Nugteren, DH Hazelhof, E Biochim Biophys Acta 326:448-61 LEFT-TO-RIGHT PTGS1 dimer binds PTGS1 Inhibitors Prostaglandins are involved in physiological functions such as protecting the stomach mucosa, platelet aggregation and regulating kidney function. They also play pathological roles in inflammation, fever and pain (Ricciotti & FitzGerald 2011). Cyclooxygenase enzymes mediate the production of protaglandins. Prostaglandin G/H synthase 1 (PTGS1, cyclooxygenase 1, COX1) is a mainly constitutively expressed enzyme that acts in a 'housekeeping' fashion producing prostaglandins for physiological functions whereas prostaglandin G/H synthase 2 (PTGS2, cyclooxygenase 2, COX2) is an inducible form which mediates protaglandin production for inflammation.<br><br>In 1971, John R Vane showed that the pharmacological actions of aspirin and similar nonsteroid anti-inflammatory drugs (NSAIDs) were due to the inhibition of cyclooxygenase (Vane 1971). Thus, aspirin-like drugs exert their anti-inflammatory, antipyretic and analgesic effects by the inhibition of cyclooxygenase (Vane & Botting 1997, Botting 2006). The beneficial actions of NSAIDs can be associated with inhibition of COX2 whereas their harmful side effects are associated with inhibition of COX1 therefore developing drugs with a high COX2 specificity is advantageous (Cryer & Feldman 1998, Warner et al. 1999, García-Rayado et al. 2018, Saad & Matthew 2020).<br><br>Most NSAIDs possess some or all of antipyretic, analgesic and anti-inflammatory properties and are used to treat rheumatic and osteoarthritic conditions, pain, inflammation and fever (Botting 2006, Crofford 2013). Authored: Jassal, Bijay, 2020-03-05 Reviewed: Huddart, Rachel, 2022-03-01 Edited: Jassal, Bijay, 2020-03-05 Edited: Matthews, Lisa, 2022-05-10 Converted from EntitySet in Reactome PTGS1 Inhibitors Reactome DB_ID: 9677343 meloxicam Mobic&reg; UHAC-62XX Reactome DB_ID: 9677371 meloxicam [Guide to Pharmacology:7220] meloxicam Mobic&reg; UHAC-62XX Guide to Pharmacology 7220 Reactome Database ID Release 81 9677371 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677371 Reactome R-ALL-9677371 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677371.1 indomethacin Indocid&reg; Indocin&reg; Reactome DB_ID: 9677460 indomethacin [Guide to Pharmacology:1909] indomethacin Indocid&reg; Indocin&reg; Guide to Pharmacology 1909 Reactome Database ID Release 81 9677460 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677460 Reactome R-ALL-9677460 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677460.1 R-805 nimesulide Reactome DB_ID: 9677334 nimesulide [Guide to Pharmacology:7401] nimesulide R-805 Guide to Pharmacology 7401 Reactome Database ID Release 81 9677334 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677334 Reactome R-ALL-9677334 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677334.1 APAP paracetamol acetaminophen Panadol&reg; Tylenol&reg; Reactome DB_ID: 9677362 paracetamol [Guide to Pharmacology:5239] paracetamol acetaminophen Panadol&reg; Tylenol&reg; Guide to Pharmacology 5239 Reactome Database ID Release 81 9677362 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677362 Reactome R-ALL-9677362 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677362.1 ChEBI 46195 bromfenac Reactome DB_ID: 9677640 bromfenac [Guide to Pharmacology:7131] bromfenac AHR-10282B Bromday&reg; Prolensa&reg; Xibrom&reg; Guide to Pharmacology 7131 Reactome Database ID Release 81 9677640 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677640 Reactome R-ALL-9677640 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677640.1 fenoprofen Reactome DB_ID: 9677638 fenoprofen [Guide to Pharmacology:4820] fenoprofen fenoprofen calcium Nalfon&reg; Guide to Pharmacology 4820 Reactome Database ID Release 81 9677638 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677638 Reactome R-ALL-9677638 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677638.1 Reactome Database ID Release 81 9677343 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677343 Reactome R-ALL-9677343 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677343.1 PTGS1 dimer:PTGS1 Inhibitors Reactome DB_ID: 9677354 1 1 Reactome Database ID Release 81 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 81 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 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 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 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 21508345 Pubmed 2011 Prostaglandins and inflammation Ricciotti, Emanuela FitzGerald, Garret A Arterioscler. Thromb. Vasc. Biol. 31:986-1000 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 LEFT-TO-RIGHT 1.14.99.1 Arachidonic acid oxidised to PGG2 Arachidonic acid is oxidised to PGG2 by PTGS2 Prostaglandin G/H synthase PTGS2 exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The cyclooxygenase function catalyzes the initial conversion of arachidonic acid to an intermediate, prostaglandin G2 (PGG2) (Hamberg et al. 1974, Nugteren 1973). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-05-28 09:06:10 Edited: Jassal, Bijay, 2008-05-19 2 ACTIVATION Reactome Database ID Release 81 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 81 2309787 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309787 Reactome R-HSA-2309787 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2309787.1 LEFT-TO-RIGHT 1.11.1.7 PGG2 is reduced to PGH2 by PTGS1 Peroxidative reduction of PGG2 to PGH2 Prostaglandin G/H synthase 1 (PTGS1) exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The peroxidase function converts prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) via a two-electron reduction (Hamberg et al. 1973, Hla & Neilson 1992, Swinney et al. 1997, Barnett et al. 1994). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 H+ hydron Reactome DB_ID: 156540 hydron [ChEBI:15378] hydron ChEBI CHEBI:15378 Reactome Database ID Release 81 156540 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=156540 Reactome R-ALL-156540 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-156540.3 COMPOUND C00080 2 e- electron Reactome DB_ID: 76342 electron [ChEBI:10545] electron ChEBI CHEBI:10545 Reactome Database ID Release 81 76342 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76342 Reactome R-ALL-76342 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-76342.3 2 H2O water Reactome DB_ID: 113519 Reactome Database ID Release 81 113519 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113519 Reactome R-ALL-113519 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113519.3 COMPOUND C00001 PGH2 (5Z,13E)-(15S)-9alpha,11alpha-Epidioxy-15-hydroxyprosta-5,13-dienoate prostaglandin H2 Reactome DB_ID: 30138 prostaglandin H2 [ChEBI:15554] prostaglandin H2 ChEBI CHEBI:15554 Reactome Database ID Release 81 30138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=30138 Reactome R-ALL-30138 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-30138.3 COMPOUND C00427 ACTIVATION GENE ONTOLOGY GO:0004601 Reactome Database ID Release 81 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 81 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 1380156 Pubmed 1992 Human cyclooxygenase-2 cDNA Hla, T Neilson, K Proc Natl Acad Sci U S A 89:7384-8 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 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 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 LEFT-TO-RIGHT 1.11.1.7 PGG2 is reduced to PGH2 by PTGS2 Peroxidative reduction of PGG2 to PGH2 Prostaglandin G/H synthase 2 (PTGS2) exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The peroxidase function converts prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) via a two-electron reduction (Hamberg et al. 1973, Hla & Neilson 1992, Swinney et al. 1997, Barnett et al. 1994). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 2 2 ACTIVATION Reactome Database ID Release 81 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 81 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 ACTIVATION Reactome Database ID Release 81 5362144 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5362144 Reactome R-HSA-5362144 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5362144.1 MNA N1MNA 1-methylnicotinamide N-1-methylnicotinamide NMN Reactome DB_ID: 549282 1-methylnicotinamide [ChEBI:16797] 1-methylnicotinamide ChEBI CHEBI:16797 Reactome Database ID Release 81 549282 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=549282 Reactome R-ALL-549282 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-549282.3 INHIBITION Reactome Database ID Release 81 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 LEFT-TO-RIGHT PGH2 diffuses from the endoplasmic reticulum lumen to the cytosol PGH2 moves from the endoplasmic reticulum to the cytosol. The mechanism of this movement has not been determined and could could simply be diffusion through the ER membrane. Authored: D'Eustachio, P, 2012-06-04 Reviewed: Rush, MG, 2012-11-10 PGH2 (5Z,13E)-(15S)-9alpha,11alpha-Epidioxy-15-hydroxyprosta-5,13-dienoate prostaglandin H2 Reactome DB_ID: 265283 Reactome Database ID Release 81 265283 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265283 Reactome R-ALL-265283 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-265283.3 COMPOUND C00427 Reactome Database ID Release 81 2299725 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2299725 Reactome R-HSA-2299725 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2299725.3 20346915 Pubmed 2010 The prostaglandin transporter PGT transports PGH(2) Chi, Yuling Schuster, Victor L Biochem. Biophys. Res. Commun. 395:168-72 LEFT-TO-RIGHT PGH2 is reduced to PGF2a by AKR1C3 Aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS is responsible for the reduction of prostaglandin H2 (PGH2) to prostaglandin F2alpha (PGF2a) (Suzuki-Yamamoto et al. 1999, Komoto et al. 2004, Komoto et al. 2006). There is an additional way of achieving this reaction involving the prostamide/prostaglandin F synthase, FAM213B and thioredoxin (TRX). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 H+ proton hydron Reactome DB_ID: 70106 Reactome Database ID Release 81 70106 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70106 Reactome R-ALL-70106 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-70106.4 COMPOUND C00080 TPNH NADPH Reactome DB_ID: 29364 NADPH(4-) [ChEBI:57783] NADPH(4-) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH NADPH tetraanion ChEBI CHEBI:57783 Reactome Database ID Release 81 29364 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29364 Reactome R-ALL-29364 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29364.3 COMPOUND C00005 PGF2a prostaglandin F2alpha Reactome DB_ID: 879535 prostaglandin F2alpha [ChEBI:15553] prostaglandin F2alpha ChEBI CHEBI:15553 Reactome Database ID Release 81 879535 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879535 Reactome R-ALL-879535 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-879535.3 TPN NADP+ NADP NADP(+) Nicotinamide adenine dinucleotide phosphate beta-Nicotinamide adenine dinucleotide phosphate Triphosphopyridine nucleotide NADP(3-) Reactome DB_ID: 29366 NADP(3-) [ChEBI:58349] NADP(3-) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADP(+) NADP trianion ChEBI CHEBI:58349 Reactome Database ID Release 81 29366 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29366 Reactome R-ALL-29366 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29366.4 COMPOUND C00006 ACTIVATION AKR1C3 Aldo-keto reductase family 1 member C3 AK1C3_HUMAN Reactome DB_ID: 2142714 UniProt:P42330 AKR1C3 AKR1C3 DDH1 HSD17B5 KIAA0119 PGFS FUNCTION Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids. Acts as a NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductase on the steroid nucleus and side chain and regulates the metabolism of androgens, estrogens and progesterone (PubMed:10622721, PubMed:11165022, PubMed:7650035, PubMed:9415401, PubMed:9927279). Displays the ability to catalyze both oxidation and reduction in vitro, but most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentration of NADPH (PubMed:14672942, PubMed:11165022). Acts preferentially as a 17-ketosteroid reductase and has the highest catalytic efficiency of the AKR1C enzyme for the reduction of delta4-androstenedione to form testosterone (PubMed:20036328). Reduces prostaglandin (PG) D2 to 11beta-prostaglandin F2, progesterone to 20alpha-hydroxyprogesterone and estrone to 17beta-estradiol (PubMed:15047184, PubMed:20036328, PubMed:10622721, PubMed:11165022, PubMed:10998348, PubMed:19010934). Catalyzes the transformation of the potent androgen dihydrotestosterone (DHT) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol) (PubMed:10998348, PubMed:14672942, PubMed:11165022, PubMed:7650035, PubMed:9415401, PubMed:10557352). Displays also retinaldehyde reductase activity toward 9-cis-retinal (PubMed:21851338).ACTIVITY REGULATION Strongly inhibited by nonsteroidal anti-inflammatory drugs (NSAID) including flufenamic acid and indomethacin. Also inhibited by the flavinoid, rutin, and by selective serotonin inhibitors (SSRIs) (PubMed:14979715, PubMed:14996743, PubMed:10557352). The oxidation reaction is inhibited by low micromolar concentrations of NADPH (PubMed:14672942).PATHWAY Steroid metabolism.TISSUE SPECIFICITY Expressed in many tissues including adrenal gland, brain, kidney, liver, lung, mammary gland, placenta, small intestine, colon, spleen, prostate and testis. High expression in prostate and mammary gland. In the prostate, higher levels in epithelial cells than in stromal cells. In the brain, expressed in medulla, spinal cord, frontotemporal lobes, thalamus, subthalamic nuclei and amygdala. Weaker expression in the hippocampus, substantia nigra and caudate.SIMILARITY Belongs to the aldo/keto reductase family. UniProt P42330 1 EQUAL 323 EQUAL Reactome Database ID Release 81 2142714 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142714 Reactome R-HSA-2142714 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142714.1 GENE ONTOLOGY GO:0036130 Reactome Database ID Release 81 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 81 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 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 14979715 Pubmed 2004 Crystal structure of human prostaglandin F synthase (AKR1C3) Komoto, J Yamada, T Watanabe, K Takusagawa, F Biochemistry 43:2188-98 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 LEFT-TO-RIGHT 1.11.1 PGH2 is reduced to PGF2a by FAM213B Prostamide/prostaglandin F synthase, FAM213B and thioredoxin (TXN) are the proteins involved in the reduction of prostaglandin H2 (PGH2) to prostaglandin F2alpha (PGF2a) (Moriuchi et al. 2008, Yoshikawa et al. 2011). This reaction has been inferred from an event in mice. An additional way of achieving this reaction involves the protein aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 TXN-S2H2 Thioredoxin thioredoxin dithiol Reduced thioredoxin Reactome DB_ID: 2142774 thioredoxin dithiol [ChEBI:15967] thioredoxin dithiol ChEBI CHEBI:15967 Reactome Database ID Release 81 2142774 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142774 Reactome R-ALL-2142774 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142774.3 TXN-S2 Thioredoxin disulphide thioredoxin disulfide Oxidised thioredoxin Reactome DB_ID: 2142833 thioredoxin disulfide [ChEBI:18191] thioredoxin disulfide ChEBI CHEBI:18191 Reactome Database ID Release 81 2142833 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142833 Reactome R-ALL-2142833 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142833.3 ACTIVATION FAM213B Prostamide/prostaglandin F synthase C1orf93 PGFS_HUMAN Reactome DB_ID: 2142703 UniProt:Q8TBF2 PRXL2B PRXL2B C1orf93 FAM213B FUNCTION Catalyzes the reduction of prostaglandin-ethanolamide H(2) (prostamide H(2)) to prostamide F(2alpha) with NADPH as proton donor. Also able to reduce prostaglandin H(2) to prostaglandin F(2alpha) (By similarity).SIMILARITY Belongs to the peroxiredoxin-like PRXL2 family. Prostamide/prostaglandin F synthase subfamily. UniProt Q8TBF2 1 EQUAL 198 EQUAL Reactome Database ID Release 81 2142703 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142703 Reactome R-HSA-2142703 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142703.1 GENE ONTOLOGY GO:0008379 Reactome Database ID Release 81 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 81 2161612 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161612 Reactome R-HSA-2161612 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161612.2 20950588 Pubmed 2011 Preferential localization of prostamide/prostaglandin F synthase in myelin sheaths of the central nervous system Yoshikawa, K Takei, S Hasegawa-Ishii, S Chiba, Y Furukawa, A Kawamura, N Hosokawa, M Woodward, DF Watanabe, K Shimada, A Brain Res 1367:22-32 18006499 Pubmed 2008 Molecular characterization of a novel type of prostamide/prostaglandin F synthase, belonging to the thioredoxin-like superfamily Moriuchi, H Koda, N Okuda-Ashitaka, E Daiyasu, H Ogasawara, K Toh, H Ito, S Woodward, DF Watanabe, K J Biol Chem 283:792-801 LEFT-TO-RIGHT 5.3.99.3 PGH2 is isomerised to PGE2 by PTGES Prostaglandin E synthase (PTGES) requires glutathione (GSH) as an essential cofactor for its enzymatic activity, and together they isomerise prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2) (Jegerschold et al. 2008). After PGH2 has been produced by the prostaglandin G/H synthases (PTGS1 and 2) on the lumenal side of the endoplasmic reticulum, it diffuses through the membrane to the active site of PTGES located on the cytoplasmic side. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGE2 prostaglandin E2 Reactome DB_ID: 265287 prostaglandin E2 [ChEBI:15551] prostaglandin E2 ChEBI CHEBI:15551 Reactome Database ID Release 81 265287 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265287 Reactome R-ALL-265287 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-265287.3 ACTIVATION PTGES trimer Prostaglandin E synthase homotrimer Reactome DB_ID: 2142686 PTGES Prostaglandin E synthase PTGES_HUMAN Reactome DB_ID: 2142717 UniProt:O14684 PTGES PTGES MGST1L1 MPGES1 PGES PIG12 FUNCTION Terminal enzyme of the cyclooxygenase (COX)-2-mediated prostaglandin E2 (PGE2) biosynthetic pathway. Catalyzes the glutathione-dependent oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2) in response to inflammatory stimuli (PubMed:18682561, PubMed:10377395, PubMed:12672824, PubMed:12460774, PubMed:10869354, PubMed:12244105). Plays a key role in inflammation response, fever and pain (By similarity). Catalyzes also the oxidoreduction of endocannabinoids into prostaglandin glycerol esters and PGG2 into 15-hydroperoxy-PGE2 (PubMed:12244105, PubMed:12672824). In addition, displays low glutathione transferase and glutathione-dependent peroxidase activities, toward 1-chloro-2,4-dinitrobenzene and 5-hydroperoxyicosatetraenoic acid (5-HPETE), respectively (PubMed:12672824).ACTIVITY REGULATION Induced by interleukin IL1B.PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Homotrimer.INDUCTION Induced by the interleukin IL1B (PubMed:10377395, PubMed:10760517). Induced By p53/TP53 (PubMed:9305847).SIMILARITY Belongs to the MAPEG family. UniProt O14684 1 EQUAL 152 EQUAL Reactome Database ID Release 81 2142717 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142717 Reactome R-HSA-2142717 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142717.1 3 GSH Reduced glutathione glutathione 5-L-Glutamyl-L-cysteinylglycine N-(N-gamma-L-Glutamyl-L-cysteinyl)glycine gamma-L-Glutamyl-L-cysteinyl-glycine Reactome DB_ID: 2239524 glutathione [ChEBI:16856] glutathione ChEBI CHEBI:16856 Reactome Database ID Release 81 2239524 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2239524 Reactome R-ALL-2239524 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2239524.3 COMPOUND C00051 3 Reactome Database ID Release 81 2142686 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142686 Reactome R-HSA-2142686 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142686.1 GENE ONTOLOGY GO:0050220 Reactome Database ID Release 81 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 81 2161660 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161660 Reactome R-HSA-2161660 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161660.3 18682561 Pubmed 2008 Structural basis for induced formation of the inflammatory mediator prostaglandin E2 Jegerschöld, C Pawelzik, SC Purhonen, P Bhakat, P Gheorghe, KR Gyobu, N Mitsuoka, K Morgenstern, R Jakobsson, PJ Hebert, H Proc Natl Acad Sci U S A 105:11110-5 LEFT-TO-RIGHT 5.3.99.3 Prostaglandin E synthase isomerizes PGH2 to PGE2 Prostaglandin E2 (PGE2) is the most abundant prostanoid in the body and is a major mediator of inflammation in diseases such as osteoarthritis and rheumatoid arthritis. The product of arachidonic acid, prostaglandin H2 (PGH2) serves as the substrate for the isomerization to PGE2. The conversion is carried out by prostaglandin E synthases. Of the three forms, two are predominanly cytosolic. Prostaglandin E synthase 3 (PTGES3) is also called cytosolic prostaglandin E2 synthase (cPGES). Prostaglandin E synthase 2 (mPGES-2, PTGES2) is synthesized as a Golgi membrane-associated protein which undergoes a spontaneous cleavage of the N-terminal hydrophobic domain leading to a truncated mature cytosolic protein. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 ACTIVATION Converted from EntitySet in Reactome PTGES2(88-377), PTGES3 Reactome DB_ID: 8864254 PGES2_HUMAN PTGES2(88-377) Prostaglandin E synthase 2 ecNumber4.1.2.-/ecNumber ecNumber5.3.99.3/ecNumber Reactome DB_ID: 5423596 UniProt:Q9H7Z7 PTGES2 PTGES2 C9orf15 PGES2 FUNCTION Isomerase that catalyzes the conversion of PGH2 into the more stable prostaglandin E2 (PGE2) (in vitro) (PubMed:12804604, PubMed:18198127, PubMed:17585783). The biological function and the GSH-dependent property of PTGES2 is still under debate (PubMed:18198127, PubMed:17585783). In vivo, PTGES2 could form a complex with GSH and heme and would not participate in PGE2 synthesis but would catalyze the degradation of prostaglandin E2 H2 (PGH2) to 12(S)-hydroxy-5(Z),8(E),10(E)-heptadecatrienoic acid (HHT) and malondialdehyde (MDA) (PubMed:17585783) (By similarity).ACTIVITY REGULATION Isomerase activity is increased by sulfhydril compounds. Dithiothreitol (DTT) is most effective, followed by dihydrolipoic acid, glutathione (GSH) and 2-mercaptoethanol.PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Homodimer. May interact with CEBPB (By similarity). Interacts with EXOSC10.TISSUE SPECIFICITY Widely expressed. Expressed in the heart, including apex, inter-ventricular septum, both atria and ventricles, but not in the aorta. Also expressed in fetal heart. Detected in various regions of the brain: cerebellum; occipital, frontal and parietal lobes. Also expressed in the lymph nodes, skeletal muscle, kidney and trachea, but not in the thymus or lung. Overexpressed in colorectal cancer.PTM Synthesized as a Golgi membrane-associated protein, and the proteolytic removal of the N-terminal hydrophobic domain leads to the formation of a mature cytosolic enzyme.SIMILARITY Belongs to the GST superfamily.CAUTION It is not known if heme and GST are required for prostaglandin synthase activity. The protein copurifies with heme and GST when DTT is omitted during the purification procedure. The GSH-heme complex-bound enzyme has been proposed to act as a lyase and catalyze the degradation of prostaglandin E2 H2 (PGH2) to 12(S)-hydroxy-5(Z),8(E),10(E)-heptadecatrienoic acid (HHT) and malondialdehyde (MDA). According to PubMed:18198127, boiling the enzyme leads to loss of prostaglandin synthase activity, but does not eliminate the lyase activity. Besides, free heme can catalyze the formation of 12L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) (PubMed:18198127). A more recent study demonstrates the GSH-dependent property of PTGES2, DTT dissociates the bound heme to produce active PGE2 synthase in vitro (By similarity). PTGES2 can only catalyzes PGE2 synthesis in the free state as an enzyme, while in vivo it forms a complex with heme and does not participate in PGE2 synthesis (By similarity). In agreement with this study, the in vivo evidence from PTGES2 deficient mice do not show that this protein is responsible for the PGE2 production under basal or pathophysiological conditions (By similarity). UniProt Q9H7Z7 88 EQUAL 377 EQUAL Reactome Database ID Release 81 5423596 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5423596 Reactome R-HSA-5423596 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5423596.2 cPGES PTGES3 Prostaglandin E synthase 3 Reactome DB_ID: 265269 UniProt:Q15185 PTGES3 PTGES3 P23 TEBP FUNCTION Cytosolic prostaglandin synthase that catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2) (PubMed:10922363). Molecular chaperone that localizes to genomic response elements in a hormone-dependent manner and disrupts receptor-mediated transcriptional activation, by promoting disassembly of transcriptional regulatory complexes (PubMed:11274138, PubMed:12077419). Facilitates HIF alpha proteins hydroxylation via interaction with EGLN1/PHD2, leading to recruit EGLN1/PHD2 to the HSP90 pathway (PubMed:24711448).PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Binds to the progesterone receptor (PubMed:8114727). Interacts with TERT; the interaction, together with HSP90AA1, is required for correct assembly and stabilization of the telomerase holoenzyme complex (PubMed:11274138). Interacts (via PXLE motif) with EGLN1/PHD2, recruiting EGLN1/PHD2 to the HSP90 pathway to facilitate HIF alpha proteins hydroxylation (PubMed:24711448). Interacts with HSP90AA1, FLCN, FNIP1 and FNIP2 (PubMed:27353360).DOMAIN The PXLE motif mediates interaction with EGLN1/PHD2.SIMILARITY Belongs to the p23/wos2 family. UniProt Q15185 1 EQUAL 160 EQUAL Reactome Database ID Release 81 265269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265269 Reactome R-HSA-265269 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265269.1 Reactome Database ID Release 81 8864254 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8864254 Reactome R-HSA-8864254 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8864254.2 Reactome Database ID Release 81 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 81 265295 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265295 Reactome R-HSA-265295 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265295.2 10922363 Pubmed 2000 Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis Tanioka, T Nakatani, Y Semmyo, N Murakami, M Kudo, I J Biol Chem 275:32775-82 12835322 Pubmed 2003 Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2 Murakami, Makoto Nakashima, Karin Kamei, Daisuke Masuda, Seiko Ishikawa, Yukio Ishii, Toshiharu Ohmiya, Yoshihiro Watanabe, Kikuko Kudo, Ichiro J. Biol. Chem. 278:37937-47 LEFT-TO-RIGHT 1.1.1.189 PGE2 is converted to PGF2a by CBR1 Carbonyl reductase (CBR1) aka prostaglandin 9-keto reductase inactivates prostaglandin E2 (PGE2) by converting it to prostaglandin F2alpha (PGF2a) (Wermuth 1981, Miura et al. 2008). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 ACTIVATION CBR1 Carbonyl reductase (NADPH)1 CBR1_HUMAN Reactome DB_ID: 2142784 UniProt:P16152 CBR1 CBR1 CBR CRN SDR21C1 FUNCTION NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol (PubMed:18449627, PubMed:15799708, PubMed:17912391, PubMed:7005231). 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).ACTIVITY REGULATION Inhibited by quercetin, rutenin and its derivatives.SUBUNIT Monomer.TISSUE SPECIFICITY Expressed in kidney (at protein level).SIMILARITY Belongs to the short-chain dehydrogenases/reductases (SDR) family. UniProt P16152 2 EQUAL 277 EQUAL Reactome Database ID Release 81 2142784 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142784 Reactome R-HSA-2142784 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142784.1 GENE ONTOLOGY GO:0050221 Reactome Database ID Release 81 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 81 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 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 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 LEFT-TO-RIGHT PGE2 is dehydrated to PGA2 Cyclopentenone prostaglandins comprise a family of molecules that are formed by dehydration of hydroxyl moieties in prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Dehydration of PGE2 leads to prostaglandin A2 (PGA2) (Hamberg & Samuelsson B 1966, Amin 1989). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGA2 prostaglandin A2 Reactome DB_ID: 2299726 prostaglandin A2 [ChEBI:27820] prostaglandin A2 ChEBI CHEBI:27820 Reactome Database ID Release 81 2299726 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2299726 Reactome R-ALL-2299726 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2299726.3 Reactome Database ID Release 81 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 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 5903721 Pubmed 1966 Prostaglandins in human seminal plasma. Prostaglandins and related factors 46 Hamberg, M Samuelsson, B J Biol Chem 241:257-63 LEFT-TO-RIGHT PGA2 is isomerised to PGC2 Dehydration in the cyclopentane ring of prostaglandin E2 (PGE2) yields prostaglandin A2 (PGA2) followed by isomerization of the double bond to yield the unstable compound prostaglandin C2 (PGC2) (Straus & Glass, 2001). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGC2 prostaglandin C2 Reactome DB_ID: 2299724 prostaglandin C2 [ChEBI:27555] prostaglandin C2 ChEBI CHEBI:27555 Reactome Database ID Release 81 2299724 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2299724 Reactome R-ALL-2299724 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2299724.3 Reactome Database ID Release 81 2161666 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161666 Reactome R-HSA-2161666 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161666.2 11301410 Pubmed 2001 Cyclopentenone prostaglandins: new insights on biological activities and cellular targets Straus, DS Glass, CK Med Res Rev 21:185-210 LEFT-TO-RIGHT PGC2 is isomerised to PGB2 Isomerization of the double bond in prostaglandin A2 (PGA2) forms prostaglandin C2 (PGC2). This is an unstable compound which undergoes a second isomerization to yield prostaglandin B2 (PGB2) (Straus & Glass, 2001). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGB2 prostaglandin B2 Reactome DB_ID: 2299721 prostaglandin B2 [ChEBI:28099] prostaglandin B2 ChEBI CHEBI:28099 Reactome Database ID Release 81 2299721 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2299721 Reactome R-ALL-2299721 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2299721.3 Reactome Database ID Release 81 2161735 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161735 Reactome R-HSA-2161735 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161735.2 LEFT-TO-RIGHT PGA2 is dehydrated to 15d-PGA2 The non-enzymatic dehydration of prostaglandin A2 (PGA2) into 15-deoxy prostaglandin A2 (15d-PGA2) which occurs in mice (Petrova et al. 1999) is inferred in humans. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 15d-PGA2 15-deoxy-Delta(12,14)-prostaglandin A2 Reactome DB_ID: 2299722 15-deoxy-Delta(12,14)-prostaglandin A2 [ChEBI:63975] 15-deoxy-Delta(12,14)-prostaglandin A2 ChEBI CHEBI:63975 Reactome Database ID Release 81 2299722 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2299722 Reactome R-ALL-2299722 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2299722.3 Reactome Database ID Release 81 2161668 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161668 Reactome R-HSA-2161668 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161668.2 10200320 Pubmed 1999 Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta12,14-prostaglandin J2 Petrova, TV Akama, KT Van Eldik, LJ Proc Natl Acad Sci U S A 96:4668-73 LEFT-TO-RIGHT 5.3.99.2 PGH2 is isomerised to PGD2 by PTGDS Prostaglandin D2 (PGD2) is a structural isomer of prostaglandin E2 (PGE2). There is a 9-keto and 11-hydroxy group on PGE2 with these substituents reversed on PGD2. PGD2 is formed by two evolutionarily distinct, but functionally convergent, prostaglandin D synthases: lipocalin-type prostaglandin-D synthase aka Prostaglandin-H2 D-isomerase (PTDGS) and hematopoietic prostaglandin D synthase (HPGDS). One of the main differences between these two proteins is that HPGDS requires glutathione (GSH) for catalysis while PTDGS can function without this cofactor. Here, PTDGS promotes the isomerisation of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2) (Zhou et al. 2010). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGD2 prostaglandin D2 Reactome DB_ID: 2161634 prostaglandin D2 [ChEBI:15555] prostaglandin D2 ChEBI CHEBI:15555 Reactome Database ID Release 81 2161634 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161634 Reactome R-ALL-2161634 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2161634.3 COMPOUND C00696 ACTIVATION PTGDS Prostaglandin-H2 D-isomerase PTGDS_HUMAN Reactome DB_ID: 2142814 UniProt:P41222 PTGDS PTGDS PDS FUNCTION Catalyzes the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation (PubMed:20667974). Involved in a variety of CNS functions, such as sedation, NREM sleep and PGE2-induced allodynia, and may have an anti-apoptotic role in oligodendrocytes. Binds small non-substrate lipophilic molecules, including biliverdin, bilirubin, retinal, retinoic acid and thyroid hormone, and may act as a scavenger for harmful hydrophobic molecules and as a secretory retinoid and thyroid hormone transporter. Possibly involved in development and maintenance of the blood-brain, blood-retina, blood-aqueous humor and blood-testis barrier. It is likely to play important roles in both maturation and maintenance of the central nervous system and male reproductive system (PubMed:20667974, PubMed:9475419). Involved in PLA2G3-dependent maturation of mast cells. PLA2G3 is secreted by immature mast cells and acts on nearby fibroblasts upstream to PTDGS to synthesize PGD2, which in turn promotes mast cell maturation and degranulation via PTGDR (By similarity).SUBUNIT Monomer.TISSUE SPECIFICITY Abundant in the brain and CNS, where it is expressed in tissues of the blood-brain barrier and secreted into the cerebro-spinal fluid. Abundantly expressed in the heart. In the male reproductive system, it is expressed in the testis, epididymis and prostate, and is secreted into the seminal fluid. Expressed in the eye and secreted into the aqueous humor. Lower levels detected in various tissue fluids such as serum, normal urine, ascitic fluid and tear fluid. Also found in a number of other organs including ovary, fimbriae of the fallopian tubes, kidney, leukocytes.DEVELOPMENTAL STAGE Expression in the amniotic fluid increases dramatically during weeks 12 to 25 of pregnancy. Levels decrease slowly after 25 weeks.INDUCTION By IL1B/interleukin-1 beta and thyroid hormone. Probably induced by dexamethasone, dihydrotestosterone (DHT), progesterone, retinoic acid and retinal. Repressed by the Notch-Hes signaling pathway.DOMAIN Forms a beta-barrel structure that accommodates hydrophobic ligands in its interior.PTM N- and O-glycosylated. Both N-glycosylation recognition sites are almost quantitatively occupied by N-glycans of the biantennary complex type, with a considerable proportion of structures bearing a bisecting GlcNAc. N-glycan at Asn-78: dHex1Hex5HexNAc4. Agalacto structure as well as sialylated and nonsialylated oligosaccharides bearing alpha2-3- and/or alpha2-6-linked NeuNAc are present.MISCELLANEOUS It has been proposed that the urinary and serum levels may provide a sensitive indicator of renal damage in diabetes mellitus and hypertension. Elevated levels in the coronary circulation may also be associated with angina. Changes in charge and molecular weight microheterogeneity, due to modification of the N-linked oligosaccharides, may be associated with neurodegenerative disease and multiple sclerosis. Detected in meningioma but not in other brain tumors and may be considered a specific cell marker for meningioma. Expression levels in amniotic fluid are altered in abnormal pregnancies. Levels are lower in pregnancies with trisomic fetuses and fetuses with renal abnormalities.SIMILARITY Belongs to the calycin superfamily. Lipocalin family. UniProt P41222 23 EQUAL 190 EQUAL Reactome Database ID Release 81 2142814 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142814 Reactome R-HSA-2142814 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142814.1 GENE ONTOLOGY GO:0004667 Reactome Database ID Release 81 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 81 2161620 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161620 Reactome R-HSA-2161620 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161620.2 20667974 Pubmed 2010 Structure-function analysis of human l-prostaglandin D synthase bound with fatty acid molecules Zhou, Y Shaw, N Li, Y Zhao, Y Zhang, R Liu, ZJ FASEB J 24:4668-77 LEFT-TO-RIGHT 5.3.99.2 PGH2 is isomerised to PGD2 by HPGDS Prostaglandin D2 (PGD2) is a structural isomer of prostaglandin E2 (PGE2). There is a 9-keto and 11-hydroxy group on PGE2 with these substituents reversed on PGD2. PGD2 is formed by two evolutionarily distinct, but functionally convergent, prostaglandin D synthases: lipocalin-type prostaglandin-D synthase aka Prostaglandin-H2 D-isomerase (PTDGS) and hematopoietic prostaglandin D synthase (HPGDS). One of the main differences between these two proteins is that HPGDS requires glutathione (GSH) for catalysis while PTDGS can function without this cofactor. Here, HPGDS with GSH promotes the isomerisation of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2) (Jowsey et al. 2001, Inoue et al. 2003). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGD2 prostaglandin D2 Reactome DB_ID: 879629 Reactome Database ID Release 81 879629 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=879629 Reactome R-ALL-879629 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-879629.3 COMPOUND C00696 ACTIVATION HPGDS dimer Reactome DB_ID: 2142683 GSH Reduced glutathione glutathione 5-L-Glutamyl-L-cysteinylglycine N-(N-gamma-L-Glutamyl-L-cysteinyl)glycine gamma-L-Glutamyl-L-cysteinyl-glycine glutathionate(1-) Reactome DB_ID: 29450 glutathionate(1-) [ChEBI:57925] glutathionate(1-) glutathionate ion glutathionate anion glutathionate glutathione ChEBI CHEBI:57925 Reactome Database ID Release 81 29450 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29450 Reactome R-ALL-29450 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29450.4 COMPOUND C00051 2 HPGDS Hematopoietic prostaglandin D synthase HPGDS_HUMAN Reactome DB_ID: 2142706 UniProt:O60760 HPGDS HPGDS GSTS PGDS PTGDS2 FUNCTION Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide.ACTIVITY REGULATION Prostaglandin PGD2 synthesis is stimulated by calcium and magnesium ions. One calcium or magnesium ion is bound between the subunits of the homodimer. The interactions with the protein are for the most part mediated via water molecules. Magnesium increases the affinity for glutathione, while calcium has no effect on the affinity for glutathione.SUBUNIT Homodimer.TISSUE SPECIFICITY Expressed in a number of megakaryocytic cell lines but not in platelets. Highly expressed in adipose tissue, macrophages and placenta. Also expressed at lower levels in lung, heart, lymph nodes, appendix, bone marrow and fetal liver.DEVELOPMENTAL STAGE Highest levels in immature megakaryocytic cells. Disappears after final differentiation to platelets.INDUCTION By 12-O-tetradecanoylphorbol-13-acetate (TPA).SIMILARITY Belongs to the GST superfamily. Sigma family. UniProt O60760 2 EQUAL 199 EQUAL Reactome Database ID Release 81 2142706 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142706 Reactome R-HSA-2142706 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142706.1 2 Reactome Database ID Release 81 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 81 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 81 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 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 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 LEFT-TO-RIGHT PGD2 is dehydrated to PGJ2 Analogous to prostaglandin E2 (PGE2), dehydration of the prostaglandin D2 (PGD2) prostane ring forms prostaglandin J2 (PGJ2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PGJ2 prostaglandin J2 Reactome DB_ID: 2142674 prostaglandin J2 [ChEBI:27485] prostaglandin J2 ChEBI CHEBI:27485 Reactome Database ID Release 81 2142674 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142674 Reactome R-ALL-2142674 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142674.3 Reactome Database ID Release 81 2161733 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161733 Reactome R-HSA-2161733 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161733.2 11907120 Pubmed 2002 15-Deoxy-delta 12,14-prostaglandins D2 and J2 are potent activators of human eosinophils Monneret, G Li, H Vasilescu, J Rokach, J Powell, WS J Immunol 168:3563-9 LEFT-TO-RIGHT PGJ2 is isomerised to delta12-PGJ2 Delta-12-prostaglandin J2 (delta12-PGJ2) is an isomerisation product of prostaglandin J2 (PGJ2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 delta12-PGJ2 13,14-dihydro-Delta(12)-prostaglandin J2 Reactome DB_ID: 2142821 13,14-dihydro-Delta(12)-prostaglandin J2 [ChEBI:28130] 13,14-dihydro-Delta(12)-prostaglandin J2 ChEBI CHEBI:28130 Reactome Database ID Release 81 2142821 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142821 Reactome R-ALL-2142821 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142821.3 Reactome Database ID Release 81 2161563 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161563 Reactome R-HSA-2161563 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161563.2 LEFT-TO-RIGHT Delta12-PGJ2 is dehydrated to 15d-PGJ2 15-Deoxy-delta(12,14)-PDJ2 (15d-PGJ2) is a dehydration product of delta-12-prostaglandin J2 (delta12-PGJ2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 15d-PGJ2 15-deoxy-Delta(12,14)-prostaglandin J2 Reactome DB_ID: 2142702 15-deoxy-Delta(12,14)-prostaglandin J2 [ChEBI:34159] 15-deoxy-Delta(12,14)-prostaglandin J2 15-Deoxy-PGJ2 15-Deoxy-delta-12,14-prostaglandin J2 15-Deoxy-delta-12,14-PGJ2 ChEBI CHEBI:34159 Reactome Database ID Release 81 2142702 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142702 Reactome R-ALL-2142702 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142702.3 Reactome Database ID Release 81 2161588 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161588 Reactome R-HSA-2161588 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161588.2 LEFT-TO-RIGHT PGD2 is dehydrated to 15d-PGD2 15-Deoxy-delta 12,14-prostaglandins D2 (15d-PGD2) is a dehydrated form of prostaglandin D2 (PGD2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 15d-PGD2 15-deoxy-Delta(12,14)-prostaglandin D2 Reactome DB_ID: 2142817 15-deoxy-Delta(12,14)-prostaglandin D2 [ChEBI:63999] 15-deoxy-Delta(12,14)-prostaglandin D2 ChEBI CHEBI:63999 Reactome Database ID Release 81 2142817 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142817 Reactome R-ALL-2142817 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142817.3 Reactome Database ID Release 81 2161673 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161673 Reactome R-HSA-2161673 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161673.2 LEFT-TO-RIGHT 1.1.1.188 PGD2 is reduced to 11-epi-PGF2a by AKRIC3 Aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS is the enzyme involved in NADPH-dependent prostaglandin D2 11-keto reductase activity of reducing prostaglandin D2 (PGD2) to 11-epi-Prostaglandin F2alpha (11-epi-PGF2a) (Liston & Roberts 1985, Koda et al. 2004). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 11epi-PGF2a 11-epi-prostaglandin F2alpha Reactome DB_ID: 2142710 11-epi-prostaglandin F2alpha [ChEBI:27595] 11-epi-prostaglandin F2alpha ChEBI CHEBI:27595 Reactome Database ID Release 81 2142710 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142710 Reactome R-ALL-2142710 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142710.3 ACTIVATION GENE ONTOLOGY GO:0036131 Reactome Database ID Release 81 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 81 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 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 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 LEFT-TO-RIGHT 1.1.1.141 PGD2/E2/F2a is oxidised to 15k-PGD2/E2/F2a by HPGD 15-Hydroxyprostaglandin dehydrogenase (HPGD) oxidises prostaglandins D2 (PGD2), E2 (PGE2), and F2alpha (PGF2a) to 15-keto-prostaglandin D2 (15k-PGD2), E2 (15k-PGE2), and F2alpha (15k-PGF2a) respectively (Cho et al. 2006). This reaction is inferred from rabbits (Bergholte & Okita 1986). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 NAD NAD+ NAD(+) Nicotinamide adenine dinucleotide DPN Diphosphopyridine nucleotide Reactome DB_ID: 29360 NAD(1-) [ChEBI:57540] NAD(1-) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD(+) NAD anion ChEBI CHEBI:57540 Reactome Database ID Release 81 29360 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29360 Reactome R-ALL-29360 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29360.5 COMPOUND C00003 Converted from EntitySet in Reactome PGD2/E2/F2a Reactome DB_ID: 2161661 Reactome Database ID Release 81 2161661 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161661 Reactome R-ALL-2161661 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2161661.1 Converted from EntitySet in Reactome 15k-PGD2,15k-PGE2,15k-PGF2a Reactome DB_ID: 2161597 15k-PGD2 15-dehydro-prostaglandin D2 Reactome DB_ID: 2142752 15-dehydro-prostaglandin D2 [ChEBI:15557] 15-dehydro-prostaglandin D2 ChEBI CHEBI:15557 Reactome Database ID Release 81 2142752 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142752 Reactome R-ALL-2142752 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142752.3 15k-PGE2 15-dehydro-prostaglandin E2 Reactome DB_ID: 2142721 15-dehydro-prostaglandin E2 [ChEBI:15547] 15-dehydro-prostaglandin E2 ChEBI CHEBI:15547 Reactome Database ID Release 81 2142721 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142721 Reactome R-ALL-2142721 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142721.3 15k-PGF2a 15-oxo-prostaglandin F2alpha 15-oxoprostaglandin F2alpha Reactome DB_ID: 2142799 15-oxoprostaglandin F2alpha [ChEBI:28442] 15-oxoprostaglandin F2alpha ChEBI CHEBI:28442 Reactome Database ID Release 81 2142799 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142799 Reactome R-ALL-2142799 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142799.3 Reactome Database ID Release 81 2161597 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161597 Reactome R-ALL-2161597 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-2161597.2 NADH Reactome DB_ID: 73473 NADH(2-) [ChEBI:57945] NADH(2-) NADH dianion adenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADH ChEBI CHEBI:57945 Reactome Database ID Release 81 73473 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73473 Reactome R-ALL-73473 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-73473.4 COMPOUND C00004 ACTIVATION HPGD dimer Reactome DB_ID: 2142778 HPGD 15-hydroxyprostaglandin dehydrogenase (NAD+) PGDH_HUMAN Reactome DB_ID: 2142677 UniProt:P15428 HPGD HPGD PGDH1 SDR36C1 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 proinflammatory 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 81 2142677 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142677 Reactome R-HSA-2142677 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-2142677.1 2 Reactome Database ID Release 81 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 GENE ONTOLOGY GO:0016404 Reactome Database ID Release 81 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 81 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 3954355 Pubmed 1986 Isolation and properties of lung 15-hydroxyprostaglandin dehydrogenase from pregnant rabbits Bergholte, JM Okita, RT Arch Biochem Biophys 245:308-15 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 LEFT-TO-RIGHT 1.3.1.48 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 Converted from EntitySet in Reactome 15k-PGE2,15k-PGF2a Reactome DB_ID: 2161650 Reactome Database ID Release 81 2161650 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161650 Reactome R-ALL-2161650 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-2161650.2 Converted from EntitySet in Reactome dhk-PGE2,dhk-PGF2a Reactome DB_ID: 2161684 dhk-PGE2 13,14-dihydro-15-oxo-prostaglandin E2 Reactome DB_ID: 2142749 13,14-dihydro-15-oxo-prostaglandin E2 [ChEBI:15550] 13,14-dihydro-15-oxo-prostaglandin E2 ChEBI CHEBI:15550 Reactome Database ID Release 81 2142749 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142749 Reactome R-ALL-2142749 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142749.3 dhk-PGF2a 13,14-dihydro-15-keto-PGF2alpha Reactome DB_ID: 2142751 13,14-dihydro-15-keto-PGF2alpha [ChEBI:63976] 13,14-dihydro-15-keto-PGF2alpha ChEBI CHEBI:63976 Reactome Database ID Release 81 2142751 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142751 Reactome R-ALL-2142751 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142751.3 Reactome Database ID Release 81 2161684 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161684 Reactome R-ALL-2161684 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-2161684.2 ACTIVATION PTGR2 Prostaglandin reductase 2 PTGR2_HUMAN Reactome DB_ID: 8940670 UniProt:Q8N8N7 PTGR2 PTGR2 ZADH1 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 Reactome Database ID Release 81 8940670 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8940670 Reactome R-HSA-8940670 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-8940670.1 GENE ONTOLOGY GO:0036132 Reactome Database ID Release 81 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 81 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 LEFT-TO-RIGHT 5.3.99.4 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 PGI2 Prostacyclin prostaglandin I2 (5Z,13E)-(15S)-6,9alpha-Epoxy-11alpha,15-dihydroxyprosta-5,13-dienoate Reactome DB_ID: 31593 prostaglandin I2 [ChEBI:15552] prostaglandin I2 ChEBI CHEBI:15552 Reactome Database ID Release 81 31593 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=31593 Reactome R-ALL-31593 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-31593.3 COMPOUND C01312 ACTIVATION Converted from EntitySet in Reactome PTGIS,CYP8B1 Reactome DB_ID: 3222410 PTGIS Prostacyclin synthase Prostaglandin I2 synthase Cytochrome P450 8A1 Reactome DB_ID: 62410 UniProt:Q16647 PTGIS PTGIS CYP8 CYP8A1 FUNCTION Catalyzes the biosynthesis and metabolism of eicosanoids. Catalyzes the isomerization of prostaglandin H2 to prostacyclin (= prostaglandin I2), a potent mediator of vasodilation and inhibitor of platelet aggregation (PubMed:18032380, PubMed:25623425, PubMed:12372404, PubMed:15115769). Additionally, displays dehydratase activity, toward hydroperoxyeicosatetraenoates (HPETEs), especially toward (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (15(S)-HPETE) (PubMed:17459323).TISSUE SPECIFICITY Widely expressed; particularly abundant in ovary, heart, skeletal muscle, lung and prostate.SIMILARITY Belongs to the cytochrome P450 family. UniProt Q16647 1 EQUAL 500 EQUAL Reactome Database ID Release 81 62410 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=62410 Reactome R-HSA-62410 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-62410.1 CYP8B1 Cytochrome P450 8B1 CP8B_HUMAN Reactome DB_ID: 192012 UniProt:Q9UNU6 CYP8B1 CYP8B1 CYP12 FUNCTION A cytochrome P450 monooxygenase involved in primary bile acid biosynthesis. Catalyzes the 12alpha-hydroxylation of 7alpha-hydroxy-4-cholesten-3-one, an intermediate metabolite in cholic acid biosynthesis (PubMed:10051404). Controls biliary balance of cholic acid and chenodeoxycholic acid, ultimately regulating the intestinal absorption of dietary lipids (By similarity). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH--hemoprotein reductase) (By similarity).PATHWAY Lipid metabolism; bile acid biosynthesis.TISSUE SPECIFICITY Liver.SIMILARITY Belongs to the cytochrome P450 family. UniProt Q9UNU6 1 EQUAL 501 EQUAL Reactome Database ID Release 81 192012 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=192012 Reactome R-HSA-192012 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-192012.1 Reactome Database ID Release 81 3222410 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3222410 Reactome R-HSA-3222410 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-3222410.1 GENE ONTOLOGY GO:0008116 Reactome Database ID Release 81 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 81 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 LEFT-TO-RIGHT 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 6k-PGF1a 6-oxo-prostaglandin F1alpha 6-oxoprostaglandin F1alpha Reactome DB_ID: 2142786 6-oxoprostaglandin F1alpha [ChEBI:28158] 6-oxoprostaglandin F1alpha ChEBI CHEBI:28158 Reactome Database ID Release 81 2142786 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142786 Reactome R-ALL-2142786 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142786.3 Reactome Database ID Release 81 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 LEFT-TO-RIGHT 5.3.99.5 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 TXA2 (5Z,13E)-(15S)-9alpha,11alpha-Epoxy-15-hydroxythromboxa-5,13-dienoate thromboxane A2 (5Z,9alpha,11alpha,13E,15S)-9,11-Epoxy-15-hydroxythromboxa-5,13-dien-1-oic acid Reactome DB_ID: 32879 thromboxane A2 [ChEBI:15627] thromboxane A2 ChEBI CHEBI:15627 Reactome Database ID Release 81 32879 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=32879 Reactome R-ALL-32879 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-32879.3 COMPOUND C02198 ACTIVATION TXS TBXAS1 Thromboxane-A synthase TXA synthase Cytochrome P450 5A1 Reactome DB_ID: 65976 UniProt:P24557 TBXAS1 TBXAS1 CYP5 CYP5A1 TXAS 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 Reactome Database ID Release 81 65976 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=65976 Reactome R-HSA-65976 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-65976.1 GENE ONTOLOGY GO:0004796 Reactome Database ID Release 81 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 81 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 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 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 LEFT-TO-RIGHT 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 TXB2 thromboxane B2 Reactome DB_ID: 443890 thromboxane B2 [ChEBI:28728] thromboxane B2 ChEBI CHEBI:28728 Reactome Database ID Release 81 443890 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=443890 Reactome R-ALL-443890 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-443890.3 Reactome Database ID Release 81 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 LEFT-TO-RIGHT 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 NAD NAD+ NAD(+) Nicotinamide adenine dinucleotide DPN Diphosphopyridine nucleotide Reactome DB_ID: 194653 Reactome Database ID Release 81 194653 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194653 Reactome R-ALL-194653 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-194653.4 COMPOUND C00003 11dh-TXB2 11-dehydro-thromboxane B2 Reactome DB_ID: 2142828 11-dehydro-thromboxane B2 [ChEBI:28667] 11-dehydro-thromboxane B2 ChEBI CHEBI:28667 Reactome Database ID Release 81 2142828 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142828 Reactome R-ALL-2142828 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142828.3 NADH Reactome DB_ID: 194697 Reactome Database ID Release 81 194697 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194697 Reactome R-ALL-194697 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-194697.3 COMPOUND C00004 ACTIVATION TXDH 11-dehydroxythromboxane B2 dehydrogenase 11-Hydroxythromboxane B2 reductase Reactome DB_ID: 2161595 Reactome Database ID Release 81 2161595 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161595 Reactome R-HSA-2161595 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-2161595.2 ChEBI 36080 GENE ONTOLOGY GO:0036133 Reactome Database ID Release 81 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 81 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 3823488 Pubmed 1986 Radioimmunoassay for 11-dehydro-TXB2: a method for monitoring thromboxane production in vivo Kumlin, M Granström, E Prostaglandins 32:741-67 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 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 LEFT-TO-RIGHT 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 12S-HHT 12S-HHTrE Reactome DB_ID: 2142797 12S-HHTrE [ChEBI:63977] 12S-HHTrE ChEBI CHEBI:63977 Reactome Database ID Release 81 2142797 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142797 Reactome R-ALL-2142797 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142797.3 MDA Malondialdehyde malonaldehyde Reactome DB_ID: 2161562 malonaldehyde [ChEBI:566274] malonaldehyde Malonyldialdehyde Malonic dialdehyde 1,3-Propanedialdehyde Malondialdehyde Malonic aldehyde Malonodialdehyde MDD 1,3-Propanedione MDA 1,3-Propanedial ChEBI CHEBI:566274 Reactome Database ID Release 81 2161562 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161562 Reactome R-ALL-2161562 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2161562.3 ACTIVATION GENE ONTOLOGY GO:0036134 Reactome Database ID Release 81 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 81 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 81 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 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 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 GENE ONTOLOGY GO:0019371 gene ontology term for cellular process MI MI:0359 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 LEFT-TO-RIGHT 2.7.11.1 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 ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 2237880 ALOX5 Arachidonate 5-lipoxygenase LOX5_HUMAN Reactome DB_ID: 429010 UniProt:P09917 ALOX5 ALOX5 LOG5 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). Also may 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 Database ID Release 81 429010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=429010 Reactome R-HSA-429010 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-429010.1 1 Fe2+ iron (ferrous) iron atom Fe(II) Fe++ Iron Fe3+ Fe(III) Reactome DB_ID: 71067 iron(2+) [ChEBI:29033] iron(2+) FE (II) ION Fe2+ Fe(2+) iron ion(2+) Fe(II) Ferrous ion ChEBI CHEBI:29033 Reactome Database ID Release 81 71067 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=71067 Reactome R-ALL-71067 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-71067.4 COMPOUND C00023 1 2 Reactome Database ID Release 81 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 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 81 113592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 COMPOUND C00002 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 81 29370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 p-S272-ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 265277 p-S272-ALOX5 phospho-ALOX5 Arachidonate 5-lipoxygenase, P-Ser-272 Reactome DB_ID: 265276 272 EQUAL 2 EQUAL 674 EQUAL Reactome Database ID Release 81 265276 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265276 Reactome R-HSA-265276 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-265276.1 1 1 2 Reactome Database ID Release 81 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 ACTIVATION p-MAPKAPK2 p-S272,T222,T334-MAPKAPK2 Phospho-MAP kinase-activated protein kinase 2 MKK2_HUMAN Reactome DB_ID: 187760 UniProt:P49137 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 222 EQUAL O-phospho-L-threonine MOD MOD:00047 272 EQUAL 334 EQUAL 1 EQUAL 400 EQUAL Reactome Database ID Release 81 187760 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=187760 Reactome R-HSA-187760 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-187760.2 GENE ONTOLOGY GO:0004674 Reactome Database ID Release 81 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 81 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 LEFT-TO-RIGHT 1.13.11.34 Oxidation of arachidonic acid to 5-HpETE Arachidonic acid is oxidised to 5S-HpETE by ALOX5 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 O2 Oxygen dioxygen Reactome DB_ID: 29368 Reactome Database ID Release 81 29368 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29368 Reactome R-ALL-29368 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29368.5 COMPOUND C00007 5S-HpETE (S)-Hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid 5(S)-HPETE Reactome DB_ID: 266010 5(S)-HPETE [ChEBI:15632] 5(S)-HPETE ChEBI CHEBI:15632 Reactome Database ID Release 81 266010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266010 Reactome R-ALL-266010 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-266010.3 COMPOUND C05356 ACTIVATION activeUnit: #Complex14 ALOX5:FLAP:LTC4S ALOX5:ALOX5AP:LTC4S Reactome DB_ID: 2318764 nuclear envelope GENE ONTOLOGY GO:0005635 p-S272-ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 2318769 Fe2+ iron (ferrous) Fe(II) Fe++ Iron Reactome DB_ID: 2318766 Reactome Database ID Release 81 2318766 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318766 Reactome R-ALL-2318766 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2318766.4 COMPOUND C00023 1 p-S272-ALOX5 phospho-ALOX5 Arachidonate 5-lipoxygenase, P-Ser-272 Reactome DB_ID: 2318765 2 EQUAL 674 EQUAL Reactome Database ID Release 81 2318765 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318765 Reactome R-HSA-2318765 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-2318765.1 1 Ca2+ Calcium calcium(2+) Reactome DB_ID: 2318767 Reactome Database ID Release 81 2318767 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318767 Reactome R-ALL-2318767 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2318767.3 COMPOUND C00076 2 Reactome Database ID Release 81 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 1 FLAP trimer ALOX5AP trimer Reactome DB_ID: 2318770 FLAP ALOX5AP Arachidonate 5-lipoxygenase-activating protein Reactome DB_ID: 2318768 UniProt:P20292 ALOX5AP ALOX5AP FLAP 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 81 2318768 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318768 Reactome R-HSA-2318768 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-2318768.1 3 Reactome Database ID Release 81 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 1 LTC4S trimer LTC4 synthase homotrimer Reactome DB_ID: 2142729 LTC4S Leukotriene C4 synthase LTC4S_HUMAN Reactome DB_ID: 266025 UniProt:Q16873 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 catalyzes 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 81 266025 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266025 Reactome R-HSA-266025 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-266025.1 3 Reactome Database ID Release 81 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 1 Reactome Database ID Release 81 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 GENE ONTOLOGY GO:0004051 Reactome Database ID Release 81 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 81 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 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 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 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 LEFT-TO-RIGHT 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 Converted from EntitySet in Reactome ALOX5 inhibitors Reactome DB_ID: 9707237 zileuton Reactome DB_ID: 9707176 zileuton [Guide to Pharmacology:5297] zileuton A-64077 ZYFLO&reg; Guide to Pharmacology 5297 Reactome Database ID Release 81 9707176 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9707176 Reactome R-ALL-9707176 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9707176.1 balsalazide Reactome DB_ID: 9707240 balsalazide [Guide to Pharmacology:11569] balsalazide Colazal&reg; Colazide&reg; Giazo&reg; Guide to Pharmacology 11569 Reactome Database ID Release 81 9707240 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9707240 Reactome R-ALL-9707240 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9707240.1 olsalazine Reactome DB_ID: 9707190 olsalazine [Guide to Pharmacology:11578] olsalazine CJ91B CJ-91B Dipentum&reg; Guide to Pharmacology 11578 Reactome Database ID Release 81 9707190 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9707190 Reactome R-ALL-9707190 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9707190.1 sulfasalazine Reactome DB_ID: 9707184 sulfasalazine [Guide to Pharmacology:4840] sulfasalazine Azulfidine&reg; Salazopyridin&reg; Salazopyrin&reg; SAS-500 Guide to Pharmacology 4840 Reactome Database ID Release 81 9707184 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9707184 Reactome R-ALL-9707184 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9707184.1 CL-583 meclofenamic acid INF-4668 Meclomen&reg; Reactome DB_ID: 9677353 meclofenamic acid [Guide to Pharmacology:7219] meclofenamic acid CL-583 INF-4668 Meclomen&reg; Guide to Pharmacology 7219 Reactome Database ID Release 81 9677353 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677353 Reactome R-ALL-9677353 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9677353.1 Reactome Database ID Release 81 9707237 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9707237 Reactome R-ALL-9707237 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-9707237.1 ALOX5:ALOX5 inhibitors Reactome DB_ID: 9707188 1 1 Reactome Database ID Release 81 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 81 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 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 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 2877850 Pubmed 1986 Pharmacological and biochemical actions of sulphasalazine Hoult, J R Drugs 32:18-26 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 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 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 2864155 Pubmed 1985 Clinical pharmacokinetics of sulphasalazine, its metabolites and other prodrugs of 5-aminosalicylic acid Klotz, U Clin Pharmacokinet 10:285-302 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 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 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 15604543 Pubmed 2005 Zileuton, an oral 5-lipoxygenase inhibitor, directly reduces sebum production Zouboulis, Ch C Saborowski, A Boschnakow, A Dermatology 210:36-8 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 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 LEFT-TO-RIGHT 1.13.11.34 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 LTA4 leukotriene A4 Reactome DB_ID: 265281 leukotriene A4 [ChEBI:15651] leukotriene A4 ChEBI CHEBI:15651 Reactome Database ID Release 81 265281 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265281 Reactome R-ALL-265281 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-265281.3 COMPOUND C00909 ACTIVATION activeUnit: #Complex14 Reactome Database ID Release 81 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 LEFT-TO-RIGHT 3.3.2.6 LTA4 is hydrolyzed to LTB4 LTA4 is hydolysed to LTB4 by LTA4H 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 LTB4 Leukotriene-B(4) omega-hydroxylase leukotriene B4 Leukotriene-B(4) 20-monooxygenase Reactome DB_ID: 266056 leukotriene B4 [ChEBI:15647] leukotriene B4 ChEBI CHEBI:15647 Reactome Database ID Release 81 266056 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266056 Reactome R-ALL-266056 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-266056.3 COMPOUND C02165 ACTIVATION LTA4H:Zn2+ LTA4 hydrolase (Zinc cofactor) Reactome DB_ID: 266038 LTA4H Leukotriene A-4 hydrolase-1 LKHA4_HUMAN Reactome DB_ID: 266022 UniProt:P09960 LTA4H LTA4H LTA4 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 proinflammatory 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 proinflammatory 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 81 266022 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266022 Reactome R-HSA-266022 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-266022.1 1 Zn2+ Zn++ zinc(2+) Zinc ion Zn(II) Reactome DB_ID: 29426 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI CHEBI:29105 Reactome Database ID Release 81 29426 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29426 Reactome R-ALL-29426 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29426.3 COMPOUND C00038 1 Reactome Database ID Release 81 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 GENE ONTOLOGY GO:0004463 Reactome Database ID Release 81 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 81 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 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 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 LEFT-TO-RIGHT 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 12-oxoLTB4 12-dehydro-leukotriene B4 Reactome DB_ID: 2142810 12-dehydro-leukotriene B4 [ChEBI:27814] 12-dehydro-leukotriene B4 ChEBI CHEBI:27814 Reactome Database ID Release 81 2142810 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142810 Reactome R-ALL-2142810 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142810.3 ACTIVATION PTGR1 Prostaglandin reductase 1 PTGR1_HUMAN Reactome DB_ID: 2142671 UniProt:Q14914 PTGR1 PTGR1 LTB4DH 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 Reactome Database ID Release 81 2142671 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142671 Reactome R-HSA-2142671 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-2142671.1 GENE ONTOLOGY GO:0097257 Reactome Database ID Release 81 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 81 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 LEFT-TO-RIGHT 1.14.14.94 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 20OH-LTB4 20-OH-Leukotriene B4 20-hydroxy-leukotriene B4 Reactome DB_ID: 2161636 20-hydroxy-leukotriene B4 [ChEBI:15646] 20-hydroxy-leukotriene B4 ChEBI CHEBI:15646 Reactome Database ID Release 81 2161636 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161636 Reactome R-ALL-2161636 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2161636.3 ACTIVATION Converted from EntitySet in Reactome Cytochrome P450 (CYP4F2/4F3 based) Reactome DB_ID: 2161611 CYP4F2 Cytochrome P450 4F2 CPF2_HUMAN Reactome DB_ID: 211016 UniProt:P78329 CYP4F2 CYP4F2 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, eicosanoids and vitamins (PubMed:18577768, PubMed:10833273, PubMed:10660572, PubMed:11997390, PubMed:17341693, PubMed:18574070). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase). Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of long- and very long-chain fatty acids. Displays high omega-hydroxylase activity toward polyunsaturated fatty acids (PUFAs) (PubMed:18577768). Participates in the conversion of arachidonic acid to omega-hydroxyeicosatetraenoic acid (20-HETE), a signaling molecule acting both as vasoconstrictive and natriuretic with overall effect on arterial blood pressure (PubMed:10660572, PubMed:17341693, PubMed:18574070). Plays a role in the oxidative inactivation of eicosanoids, including both proinflammatory and anti-inflammatory mediators such as leukotriene B4 (LTB4), lipoxin A4 (LXA4), and several HETEs (PubMed:8026587, PubMed:9799565, PubMed:10833273, PubMed:10660572, PubMed:17341693, PubMed:18574070, PubMed:18577768). Catalyzes omega-hydroxylation of 3-hydroxy fatty acids (PubMed:18065749). Converts monoepoxides of linoleic acid leukotoxin and isoleukotoxin to omega-hydroxylated metabolites (PubMed:15145985). Contributes to the degradation of very long-chain fatty acids (VLCFAs) by catalyzing successive omega-oxidations and chain shortening (PubMed:16547005, PubMed:18182499). Plays an important role in vitamin metabolism by chain shortening. Catalyzes omega-hydroxylation of the phytyl chain of tocopherols (forms of vitamin E), with preference for gamma-tocopherols over alpha-tocopherols, thus promoting retention of alpha-tocopherols in tissues (PubMed:11997390). Omega-hydroxylates and inactivates phylloquinone (vitamin K1), and menaquinone-4 (MK-4, a form of vitamin K2), both acting as cofactors in blood coagulation (PubMed:19297519, PubMed:24138531).ACTIVITY REGULATION Inhibited by dietary sesamin.PATHWAY Lipid metabolism; arachidonate metabolism.PATHWAY Lipid metabolism; leukotriene B4 degradation.PATHWAY Cofactor degradation; phylloquinone degradation.TISSUE SPECIFICITY Liver. Also present in kidney: specifically expressed in the S2 and S3 segments of proximal tubules in cortex and outer medulla (PubMed:10660572).SIMILARITY Belongs to the cytochrome P450 family. UniProt P78329 1 EQUAL 520 EQUAL Reactome Database ID Release 81 211016 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211016 Reactome R-HSA-211016 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-211016.1 CYP4F3 Cytochrome P450 4F3 CPF3_HUMAN Reactome DB_ID: 211037 UniProt:Q08477 CYP4F3 CYP4F3 LTB4H FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and their oxygenated derivatives (oxylipins) (PubMed:8486631, PubMed:9675028, PubMed:11461919, PubMed:15145985, PubMed:16547005, PubMed:16820285, PubMed:18182499, PubMed:18065749, PubMed:18577768). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:9675028). May play a role in inactivation of proinflammatory and anti-inflammatory oxylipins during the resolution of inflammation (PubMed:8486631, PubMed:9675028, PubMed:11461919, PubMed:15145985, PubMed:15364545, PubMed:16547005, PubMed:16820285, PubMed:18182499, PubMed:18065749, PubMed:18577768).ACTIVITY REGULATION Inhibited by carbon monoxide (CO).PATHWAY Lipid metabolism; arachidonate metabolism.SIMILARITY Belongs to the cytochrome P450 family. UniProt Q08477 1 EQUAL 520 EQUAL Reactome Database ID Release 81 211037 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211037 Reactome R-HSA-211037 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-211037.1 CYP4F11 Cytochrome P450 4F11 CPFB_HUMAN Reactome DB_ID: 211051 UniProt:Q9HBI6 CYP4F11 CYP4F11 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and their oxygenated derivatives (oxylipins) (PubMed:24138531, PubMed:15364545, PubMed:18065749). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:15364545, PubMed:18065749, PubMed:24138531). Catalyzes with high efficiency the oxidation of the terminal carbon (omega-oxidation) of 3-hydroxy fatty acids, such as 3-hydroxyhexadecanoic and 3-hydroxyoctadecanoic acids, likely participating in the biosynthesis of long-chain 3-hydroxydicarboxylic acids (PubMed:18065749, PubMed:19932081). Omega-hydroxylates and inactivates phylloquinone (vitamin K1), and menaquinone-4 (MK-4, a form of vitamin K2), both acting as cofactors in blood coagulation (PubMed:24138531). Metabolizes with low efficiciency fatty acids, including (5Z,8Z,11Z,14Z)-eicosatetraenoic acid (arachidonate) and its oxygenated metabolite 8-hydroxyeicosatetraenoic acid (8-HETE) (PubMed:15364545, PubMed:19932081). Catalyzes N- and O-demethylation of drugs such as erythromycin, benzphetamine, ethylmorphine, chlorpromazine, imipramine and verapamil (PubMed:15364545).PATHWAY Lipid metabolism; arachidonate metabolism.PATHWAY Lipid metabolism; oxylipin biosynthesis.PATHWAY Cofactor degradation; phylloquinone degradation.PATHWAY Xenobiotic degradation.TISSUE SPECIFICITY Expressed mainly in human liver, followed by kidney, heart, and skeletal muscle.SIMILARITY Belongs to the cytochrome P450 family. UniProt Q9HBI6 1 EQUAL 524 EQUAL Reactome Database ID Release 81 211051 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211051 Reactome R-HSA-211051 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-211051.1 CYP4F22 Cytochrome P450 4F22 CP4FN_HUMAN Reactome DB_ID: 211056 UniProt:Q6NT55 CYP4F22 CYP4F22 FUNCTION A cytochrome P450 monooxygenase involved in epidermal ceramide biosynthesis. Hydroxylates the terminal carbon (omega-hydroxylation) of ultra-long-chain fatty acyls (C28-C36) prior to ceramide synthesis (PubMed:26056268). Contributes to the synthesis of three classes of omega-hydroxy-ultra-long chain fatty acylceramides having sphingosine, 6-hydroxysphingosine and phytosphingosine bases, all major lipid components that underlie the permeability barrier of the stratum corneum (PubMed:26056268). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:26056268).SIMILARITY Belongs to the cytochrome P450 family.CAUTION A second transmembrane domain at positions 95-115 is predicted by three programs ESKW, MEMSAT and Phobius. However experimental evidence supports the presence of a single signal-anchor transmembrane domain at the N-terminus. UniProt Q6NT55 1 EQUAL 531 EQUAL Reactome Database ID Release 81 211056 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211056 Reactome R-HSA-211056 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-211056.1 CYP4A11 Cytochrome P450 4A11 CYPIVA11 Fatty acid omega-hydroxylase P-450 HK omega Lauric acid omega-hydroxylase CYP4AII P450-HL-omega Reactome DB_ID: 52649 UniProt:Q02928 CYP4A11 CYP4A11 CYP4A2 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of fatty acids and their oxygenated derivatives (oxylipins) (PubMed:7679927, PubMed:1739747, PubMed:8914854, PubMed:10553002, PubMed:10660572, PubMed:15611369). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase) (PubMed:7679927, PubMed:1739747, PubMed:8914854, PubMed:10553002, PubMed:10660572, PubMed:15611369). Catalyzes predominantly the oxidation of the terminal carbon (omega-oxidation) of saturated and unsaturated fatty acids, the catalytic efficiency decreasing in the following order: dodecanoic &gt; tetradecanoic &gt; (9Z)-octadecenoic &gt; (9Z,12Z)-octadecadienoic &gt; hexadecanoic acid (PubMed:10553002, PubMed:10660572). Acts as a major omega-hydroxylase for dodecanoic (lauric) acid in liver (PubMed:7679927, PubMed:1739747, PubMed:8914854, PubMed:15611369). Participates in omega-hydroxylation of (5Z,8Z,11Z,14Z)-eicosatetraenoic acid (arachidonate) to 20-hydroxyeicosatetraenoic acid (20-HETE), a signaling molecule acting both as vasoconstrictive and natriuretic with overall effect on arterial blood pressure (PubMed:10620324, PubMed:10660572, PubMed:15611369). Can also catalyze the oxidation of the penultimate carbon (omega-1 oxidation) of fatty acids with lower efficiency (PubMed:7679927). May contribute to the degradation of saturated very long-chain fatty acids (VLCFAs) such as docosanoic acid, by catalyzing successive omega-oxidations to the corresponding dicarboxylic acid, thereby initiating chain shortening (PubMed:18182499). Omega-hydroxylates (9R,10S)-epoxy-octadecanoate stereoisomer (PubMed:15145985). Plays a minor role in omega-oxidation of long-chain 3-hydroxy fatty acids (PubMed:18065749). Has little activity toward prostaglandins A1 and E1 (PubMed:7679927).ACTIVITY REGULATION Activated by cytochrome b5.PATHWAY Lipid metabolism; arachidonate metabolism.PATHWAY Lipid metabolism; oxylipin biosynthesis.TISSUE SPECIFICITY Expressed in liver (PubMed:7679927). Expressed in S2 and S3 segments of proximal tubules in cortex and outer medulla of kidney (PubMed:7679927, PubMed:10660572).POLYMORPHISM CYP4A11v seems to be a rare allelic variant of CYP4A11, it seems to be unstable and not to metabolize lauric acid.SIMILARITY Belongs to the cytochrome P450 family. UniProt Q02928 5 EQUAL 519 EQUAL Reactome Database ID Release 81 52649 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=52649 Reactome R-HSA-52649 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-52649.1 CYP4B1 Cytochrome P450 4B1 CP4B_HUMAN Reactome DB_ID: 211013 UniProt:P13584 CYP4B1 CYP4B1 FUNCTION Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.TISSUE SPECIFICITY Detected in the liver and lung (at protein level).INDUCTION P450 can be induced to high levels in liver and other tissues by various foreign compounds, including drugs, pesticides, and carcinogens.SIMILARITY Belongs to the cytochrome P450 family. UniProt P13584 2 EQUAL 511 EQUAL Reactome Database ID Release 81 211013 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211013 Reactome R-HSA-211013 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-211013.1 CYP4A22 Cytochrome P450 4A22-1 CP4AM_HUMAN Reactome DB_ID: 400116 UniProt:Q5TCH4 CYP4A22 CYP4A22 FUNCTION Catalyzes the omega- and (omega-1)-hydroxylation of various fatty acids such as laurate and palmitate. Shows no activity towards arachidonic acid and prostaglandin A1. Lacks functional activity in the kidney and does not contribute to renal 20-hydroxyeicosatetraenoic acid (20-HETE) biosynthesis.SIMILARITY Belongs to the cytochrome P450 family.CAUTION Was originally termed CYP4A11. UniProt Q5TCH4 5 EQUAL 519 EQUAL Reactome Database ID Release 81 400116 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=400116 Reactome R-HSA-400116 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-400116.1 CYP4F8 Cytochrome P450 4F8 CPF8_HUMAN Reactome DB_ID: 211050 UniProt:P98187 CYP4F8 CYP4F8 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of endogenous polyunsaturated fatty acids (PUFAs) and their oxygenated derivatives (oxylipins). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase). Catalyzes the hydroxylation of carbon hydrogen bonds, with preference for omega-1 and omega-2 positions (PubMed:10791960, PubMed:16112640, PubMed:15789615). Hydroxylates (5Z,8Z,11Z,14Z)-eicosatetraenoic acid (arachidonate) predominantly at omega-2 position to form (18R)-hydroxyeicosatetraenoic acid (18R-HETE) (PubMed:10791960). Exhibits omega-1 hydroxylase activity toward prostaglandin (PG) H1, PGH2 and PGI2 (PubMed:10791960, PubMed:15789615). Catalyzes the epoxidation of double bonds of PUFAs, including docosahexaenoic and docosapentaenoic acids (PubMed:16112640). Shows little activity against PGD2, PGE1, PGE2, PGF2alpha, and leukotriene B4.PATHWAY Lipid metabolism; fatty acid metabolism.TISSUE SPECIFICITY Expressed in the epithelium of seminal vesicles, in renal cortex, in adult and fetal liver, in epidermis, in corneal epithelium, in sweat glands, hair follicles, epithelial linings of the ampulla of vas deferens and of the stomach and small intestine, as well as in the transitional epithelium of the bladder and ureter (at protein level). In the epidermis, expressed from the basal cell to the granular cell layers. In the corneal epithelium, expressed in all cell layers. Also detected in prostate. Up-regulated in the epidermis of psoriatic lesions.SIMILARITY Belongs to the cytochrome P450 family. UniProt P98187 1 EQUAL 520 EQUAL Reactome Database ID Release 81 211050 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211050 Reactome R-HSA-211050 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-211050.1 Reactome Database ID Release 81 2161611 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161611 Reactome R-HSA-2161611 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-2161611.1 GENE ONTOLOGY GO:0050051 Reactome Database ID Release 81 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 81 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 LEFT-TO-RIGHT 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 20cho-LTB4 20-oxoleukotriene B4 Reactome DB_ID: 2142740 20-oxoleukotriene B4 [ChEBI:63979] 20-oxoleukotriene B4 ChEBI CHEBI:63979 Reactome Database ID Release 81 2142740 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142740 Reactome R-ALL-2142740 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142740.3 2 ACTIVATION GENE ONTOLOGY GO:0097258 Reactome Database ID Release 81 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 81 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 LEFT-TO-RIGHT 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 20cooh-LTB4 20-hydroxy-20-oxo-leukotriene B4 20-hydroxy-20-oxoleukotriene B4 Reactome DB_ID: 2161582 20-hydroxy-20-oxoleukotriene B4 [ChEBI:27562] 20-hydroxy-20-oxoleukotriene B4 ChEBI CHEBI:27562 Reactome Database ID Release 81 2161582 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161582 Reactome R-ALL-2161582 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2161582.3 ACTIVATION GENE ONTOLOGY GO:0097259 Reactome Database ID Release 81 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 81 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 LEFT-TO-RIGHT 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 ACTIVATION ALDH Aldehyde dehydrogenase Reactome DB_ID: 2161598 Reactome Database ID Release 81 2161598 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161598 Reactome R-HSA-2161598 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-2161598.2 ChEBI 36080 Reactome Database ID Release 81 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 81 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 LEFT-TO-RIGHT 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 18cooh-LTB4 18-hydroxy-18-oxo-dinorleukotriene B4 Reactome DB_ID: 2142676 18-hydroxy-18-oxo-dinorleukotriene B4 [ChEBI:63980] 18-hydroxy-18-oxo-dinorleukotriene B4 ChEBI CHEBI:63980 Reactome Database ID Release 81 2142676 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142676 Reactome R-ALL-2142676 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142676.3 Reactome Database ID Release 81 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 LEFT-TO-RIGHT 4.4.1.20 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 LTC4 leukotriene C4 Reactome DB_ID: 266066 leukotriene C4 [ChEBI:16978] leukotriene C4 ChEBI CHEBI:16978 Reactome Database ID Release 81 266066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266066 Reactome R-ALL-266066 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-266066.3 COMPOUND C02166 ACTIVATION activeUnit: #Complex16 GENE ONTOLOGY GO:0004464 Reactome Database ID Release 81 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 81 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 LEFT-TO-RIGHT ABCC1 mediates LTC4 export from the cell LTC4 is exported from the cytosol by ABCC1 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 LTC4 leukotriene C4 Reactome DB_ID: 266013 extracellular region GENE ONTOLOGY GO:0005576 Reactome Database ID Release 81 266013 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266013 Reactome R-ALL-266013 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-266013.3 COMPOUND C02166 ACTIVATION MRP1 ABCC1 Multidrug resistance-associated protein 1 Reactome DB_ID: 266068 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:P33527 ABCC1 ABCC1 MRP MRP1 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 Reactome Database ID Release 81 266068 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266068 Reactome R-HSA-266068 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-266068.2 GENE ONTOLOGY GO:0140359 Reactome Database ID Release 81 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 81 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 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 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 LEFT-TO-RIGHT 3.4.19.13 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 H2O water Reactome DB_ID: 109276 Reactome Database ID Release 81 109276 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=109276 Reactome R-ALL-109276 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-109276.4 COMPOUND C00001 L-Glu L-Glutamate L-glutamate(1-) L-glutamic acid L-Glutaminic acid Reactome DB_ID: 210382 L-glutamate(1-) [ChEBI:29985] L-glutamate(1-) L-glutamic acid, ion(1-) [NH3+][C@@H](CCC([O-])=O)C([O-])=O WHUUTDBJXJRKMK-VKHMYHEASA-M C5H8NO4 146.12136 (2S)-2-ammoniopentanedioate hydrogen L-glutamate L-glutamate L-glutamic acid monoanion 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 ChEBI CHEBI:29985 Reactome Database ID Release 81 210382 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210382 Reactome R-ALL-210382 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-210382.4 COMPOUND C00025 LTD4 leukotriene D4 Reactome DB_ID: 266074 leukotriene D4 [ChEBI:28666] leukotriene D4 ChEBI CHEBI:28666 Reactome Database ID Release 81 266074 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266074 Reactome R-ALL-266074 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-266074.3 COMPOUND C05951 ACTIVATION Converted from EntitySet in Reactome GGT1, 5 dimers Reactome DB_ID: 2162130 GGT1 dimer Gamma-glutamyltransferase 1 Reactome DB_ID: 1247898 GGT1 GGT1(1-380) GGT1 heavy chain GGT1hc Gamma-glutamyltranspeptidase 1 GGT1_HUMAN Reactome DB_ID: 1247889 UniProt:P19440 GGT1 GGT1 GGT FUNCTION Cleaves the gamma-glutamyl bond of extracellular glutathione (gamma-Glu-Cys-Gly), glutathione conjugates and other gamma-glutamyl compounds, such as leukotriene C4 (LTC4). The metabolism of glutathione by GGT1 releases free glutamate and the dipeptide cysteinyl-glycine, which is hydrolyzed to cysteine and glycine by dipeptidases. In the presence of high concentrations of dipeptides and some amino acids, can also catalyze a transpeptidation reaction, transferring the gamma-glutamyl moiety to an acceptor amino acid to form a new gamma-glutamyl compound (PubMed:17924658, PubMed:7673200, PubMed:7759490, PubMed:8095045, PubMed:8827453, PubMed:21447318). Contributes to cysteine homeostasis, glutathione homeostasis and in the conversion of the leukotriene LTC4 to LTD4.ACTIVITY REGULATION Activated by autocatalytic cleavage (PubMed:23682772). Inhibited by serine-borate (PubMed:21447318).PATHWAY Lipid metabolism; leukotriene D4 biosynthesis.PATHWAY Sulfur metabolism; glutathione metabolism.SUBUNIT Heterodimer composed of the light and heavy chains. The active site is located in the light chain.TISSUE SPECIFICITY Detected in fetal and adult kidney and liver, adult pancreas, stomach, intestine, placenta and lung. There are several other tissue-specific forms that arise from alternative promoter usage but that produce the same protein.PTM N-glycosylated on both chains. Contains hexoses, hexosamines and sialic acid residues. Glycosylation profiles tested in kidney and liver tissues reveal the presence of tissue-specific and site-specific glycan composition, despite the overlap in composition among the N-glycans. A total of 36 glycan compositions, with 40 unique structures are observed. Up to 15 different glycans are observed at a single site, with site-specific variation in glycan composition. The difference in glycosylation profiles in the 2 tissues do not affect the enzyme activity.PTM Cleaved by autocatalysis into a large and a small subunit and the autocatalytic cleavage is essential to the functional activation of the enzyme.MISCELLANEOUS Cys-454 was thought to bind the gamma-glutamyl moiety, but mutagenesis of this residue had no effect on activity.MISCELLANEOUS Chloride ions bound in the active site cavity may contribute to stabilize the protein fold.SIMILARITY Belongs to the gamma-glutamyltransferase family. UniProt P19440 1 EQUAL 380 EQUAL Reactome Database ID Release 81 1247889 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1247889 Reactome R-HSA-1247889 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-1247889.1 1 GGT1 GGT1(381-569) GGT1 light chain GGT1lc Gamma-glutamyltranspeptidase 1 GGT1_HUMAN Reactome DB_ID: 8943263 381 EQUAL 569 EQUAL Reactome Database ID Release 81 8943263 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8943263 Reactome R-HSA-8943263 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-8943263.1 1 Reactome Database ID Release 81 1247898 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1247898 Reactome R-HSA-1247898 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-1247898.2 GGT5 dimer Gamma-glutamyltransferase 5 Reactome DB_ID: 265314 GGTLA1 GGT5(388-586) GGT5 light chain GGT5_HUMAN Reactome DB_ID: 265312 UniProt:P36269 GGT5 GGT5 GGTLA1 FUNCTION Cleaves the gamma-glutamyl peptide bond of glutathione and glutathione-S-conjugate such as leukotriene C4 (PubMed:21447318). Does not cleaves gamma-glutamyl compounds such as gamma-glutamyl leucine (PubMed:21447318). May also catalyze a transpeptidation reaction in addition to the hydrolysis reaction, transferring the gamma-glutamyl moiety to an acceptor amino acid to form a new gamma-glutamyl compound (PubMed:21447318). Acts as a negative regulator of geranylgeranyl glutathione bioactivity by cleaving off its gamma-glutamyl group, playing a role in adaptive immune responses (PubMed:30842656).ACTIVITY REGULATION Inhibited by serine-borate.PATHWAY Sulfur metabolism; glutathione metabolism.PATHWAY Lipid metabolism; leukotriene D4 biosynthesis.SUBUNIT Heterodimer composed of the light and heavy chains. The active site is located in the light chain.PTM Cleaved by autocatalysis into a large and a small subunit.PTM Glycosylated.MISCELLANEOUS A previous study reported that GSH and oxidized glutathione (GSSG) are not substrates for murine GGT5 (By similarity). However, this result contrasts with two studies reported that GSH is indeed a substrate for GGT5 (PubMed:21447318, PubMed:1676842).SIMILARITY Belongs to the gamma-glutamyltransferase family. UniProt P36269 388 EQUAL 586 EQUAL Reactome Database ID Release 81 265312 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265312 Reactome R-HSA-265312 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-265312.1 1 GGT5 GGT5(1-387) GGT5 heavy chain GGT5_HUMAN GGTLA1 Reactome DB_ID: 265313 1 EQUAL 387 EQUAL Reactome Database ID Release 81 265313 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265313 Reactome R-HSA-265313 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-265313.1 1 Reactome Database ID Release 81 265314 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265314 Reactome R-HSA-265314 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-265314.2 Reactome Database ID Release 81 2162130 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162130 Reactome R-HSA-2162130 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-2162130.2 GENE ONTOLOGY GO:0036374 Reactome Database ID Release 81 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 81 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 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 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 LEFT-TO-RIGHT 3.4.13.21 3.4.13.18 Further cleavage of LTD4 forms LTE4 LTD4 is converted to LTE4 by DPEP1/2 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 LTE4 leukotriene E4 Reactome DB_ID: 266033 leukotriene E4 [ChEBI:15650] leukotriene E4 ChEBI CHEBI:15650 Reactome Database ID Release 81 266033 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266033 Reactome R-ALL-266033 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-266033.3 COMPOUND C05952 Gly Aminoacetic acid glycine zwitterion glycine Reactome DB_ID: 266029 glycine zwitterion [ChEBI:57305] glycine zwitterion glycine DHMQDGOQFOQNFH-UHFFFAOYSA-N 2-azaniumylacetate C2H5NO2 InChI=1S/C2H5NO2/c3-1-2(4)5/h1,3H2,(H,4,5) [NH3+]CC([O-])=O 75.06660 ChEBI CHEBI:57305 Reactome Database ID Release 81 266029 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266029 Reactome R-ALL-266029 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-266029.4 COMPOUND C00037 ACTIVATION Converted from EntitySet in Reactome DPEP1,2,3 dimers Reactome DB_ID: 2162149 DPEP1 dimer Reactome DB_ID: 2142831 DPEP1 Dipeptidase 1 DPEP1_HUMAN Reactome DB_ID: 2142820 UniProt:P16444 DPEP1 DPEP1 MDP RDP FUNCTION Hydrolyzes a wide range of dipeptides including the conversion of leukotriene D4 to leukotriene E4 (PubMed:2303490, PubMed:6334084, PubMed:31442408). Hydrolyzes cystinyl-bis-glycine (cys-bis-gly) formed during glutathione degradation (By similarity). Possesses also beta lactamase activity and hydrolytically inactivates beta-lactam antibiotics (PubMed:6334084).FUNCTION Independently of its dipeptidase activity, acts as an adhesion receptor for neutrophil recruitment from bloodstream into inflamed lungs and liver.ACTIVITY REGULATION Inhibited by L-penicillamine (PubMed:31442408). Beta-lactamase activity is inhibited by cilastatin (PubMed:6334084, PubMed:31442408).SUBUNIT Homodimer; disulfide-linked.TISSUE SPECIFICITY Expressed in lung and kidneys.INDUCTION Up-regulated in n colorectal cancers.SIMILARITY Belongs to the metallo-dependent hydrolases superfamily. Peptidase M19 family. UniProt P16444 17 EQUAL 385 EQUAL Reactome Database ID Release 81 2142820 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142820 Reactome R-HSA-2142820 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-2142820.1 2 1 Reactome Database ID Release 81 2142831 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142831 Reactome R-HSA-2142831 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-2142831.1 DPEP2 dimer Dipeptidase homodimer (zinc cofactor) Reactome DB_ID: 266059 DPEP2 Dipeptidase 2-1 DPEP2_HUMAN Reactome DB_ID: 266067 UniProt:Q9H4A9 DPEP2 DPEP2 UNQ284/PRO323 FUNCTION Dipeptidase that hydrolyzes leukotriene D4 (LTD4) into leukotriene E4 (LTE4). Does not hydrolyze cystinyl-bis-glycine.FUNCTION Independently of its dipeptidase activity can also modulate macrophage inflammatory response by acting as a regulator of NF-kappaB inflammatory signaling pathway.ACTIVITY REGULATION Inhibited by L-penicillamine.SUBUNIT Homodimer; disulfide-linked.SIMILARITY Belongs to the metallo-dependent hydrolases superfamily. Peptidase M19 family. UniProt Q9H4A9 33 EQUAL 463 EQUAL Reactome Database ID Release 81 266067 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266067 Reactome R-HSA-266067 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-266067.1 2 1 Reactome Database ID Release 81 266059 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266059 Reactome R-HSA-266059 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-266059.1 DPEP3 dimer Reactome DB_ID: 5490228 DPEP3 Dipeptidase 3 ecNumber3.4.13.19/ecNumber DPEP3_HUMAN Reactome DB_ID: 5490265 UniProt:Q9H4B8 DPEP3 DPEP3 UNQ834/PRO1772 FUNCTION Dipeptidase that hydrolyzes cystinyl-bis-glycine. Does not hydrolyze leukotriene D4 (LTD4) into leukotriene E4 (LTE4).ACTIVITY REGULATION Inhibited by L-penicillamine.SUBUNIT Homodimer; disulfide-linked (By similarity). Interacts with TEX101; co-localized on the cell surface of spermatocytes, spermatids, and testicular spermatozoa, co-localized only in cytoplasmic droplets of caput and corpus epididymal sperm (By similarity).SIMILARITY Belongs to the metallo-dependent hydrolases superfamily. Peptidase M19 family. UniProt Q9H4B8 36 EQUAL 463 EQUAL Reactome Database ID Release 81 5490265 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5490265 Reactome R-HSA-5490265 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-5490265.1 2 1 Reactome Database ID Release 81 5490228 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5490228 Reactome R-HSA-5490228 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-5490228.1 Reactome Database ID Release 81 2162149 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162149 Reactome R-HSA-2162149 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-2162149.1 GENE ONTOLOGY GO:0016805 Reactome Database ID Release 81 266039 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266039 Reactome Database ID Release 81 266012 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266012 Reactome R-HSA-266012 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-266012.3 3563417 Pubmed 1987 Release and functional characterization of the leukotriene D4-metabolizing enzyme (dipeptidase) from human polymorphonuclear leucocytes Raulf, M König, W Köller, M Stüning, M Scand J Immunol 25:305-13 6293969 Pubmed 1983 Conversion of leukotriene D4 to leukotriene E4 by a dipeptidase released from the specific granule of human polymorphonuclear leucocytes Lee, CW Lewis, RA Corey, EJ Austen, KF Immunology 48:27-35 2768222 Pubmed 1989 Purification and characterization of human microsomal dipeptidase Adachi, Hideki Kubota, I Okamura, N Iwata, H Tsujimoto, M Nakazato, H Nishihara, T Noguchi, T J Biochem 105:957-61 LEFT-TO-RIGHT LTA4 is hydrolysed to 6t-/6t,12epi-LTB4 Non-enzymatic hydrolysis of the leukotriene A4 (LTA4) epoxide bond creates 6-trans leukotriene B4 (6t-LTB4) and 6-trans,12-epi leukotriene B4 (6t,12epi-LTB4) stereoisomers (Mansour & Agha 1999, Sirois et al. 1985). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Converted from EntitySet in Reactome 6t/6t,12epi-LTB4 Reactome DB_ID: 2161801 6t-LTB4 Delta(6)-trans-leukotriene B4 6-trans-leukotriene B4 Reactome DB_ID: 2142827 6-trans-leukotriene B4 [ChEBI:63981] 6-trans-leukotriene B4 ChEBI CHEBI:63981 Reactome Database ID Release 81 2142827 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142827 Reactome R-ALL-2142827 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142827.3 6t,12epi-LTB4 Delta(6)-trans-12-epi-leukotriene B4 Reactome DB_ID: 2142669 Delta(6)-trans-12-epi-leukotriene B4 [ChEBI:63982] Delta(6)-trans-12-epi-leukotriene B4 ChEBI CHEBI:63982 Reactome Database ID Release 81 2142669 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142669 Reactome R-ALL-2142669 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142669.3 Reactome Database ID Release 81 2161801 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161801 Reactome R-ALL-2161801 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2161801.1 Reactome Database ID Release 81 2161962 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161962 Reactome R-HSA-2161962 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-2161962.2 10741385 Pubmed 1999 Inhibition of calcium ionophore-stimulated leukotriene generation from intact human neutrophils by captopril Mansour, M Agha, A Res Commun Mol Pathol Pharmacol 104:345-60 2998743 Pubmed 1985 Metabolism of leukotrienes by adult and fetal human lungs Sirois, P Brousseau, Y Chagnon, M Gentile, J Gladu, M Salari, H Borgeat, P Exp Lung Res 9:17-30 LEFT-TO-RIGHT LTA4 is converted to EXA4 by ALOX15 Analogous to arachidonate 5-lipoxygenase (ALOX5) biosynthesis of leukotriene A4 (LTA4), arachidonate 15-lipoxygenase (ALOX15) can form an epoxide across C-14 and C-15 to form 14,15-LTA4 aka eoxin A4 (EXA4) (Feltenmark et al. 2008, Claesson et al. 2008). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 EXA4 eoxin A4 Reactome DB_ID: 2142772 eoxin A4 [ChEBI:63983] eoxin A4 ChEBI CHEBI:63983 Reactome Database ID Release 81 2142772 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142772 Reactome R-ALL-2142772 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142772.3 ACTIVATION ALOX15:Fe2+ Reactome DB_ID: 2142744 1 ALOX15 Arachidonate 15-lipoxygenase LOX15_HUMAN Reactome DB_ID: 2142838 UniProt:P16050 ALOX15 ALOX15 LOG15 FUNCTION Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids generating a spectrum of bioactive lipid mediators (PubMed:1944593, PubMed:8334154, PubMed:17052953, PubMed:24282679, PubMed:25293588, PubMed:32404334). It inserts peroxyl groups at C12 or C15 of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) producing both 12-hydroperoxyeicosatetraenoate/12-HPETE and 15-hydroperoxyeicosatetraenoate/15-HPETE (PubMed:1944593, PubMed:8334154, PubMed:17052953, PubMed:24282679). It may then act on 12-HPETE to produce hepoxilins, which may show proinflammatory properties (By similarity). Can also peroxidize linoleate ((9Z,12Z)-octadecadienoate) to 13-hydroperoxyoctadecadienoate/13-HPODE (PubMed:8334154). May participate in the sequential oxidations of DHA ((4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate) to generate specialized pro-resolving mediators (SPMs)like resolvin D5 ((7S,17S)-diHPDHA) and (7S,14S)-diHPDHA, that actively down-regulate the immune response and have anti-aggregation properties with platelets (PubMed:32404334). Can convert epoxy fatty acids to hydroperoxy-epoxides derivatives followed by an intramolecular nucleophilic substitution leading to the formation of monocyclic endoperoxides (PubMed:25293588). Plays an important role during the maintenance of self-tolerance by peroxidizing membrane-bound phosphatidylethanolamine which can then signal the sorting process for clearance of apoptotic cells during inflammation and prevent an autoimmune response. In addition to its role in the immune and inflammatory responses, this enzyme may play a role in epithelial wound healing in the cornea through production of lipoxin A4 (LXA(4)) and docosahexaenoic acid-derived neuroprotectin D1 (NPD1; 10R,17S-HDHA), both lipid autacoids exhibit anti-inflammatory and neuroprotective properties. Furthermore, it may regulate actin polymerization which is crucial for several biological processes such as the phagocytosis of apoptotic cells. It is also implicated in the generation of endogenous ligands for peroxisome proliferator activated receptor (PPAR-gamma), hence modulating macrophage development and function. It may also exert a negative effect on skeletal development by regulating bone mass through this pathway. As well as participates in ER stress and downstream inflammation in adipocytes, pancreatic islets, and liver (By similarity). Finally, it is also involved in the cellular response to IL13/interleukin-13 (PubMed:21831839).ACTIVITY REGULATION Activity is increased by binding phosphatidylinositol phosphates, especially phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 4,5-bisphosphate (PubMed:17052953). Inactivated at 37 degrees Celsius by (13S)-hydroperoxy-(9Z,11E)-octadecadienoate (PubMed:8334154).PATHWAY Lipid metabolism; hydroperoxy eicosatetraenoic acid biosynthesis.SUBUNIT Interacts with PEBP1; in response to IL13/interleukin-13, prevents the interaction of PEBP1 with RAF1 to activate the ERK signaling cascade.TISSUE SPECIFICITY Detected in monocytes and eosinophils (at protein level). Expressed in airway epithelial cells.INDUCTION Up-regulated by UV-irradiation.DOMAIN The PLAT domain can bind calcium ions; this promotes association with membranes.DISEASE Disease susceptibility may be associated with variants affecting the gene represented in this entry. Met at position 560 may confer interindividual susceptibility to coronary artery disease (CAD) (PubMed:17959182).SIMILARITY Belongs to the lipoxygenase family. UniProt P16050 2 EQUAL 662 EQUAL Reactome Database ID Release 81 2142838 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142838 Reactome R-HSA-2142838 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-2142838.1 1 Reactome Database ID Release 81 2142744 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142744 Reactome R-HSA-2142744 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-2142744.1 GENE ONTOLOGY GO:0097260 Reactome Database ID Release 81 2161993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161993 Reactome Database ID Release 81 2162019 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162019 Reactome R-HSA-2162019 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-2162019.2 18184802 Pubmed 2008 Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells Feltenmark, S Gautam, N Brunnström, A Griffiths, W Backman, L Edenius, C Lindbom, L Björkholm, M Claesson, HE Proc Natl Acad Sci U S A 105:680-5 18647347 Pubmed 2008 Hodgkin Reed-Sternberg cells express 15-lipoxygenase-1 and are putative producers of eoxins in vivo: novel insight into the inflammatory features of classical Hodgkin lymphoma Claesson, HE Griffiths, WJ Brunnström, A Schain, F Andersson, E Feltenmark, S Johnson, HA Porwit, A Sjöberg, J Björkholm, M FEBS J 275:4222-34 LEFT-TO-RIGHT EXA4 is converted to EXC4 by LTC4S In addition to its role converting leukotriene A4 (LTA4) into leukotriene C4 (LTC4), the enzyme leukotriene C4 synthase (LTC4S) analogously converts eoxin A4 (EXA4), with reduced glutathione (GSH), to eoxin C4 (EXC4) (Feltenmark et al. 2008, Claesson et al. 2008). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 EXC4 eoxin C4 Reactome DB_ID: 2142726 eoxin C4 [ChEBI:63984] eoxin C4 ChEBI CHEBI:63984 Reactome Database ID Release 81 2142726 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142726 Reactome R-ALL-2142726 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142726.3 ACTIVATION activeUnit: #Complex16 GENE ONTOLOGY GO:0097261 Reactome Database ID Release 81 2161978 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161978 Reactome Database ID Release 81 2161768 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161768 Reactome R-HSA-2161768 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-2161768.2 LEFT-TO-RIGHT EXC4 is converted to EXD4 by GGT In an analogous reaction to the formation of leukotriene D4 (LTD4), eoxin C4 (EXC4) is converted to eoxin D4 (EXD4) by a class of gamma-glutamyltransferase (GGT) (Feltenmark et al. 2008, Claesson et al. 2008) which has not yet been identified. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 L-Glu L-Glutamate L-glutamate(1-) L-glutamic acid L-Glutaminic acid Reactome DB_ID: 29404 Reactome Database ID Release 81 29404 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29404 Reactome R-ALL-29404 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29404.4 COMPOUND C00025 EXD4 eoxin D4 Reactome DB_ID: 2142758 eoxin D4 [ChEBI:63985] eoxin D4 ChEBI CHEBI:63985 Reactome Database ID Release 81 2142758 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142758 Reactome R-ALL-2142758 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142758.3 ACTIVATION GGT gamma-glutamyltransferase Reactome DB_ID: 2161915 Reactome Database ID Release 81 2161915 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161915 Reactome R-HSA-2161915 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-2161915.2 ChEBI 36080 GENE ONTOLOGY GO:0097262 Reactome Database ID Release 81 2161784 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161784 Reactome Database ID Release 81 2161945 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161945 Reactome R-HSA-2161945 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-2161945.2 LEFT-TO-RIGHT EXD4 is converted to EXE4 by DPEP In an analogous reaction to the formation of leukotriene E4 (LTE4), eoxin D4 (EXD4) is converted to eoxin E4 (EXE4) by a dipeptidase (DPEP) (Feltenmark et al. 2008, Claesson et al. 2008) which has not yet been identified. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Gly L-glycine glycine zwitterion glycine Aminoacetic acid Reactome DB_ID: 29424 Reactome Database ID Release 81 29424 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29424 Reactome R-ALL-29424 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29424.4 COMPOUND C00037 EXE4 eoxin E4 Reactome DB_ID: 2142730 eoxin E4 [ChEBI:63986] eoxin E4 ChEBI CHEBI:63986 Reactome Database ID Release 81 2142730 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142730 Reactome R-ALL-2142730 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142730.3 ACTIVATION DPEP Dipeptidase Reactome DB_ID: 2161751 Reactome Database ID Release 81 2161751 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161751 Reactome R-HSA-2161751 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-2161751.2 ChEBI 36080 GENE ONTOLOGY GO:0097263 Reactome Database ID Release 81 2161981 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161981 Reactome Database ID Release 81 2161868 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161868 Reactome R-HSA-2161868 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-2161868.2 Reactome Database ID Release 81 2142691 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142691 Reactome R-HSA-2142691 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-2142691.2 19130894 Pubmed 2009 On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphoma Claesson, HE Prostaglandins Other Lipid Mediat 89:120-5 17623009 Pubmed 2007 Biosynthesis and metabolism of leukotrienes Murphy, RC Gijon, MA Biochem J 405:379-95 6311078 Pubmed 1983 Leukotrienes Hammarström, Sven Annu Rev Biochem 52:355-77 GENE ONTOLOGY GO:0006691 Synthesis of 5-eicosatetraenoic acids 5-hydroperoxy-eicosatetraenoic acid (5-HpETE), 5-hydroxyeicosatetraenoic acid (5S-HETE) and 5-oxo-eicosatetraenoic acid (5-oxoETE) are formed after the initial step of arachidonic acid oxidation by arachidonate 5-lipoxygenase (ALOX5) (Buczynski et al. 2009, Vance & Vance 2008). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 LEFT-TO-RIGHT 1.11.1.9 5S-HpETE is reduced to 5S-HETE by GPX1/2/4 Glutathione peroxidase 1 (GPX1) (Bryant et al. 1982, Sutherland et al. 2001), 2 (GPX2) (Chu et al. 1993), and 4 (Bryant et al. 1982, Sutherland et al. 2001) reduce 5-hydroperoxyeicosatetraenoic acid (5-HpETE) to 5-hydroxyeicosatetraenoic acid (5-HETE) in the presence of glutathione (GSH). This reaction is inferred from the event in rabbit involving the protein GPX1 (Chiba et al. 1999). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 2 5S-HETE 5(S)-HETE Reactome DB_ID: 2142733 5(S)-HETE [ChEBI:28209] 5(S)-HETE ChEBI CHEBI:28209 Reactome Database ID Release 81 2142733 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142733 Reactome R-ALL-2142733 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142733.3 GSSG oxidized glutathione glutathione disulfide glutathione disulfide(2-) Reactome DB_ID: 111745 glutathione disulfide(2-) [ChEBI:58297] glutathione disulfide(2-) (2S,2'S)-5,5'-[disulfanediylbis({(2R)-3-[(carboxylatomethyl)amino]-3-oxopropane-1,2-diyl}imino)]bis(2-azaniumyl-5-oxopentanoate) glutathione disulfide glutathione disulfide dianion ChEBI CHEBI:58297 Reactome Database ID Release 81 111745 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111745 Reactome R-ALL-111745 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-111745.4 COMPOUND C00127 ACTIVATION Converted from EntitySet in Reactome GPX1/2/4 Reactome DB_ID: 2161954 GPX1 tetramer glutathione peroxidase tetramer Reactome DB_ID: 71674 GPX1 L-selenocysteine residue-GPX1 glutathione peroxidase monomer GSHC_HUMAN Glutathione peroxidase 1 GSHPx-1 Cellular glutathione peroxidase Reactome DB_ID: 71673 UniProt:P07203 GPX1 GPX1 FUNCTION Protects the hemoglobin in erythrocytes from oxidative breakdown. In platelets, plays a crucial role of glutathione peroxidase in the arachidonic acid metabolism (PubMed:11115402).SUBUNIT Homotetramer. Interacts with MIEN1.TISSUE SPECIFICITY Expressed in platelets (at protein level).PTM During periods of oxidative stress, Sec-49 may react with a superoxide radical, irreversibly lose hydroselenide and be converted to dehydroalanine.SIMILARITY Belongs to the glutathione peroxidase family. UniProt P07203 49 EQUAL L-selenocysteine residue MOD MOD:00031 1 EQUAL 203 EQUAL Reactome Database ID Release 81 71673 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=71673 Reactome R-HSA-71673 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-71673.1 4 Reactome Database ID Release 81 71674 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=71674 Reactome R-HSA-71674 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-71674.1 GPX4 L-selenocysteine-residue-GPX4(?-197) Phospholipid hydroperoxide glutathione peroxidase, mitochondrial GPX4_HUMAN Reactome DB_ID: 2142826 UniProt:P36969 GPX4 GPX4 FUNCTION Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins (By similarity). Can also reduce fatty acid hydroperoxide, cholesterol hydroperoxide and thymine hydroperoxide (By similarity). Plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation (By similarity). Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron-dependent accumulation of lipid reactive oxygen species (PubMed:24439385). The presence of selenocysteine (Sec) versus Cys at the active site is essential for life: it provides resistance to overoxidation and prevents cells against ferroptosis (By similarity). The presence of Sec at the active site is also essential for the survival of a specific type of parvalbumin-positive interneurons, thereby preventing against fatal epileptic seizures (By similarity). May be required to protect cells from the toxicity of ingested lipid hydroperoxides (By similarity). Required for normal sperm development and male fertility (By similarity). Essential for maturation and survival of photoreceptor cells (By similarity). Plays a role in a primary T-cell response to viral and parasitic infection by protecting T-cells from ferroptosis and by supporting T-cell expansion (By similarity). Plays a role of glutathione peroxidase in platelets in the arachidonic acid metabolism (PubMed:11115402). Reduces hydroperoxy ester lipids formed by a 15-lipoxygenase that may play a role as down-regulator of the cellular 15-lipoxygenase pathway (By similarity).SUBUNIT Monomer. Has a tendency to form higher mass oligomers.TISSUE SPECIFICITY Present primarily in testis. Expressed in platelets (at protein level) (PubMed:11115402).SIMILARITY Belongs to the glutathione peroxidase family. UniProt P36969 73 EQUAL 1 EQUAL 197 EQUAL Reactome Database ID Release 81 2142826 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142826 Reactome R-HSA-2142826 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-2142826.2 GPX2 tetramer glutathione peroxidase tetramer Reactome DB_ID: 2142735 GPX2 L-selenocysteine-residue-GPX2 Glutathione peroxidase 2 GPX2_HUMAN Reactome DB_ID: 2142687 UniProt:P18283 GPX2 GPX2 FUNCTION Could play a major role in protecting mammals from the toxicity of ingested organic hydroperoxides. Tert-butyl hydroperoxide, cumene hydroperoxide and linoleic acid hydroperoxide but not phosphatidycholine hydroperoxide, can act as acceptors.SUBUNIT Homotetramer.TISSUE SPECIFICITY Mostly in liver and gastrointestinal tract, not found in heart or kidney.SIMILARITY Belongs to the glutathione peroxidase family. UniProt P18283 40 EQUAL 1 EQUAL 190 EQUAL Reactome Database ID Release 81 2142687 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142687 Reactome R-HSA-2142687 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-2142687.2 4 Reactome Database ID Release 81 2142735 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142735 Reactome R-HSA-2142735 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-2142735.1 Reactome Database ID Release 81 2161954 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161954 Reactome R-HSA-2161954 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-2161954.1 GENE ONTOLOGY GO:0004602 Reactome Database ID Release 81 2161908 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161908 Reactome Database ID Release 81 2161946 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161946 Reactome R-HSA-2161946 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-2161946.2 8428933 Pubmed 1993 Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GI Chu, FF Doroshow, JH Esworthy, RS J Biol Chem 268:2571-6 6816802 Pubmed 1982 Role of glutathione peroxidase and hexose monophosphate shunt in the platelet lipoxygenase pathway Bryant, RW Simon, TC Bailey, JM J Biol Chem 257:14937-43 10549853 Pubmed 1999 Cellular glutathione peroxidase as a predominant scavenger of hydroperoxyeicosatetraenoic acids in rabbit alveolar macrophages Chiba, N Imai, H Narashima, K Arai, M Oshima, G Kunimoto, M Nakagawa, Y Biol Pharm Bull 22:1047-51 11115402 Pubmed 2001 Evidence for the presence of phospholipid hydroperoxide glutathione peroxidase in human platelets: implications for its involvement in the regulatory network of the 12-lipoxygenase pathway of arachidonic acid metabolism Sutherland, M Shankaranarayanan, P Schewe, T Nigam, S Biochem J 353:91-100 LEFT-TO-RIGHT 5S-HETE is oxidised to 5-oxoETE by 5-HEDH Current literature suggests that 5S-hydroxy-eicosatetraenoic acid (5S-HETE) itself does not appear to play a significant role in biological signalling. However, it can be further oxidised by a 5-hydroxy-eicosatetraenoic acid dehydrogenase (5-HEDH) to form the bioactive 5-oxo-eicosatetraenoic acid (5-oxoETE, also known as 5-KETE. While the gene has not yet been cloned, the biophysical properties of the human enzyme have been well characterised (Powell et al. 1992). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 5-oxoETE 5-oxo-ETE Reactome DB_ID: 2161921 5-oxo-ETE [ChEBI:52449] 5-oxo-ETE ChEBI CHEBI:52449 Reactome Database ID Release 81 2161921 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161921 Reactome R-ALL-2161921 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2161921.3 ACTIVATION 5-HEDH 5-hydroxy-eicosatetraenoic acid dehydrogenase Reactome DB_ID: 2161764 Reactome Database ID Release 81 2161764 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161764 Reactome R-HSA-2161764 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-2161764.2 ChEBI 36080 GENE ONTOLOGY GO:0097265 Reactome Database ID Release 81 2161975 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161975 Reactome Database ID Release 81 2161776 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161776 Reactome R-HSA-2161776 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-2161776.2 1326548 Pubmed 1992 Metabolism of 5(S)-hydroxy-6,8,11,14-eicosatetraenoic acid and other 5(S)-hydroxyeicosanoids by a specific dehydrogenase in human polymorphonuclear leukocytes Powell, WS Gravelle, F Gravel, S J Biol Chem 267:19233-41