BioPAX pathway converted from "Arachidonic acid metabolism" in the Reactome database. Arachidonic acid metabolism Arachidonic acid metabolism Eicosanoids, oxygenated, 20-carbon fatty acids, are autocrine and paracrine signaling molecules that modulate physiological processes including pain, fever, inflammation, blood clot formation, smooth muscle contraction and relaxation, and the release of gastric acid. Eicosanoids are synthesized in humans primarily from arachidonic acid (all-cis 5,8,11,14-eicosatetraenoic acid) that is released from membrane phospholipids. Once released, arachidonic acid is acted on by prostaglandin G/H synthases (PTGS, also known as cyclooxygenases (COX)) to form prostaglandins and thromboxanes, by arachidonate lipoxygenases (ALOX) to form leukotrienes, epoxygenases (cytochrome P450s and epoxide hydrolase) to form epoxides such as 15-eicosatetraenoic acids, and omega-hydrolases (cytochrome P450s) to form hydroxyeicosatetraenoic acids (Buczynski et al. 2009, Vance & Vance 2008).<br>Levels of free arachidonic acid in the cell are normally very low so the rate of synthesis of eicosanoids is determined primarily by the activity of phospholipase A2, which mediates phospholipid cleavage to generate free arachidonic acid. The enzymes involved in arachidonic acid metabolism are typically constitutively expressed so the subset of these enzymes expressed by a cell determines the range of eicosanoids it can synthesize.<br>Eicosanoids are unstable, undergoing conversion to inactive forms with half-times under physiological conditions of seconds or minutes. Many of these reactions appear to be spontaneous. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Hydrolysis of phosphatidylcholine Hydrolysis of phosphatidylcholine Once bound to the membrane, cPLA2 hydrolyzes phosphatidylcholine to produce arachidonic acid (AA), a precursor to inflammatory mediators. While several phospholipases can catalyze this reaction in cells overexpressing the enzymes, PLA2G4A is the major enzyme that catalyzes this reaction in vivo (Reed et al. 2011). At the same time, possible physiological roles have been described for soluble phospholipases (sPLA) in the mobilization of arachidonic acid in some cell types or under some physiological conditions (Murakami et al. 2011). Here, the major role of PLA2G4A has been annotated. Authored: Le Novere, N, Jassal, B, 2004-03-31 12:22:05 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-11-06 Reactome DB_ID: 426925 1 endoplasmic reticulum membrane GO 0005789 1,2-diacyl-sn-glycero-3-phosphocholine [ChEBI:57643] 1,2-diacyl-sn-glycero-3-phosphocholine 1,2-diacyl-sn-glycero-3-phosphocholine betaine PC 1,2-diacyl-sn-glycero-3-phosphocholines 3-sn-phosphatidylcholine Diacyl PC Phosphatidylcholine 3-sn-phosphatidylcholines lecithin a 1,2-diacyl-sn-glycero-3-phosphocholine Reactome http://www.reactome.org ChEBI 57643 Reactome DB_ID: 29356 1 cytosol GO 0005829 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 428981 1 1-O-acyl-sn-glycero-3-phosphocholine(1+) [ChEBI:17504] 1-O-acyl-sn-glycero-3-phosphocholine(1+) ChEBI 17504 Reactome DB_ID: 140356 1 endoplasmic reticulum lumen GO 0005788 arachidonate [ChEBI:32395] arachidonate (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (20:4n6) (5Z,8Z,11Z,14Z)-eicosatetraenoate ChEBI 32395 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 111860 Active PLA2:phosphatidylcholine [endoplasmic reticulum membrane] Active PLA2:phosphatidylcholine Reactome DB_ID: 426925 1 Reactome DB_ID: 111859 1 UniProt:P47712 PLA2G4A PLA2G4A CPLA2 PLA2G4A PLA2G4 FUNCTION Has primarily calcium-dependent phospholipase and lysophospholipase activities, with a major role in membrane lipid remodeling and biosynthesis of lipid mediators of the inflammatory response (PubMed:7794891, PubMed:8619991, PubMed:8702602, PubMed:9425121, PubMed:10358058, PubMed:14709560, PubMed:16617059, PubMed:17472963, PubMed:27642067, PubMed:18451993). Plays an important role in embryo implantation and parturition through its ability to trigger prostanoid production (By similarity). Preferentially hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) (PubMed:7794891, PubMed:8619991, PubMed:9425121, PubMed:10358058, PubMed:17472963, PubMed:18451993). Selectively hydrolyzes sn-2 arachidonoyl group from membrane phospholipids, providing the precursor for eicosanoid biosynthesis via the cyclooxygenase pathway (PubMed:18451993, PubMed:7794891, PubMed:9425121, PubMed:10358058, PubMed:17472963). In an alternative pathway of eicosanoid biosynthesis, hydrolyzes sn-2 fatty acyl chain of eicosanoid lysophopholipids to release free bioactive eicosanoids (PubMed:27642067). Hydrolyzes the ester bond of the fatty acyl group attached at sn-1 position of phospholipids (phospholipase A1 activity) only if an ether linkage rather than an ester linkage is present at the sn-2 position. This hydrolysis is not stereospecific (PubMed:7794891). Has calcium-independent phospholipase A2 and lysophospholipase activities in the presence of phosphoinositides (PubMed:12672805). Has O-acyltransferase activity. Catalyzes the transfer of fatty acyl chains from phospholipids to a primary hydroxyl group of glycerol (sn-1 or sn-3), potentially contributing to monoacylglycerol synthesis (PubMed:7794891).ACTIVITY REGULATION Activated by cytosolic calcium, which is necessary for binding to membrane lipids (PubMed:12672805). Activated by phosphorylation in response to mitogenic stimuli (PubMed:8381049). Activated by ceramide-1-phosphate. Binding (via C2 domain) to ceramide-1-phosphate increases the affinity for membrane lipids (PubMed:17472963). Can be activated by phosphoinositides in the absence of calcium (PubMed:12672805). Inhibited by ANXA5 in a calcium- and substrate-dependent way (PubMed:9425121).PATHWAY Membrane lipid metabolism; glycerophospholipid metabolism.PATHWAY Lipid metabolism; arachidonate metabolism.PATHWAY Lipid metabolism; prostaglandin biosynthesis.PATHWAY Lipid metabolism; leukotriene B4 biosynthesis.SUBUNIT Interacts with KAT5.TISSUE SPECIFICITY Expressed in various cells and tissues such as macrophages, neutrophils, fibroblasts and lung endothelium. Expressed in platelets (at protein level) (PubMed:25102815).DOMAIN The N-terminal C2 domain associates with lipid membranes upon calcium binding. It modulates enzyme activity by presenting the active site to its substrate in response to elevations of cytosolic calcium (PubMed:9430701, PubMed:9665851, PubMed:11375391). In the presence of phosphoinositides, regulates phospholipase A2 and lysophospholipase activities in a calcium-independent way (PubMed:12672805).PTM Phosphorylated at both Ser-505 and Ser-727 in response to mitogenic stimuli. Homo sapiens NCBI Taxonomy 9606 UniProt P47712 O-phospho-L-serine at 505 505 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 727 727 EQUAL Chain Coordinates 1 EQUAL 749 EQUAL Reactome DB_ID: 74016 1 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI 29108 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 GO 0047498 GO molecular function 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 Arachidonate diffuses across the ER membrane Arachidonate diffuses across the ER membrane Arachidonate released by phospholipases diffuses within the membrane and out of the membrane into the ER lumen and cytosol. The relatively low level of arachidonate in the cytoplasm is probably due to reesterification into complex lipids by acyl transferases. Authored: Jupe, S, 2009-07-14 Reviewed: Rush, MG, 2012-11-10 Edited: Jupe, S, 2009-07-14 Reactome DB_ID: 140356 1 Reactome DB_ID: 29768 1 Reactome Database ID Release 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 2.3.1.75 AWAT1 transfers acyl group from acyl-CoA to ARACOH, forming wax esters AWAT1 transfers acyl group from acyl-CoA to ARACOH, forming wax esters Arachidyl alcohol (ARACOH) is straight-chain fatty alcohol of C20 length used as an emollient in cosmetics. Esterification of alcohols with fatty acids represents the formation of both storage and cytoprotective molecules in the body. Overproduction of these esters is associated with several disease pathologies, including atherosclerosis and obesity. The ER membrane-associated acyl-CoA wax alcohol acyltransferase 1 (AWAT1) mediates the esterification of its preferred substrate ARACOH (Turkish et al. 2005). Authored: Jassal, Bijay, 2015-05-29 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-05-29 Reactome DB_ID: 5696426 1 icosan-1-ol [ChEBI:75627] icosan-1-ol arachidyl alcohol eicosyl alcohol eicosan-1-ol arachidic alcohol 1-eicosanol ChEBI 75627 Reactome DB_ID: 192172 1 acyl-CoA [ChEBI:17984] acyl-CoA ChEBI 17984 Reactome DB_ID: 162743 1 coenzyme A(4-) [ChEBI:57287] coenzyme A(4-) CoA 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-({3-oxo-3-[(2-sulfanylethyl)amino]propyl}amino)butyl] diphosphate} ChEBI 57287 Reactome DB_ID: 5696412 1 wax ester [ChEBI:10036] wax ester Wax esters ChEBI 10036 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5696425 UniProt:Q58HT5 AWAT1 AWAT1 AWAT1 DGAT2L3 DGA2 FUNCTION Acyltransferase that catalyzes the formation of ester bonds between fatty alcohols and fatty acyl-CoAs to form wax monoesters (PubMed:15671038). Shows a strong preference for decyl alcohol (C10), with less activity towards C16 and C18 alcohols (PubMed:15671038). Shows a strong preference for saturated acyl-CoAs (PubMed:15671038).TISSUE SPECIFICITY Predominantly expressed in skin, where it is limited to the sebaceous gland. Expressed in more mature, centrally located cells just before their rupture and sebum release. Also expressed in all tissues except spleen. Expressed at higher level in thymus, prostate and testis.SIMILARITY Belongs to the diacylglycerol acyltransferase family. UniProt Q58HT5 1 EQUAL 328 EQUAL GO 0047196 GO molecular function Reactome Database ID Release 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 FAAH hydrolyses AEA to AA and ETA FAAH hydrolyses AEA to AA and ETA Fatty acid amides are a class of lipid transmitters that include the endogenous cannabinoid anandamide (AEA) and the sleep-inducing chemical oleamide. The magnitude and duration of their signalling are controlled by enzymatic hydrolysis mediated by fatty-acid amide hydrolases 1 and 2 (FAAH, H2). Hydrolysis of AEA is described here (Wei et al. 2006). FAAH is localised to the ER membrane whereas FAAH2 is localised to lipid droplets (Kaczocha et al. 2010). Authored: Jassal, Bijay, 2015-05-18 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-05-18 Reactome DB_ID: 29356 1 Reactome DB_ID: 5693754 1 anandamide [ChEBI:2700] anandamide ChEBI 2700 Reactome DB_ID: 1498751 1 ethanolamine [ChEBI:16000] ethanolamine ChEBI 16000 Reactome DB_ID: 29768 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5693746 UniProt:O00519 FAAH FAAH FAAH FAAH1 FUNCTION Catalyzes the hydrolysis of endogenous amidated lipids like the sleep-inducing lipid oleamide ((9Z)-octadecenamide), the endocannabinoid anandamide (N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine), as well as other fatty amides, to their corresponding fatty acids, thereby regulating the signaling functions of these molecules (PubMed:9122178, PubMed:17015445, PubMed:19926788). Hydrolyzes polyunsaturated substrate anandamide preferentially as compared to monounsaturated substrates (PubMed:9122178, PubMed:17015445). It can also catalyze the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol) (PubMed:21049984). FAAH cooperates with PM20D1 in the hydrolysis of amino acid-conjugated fatty acids such as N-fatty acyl glycine and N-fatty acyl-L-serine, thereby acting as a physiological regulator of specific subsets of intracellular, but not of extracellular, N-fatty acyl amino acids (By similarity).ACTIVITY REGULATION Inhibited by O-aryl carbamates and alpha-keto heterocycles (PubMed:17015445). Inhibited by trifluoromethyl ketone (PubMed:9122178).SUBUNIT Homodimer.TISSUE SPECIFICITY Highly expressed in the brain, small intestine, pancreas, skeletal muscle and testis. Also expressed in the kidney, liver, lung, placenta and prostate.POLYMORPHISM Genetic variations in FAAH can be associated with susceptibility to polysubstance abuse [MIM:606581]. At homozygosity, variant Thr-129 is strongly associated with drug and alcohol abuse, and methamphetamine dependence.SIMILARITY Belongs to the amidase family. UniProt O00519 1 EQUAL 579 EQUAL GO 0017064 GO molecular function Reactome Database ID Release 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 FAAH2 hydrolyses AEA to AA and ETA FAAH2 hydrolyses AEA to AA and ETA Fatty acid amides are a class of lipid transmitters that include the endogenous cannabinoid anandamide (AEA) and the sleep-inducing chemical oleamide. The magnitude and duration of their signalling are controlled by enzymatic hydrolysis mediated by fatty-acid amide hydrolases 1 and 2 (FAAH, H2). Hydrolysis of AEA is described here (Wei et al. 2006). FAAH is localised to the ER membrane whereas FAAH2 is localised to lipid droplets (Kaczocha et al. 2010). Authored: Jassal, Bijay, 2015-05-18 Reviewed: D'Eustachio, Peter, 2015-06-26 Edited: Jassal, Bijay, 2015-05-18 Reactome DB_ID: 5693752 1 lipid droplet GO 0005811 Reactome DB_ID: 5693747 1 Reactome DB_ID: 5693736 1 Reactome DB_ID: 5693733 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5693745 UniProt:Q6GMR7 FAAH2 FAAH2 AMDD FAAH2 FUNCTION Catalyzes the hydrolysis of endogenous amidated lipids like the sleep-inducing lipid oleamide ((9Z)-octadecenamide), the endocannabinoid anandamide (N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-ethanolamine), as well as other fatty amides, to their corresponding fatty acids, thereby regulating the signaling functions of these molecules (PubMed:17015445, PubMed:19926788). Hydrolyzes monounsaturated substrate anandamide preferentially as compared to polyunsaturated substrates.ACTIVITY REGULATION Inhibited by O-aryl carbamates and alpha-keto heterocytes.SUBUNIT Homodimer.TISSUE SPECIFICITY Expressed in kidney, liver, lung, prostate, heart and ovary.SIMILARITY Belongs to the amidase family. UniProt Q6GMR7 1 EQUAL 532 EQUAL Reactome Database ID Release 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) Synthesis of Prostaglandins (PG) and Thromboxanes (TX) The bioactive prostaglandin (PG) signalling molecules, including PGA2, PGE2, PGF2a, and PGI2 (prostacyclin) are synthesised from arachidonic acid and its products by various prostaglandin synthase type enzymes. Prostaglandin H2 (PGH2) is the starting point for the synthesis of Thromboxanes (TXs) (Buczynski et al. 2009, Vance & Vance 2008). PGs and TXs are collectively known as the prostanoids.<br>Two enzymes, PTGS1 and 2 (COX1 and 2) both catalyze the two-step conversion of arachidonic acid to PGH2. PTGS1 is constitutively expressed in many cell types while PTGS2 is induced in response to stress and mediates the syntheses of prostaglandins associated with pain, fever, and inflammation. Aspirin irreversibly inactivates both enzymes (though it acts more efficiently on PTGS1), explaining both its antiinflammatory effects and side effects like perturbed gastic acid secretion. Drugs like celecoxib, by specifically inhibiting PTGS2, have a strong anti-inflammatory effect with fewer side effects. These PTGS2-specific drugs, however, probably because of their effects on the balance of prostaglandin synthesis in platelets and endothelial cells, can also promote blood clot formation (Buczynski et al. 2009; Stables & Gilroy 2011). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 PTGS2 dimer binds PTGS2 inhibitors PTGS2 dimer binds PTGS2 inhibitors While closely similar, PTGS1 and 2 differ sufficiently in the structures of their active sites so that the latter enzyme selectively binds and is inhibited by PTGS2 inhibitors (benzquinamide, carprofen, celecoxib, etodolac, etoricoxib, lumiracoxib, rofecoxib, valdecoxib) (Luong et al. 1996; Smith et al. 2000; Dong et al. 2011). Authored: D'Eustachio, P, 2012-06-05 Reviewed: Rush, MG, 2012-11-10 Edited: D'Eustachio, P, 2012-06-05 Reactome DB_ID: 140491 1 PTGS2 dimer [endoplasmic reticulum membrane] PTGS2 dimer PGHS2 dimer Reactome DB_ID: 2311355 1 heme b [ChEBI:26355] heme b protoheme heme [3,7,12,17-tetramethyl-8,13-divinylporphyrin-2,18-dipropanoato(2-)]iron haem b PROTOPORPHYRIN IX CONTAINING FE protoheme IX (7,12-diethenyl-3,8,13,17-tetramethylporphyrin-2,18-dipropanoato)iron ChEBI 26355 Reactome DB_ID: 61605 2 UniProt:P35354 PTGS2 PTGS2 COX2 PTGS2 FUNCTION Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate, with a particular role in the inflammatory response (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593, PubMed:11939906, PubMed:19540099). The cyclooxygenase activity oxygenates arachidonate (AA, C20:4(n-6)) to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide PGH2, the precursor of all 2-series prostaglandins and thromboxanes (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593). This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:7947975, PubMed:7592599, PubMed:9261177, PubMed:16373578, PubMed:22942274, PubMed:26859324, PubMed:27226593). Similarly catalyzes successive cyclooxygenation and peroxidation of dihomo-gamma-linoleate (DGLA, C20:3(n-6)) and eicosapentaenoate (EPA, C20:5(n-3)) to corresponding PGH1 and PGH3, the precursors of 1- and 3-series prostaglandins (PubMed:11939906, PubMed:19540099). In an alternative pathway of prostanoid biosynthesis, converts 2-arachidonoyl lysophopholipids to prostanoid lysophopholipids, which are then hydrolyzed by intracellular phospholipases to release free prostanoids (PubMed:27642067). Metabolizes 2-arachidonoyl glycerol yielding the glyceryl ester of PGH2, a process that can contribute to pain response (PubMed:22942274). Generates lipid mediators from n-3 and n-6 polyunsaturated fatty acids (PUFAs) via a lipoxygenase-type mechanism. Oxygenates PUFAs to hydroperoxy compounds and then reduces them to corresponding alcohols (PubMed:11034610, PubMed:11192938, PubMed:9048568, PubMed:9261177). Plays a role in the generation of resolution phase interaction products (resolvins) during both sterile and infectious inflammation (PubMed:12391014). Metabolizes docosahexaenoate (DHA, C22:6(n-3)) to 17R-HDHA, a precursor of the D-series resolvins (RvDs) (PubMed:12391014). As a component of the biosynthetic pathway of E-series resolvins (RvEs), converts eicosapentaenoate (EPA, C20:5(n-3)) primarily to 18S-HEPE that is further metabolized by ALOX5 and LTA4H to generate 18S-RvE1 and 18S-RvE2 (PubMed:21206090). In vascular endothelial cells, converts docosapentaenoate (DPA, C22:5(n-3)) to 13R-HDPA, a precursor for 13-series resolvins (RvTs) shown to activate macrophage phagocytosis during bacterial infection (PubMed:26236990). In activated leukocytes, contributes to oxygenation of hydroxyeicosatetraenoates (HETE) to diHETES (5,15-diHETE and 5,11-diHETE) (PubMed:22068350, PubMed:26282205). During neuroinflammation, plays a role in neuronal secretion of specialized preresolving mediators (SPMs) 15R-lipoxin A4 that regulates phagocytic microglia (By similarity).ACTIVITY REGULATION The cyclooxygenase activity is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, flurbiprofen, celecoxib, flufenamic, mefenamic and tolfenamic acids as well as by hydroperoxide scavenger erythrocyte glutathione peroxidase GPX1 (PubMed:26859324, PubMed:27226593, PubMed:7592599, PubMed:9048568). Aspirin triggers enzyme acetylation turning off its ability to generate 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 140491 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140491 Reactome R-HSA-140491 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-140491.1 Converted from EntitySet in Reactome Reactome DB_ID: 9716714 1 PTGS2 inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity valdecoxib [cytosol] carprofen [cytosol] rofecoxib [cytosol] etodolac [cytosol] benzquinamide [cytosol] celecoxib [cytosol] etoricoxib [cytosol] lumiracoxib [cytosol] Guide to Pharmacology 2894 Guide to Pharmacology 7141 Guide to Pharmacology 2893 Guide to Pharmacology 7185 Guide to Pharmacology 7124 Guide to Pharmacology 2892 Guide to Pharmacology 2896 Guide to Pharmacology 2897 Reactome DB_ID: 2309778 1 PTGS2 dimer:PTGS2 inhibitors [endoplasmic reticulum membrane] PTGS2 dimer:PTGS2 inhibitors Reactome DB_ID: 140491 1 Converted from EntitySet in Reactome Reactome DB_ID: 9716714 1 Reactome Database ID Release 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 ASA- acetylates PTGS1 ASA- acetylates PTGS1 The ionized form of aspirin, acetylsalicylate (ASA-) reacts spontaneously with one subunit of PTGS1 dimer to acetylate serine residue 516. The modified enzyme is no longer capable of catalyzing the conversion of arachidonic acid to PGH2. The identity of the acetylated residue is inferred from data for the humann PTGS2 enzyme (Lecomte et al. 1994) and the ovine PGHS1 enzyme (Loll et al. 1995). Authored: D'Eustachio, P, 2012-06-07 Reviewed: Rush, MG, 2012-11-10 Edited: D'Eustachio, P, 2012-06-07 Reactome DB_ID: 428986 1 PTGS1 dimer [endoplasmic reticulum membrane] PTGS1 dimer PGHS1 homodimer COX1 Reactome DB_ID: 2311355 1 Reactome DB_ID: 428931 2 UniProt:P23219 PTGS1 PTGS1 COX1 PTGS1 FUNCTION Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate, with a particular role in the inflammatory response. The cyclooxygenase activity oxygenates arachidonate (AA, C20:4(n-6)) to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide PGH2, the precursor of all 2-series prostaglandins and thromboxanes. This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons (PubMed:7947975). Involved in the constitutive production of prostanoids in particular in the stomach and platelets. In gastric epithelial cells, it is a key step in the generation of prostaglandins, such as prostaglandin E2 (PGE2), which plays an important role in cytoprotection. In platelets, it is involved in the generation of thromboxane A2 (TXA2), which promotes platelet activation and aggregation, vasoconstriction and proliferation of vascular smooth muscle cells (Probable).ACTIVITY REGULATION The cyclooxygenase activity is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen, flurbiprofen, ketoprofen, naproxen, flurbiprofen, anirolac, fenclofenac and diclofenac.PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Homodimer.MISCELLANEOUS The conversion of arachidonate to prostaglandin H2 is a 2 step reaction: a cyclooxygenase (COX) reaction which converts arachidonate to prostaglandin G2 (PGG2) and a peroxidase reaction in which PGG2 is reduced to prostaglandin H2 (PGH2). The cyclooxygenase reaction occurs in a hydrophobic channel in the core of the enzyme. The peroxidase reaction occurs at a heme-containing active site located near the protein surface. The nonsteroidal anti-inflammatory drugs (NSAIDs) binding site corresponds to the cyclooxygenase active site.MISCELLANEOUS Conversion of arachidonate to prostaglandin H2 is mediated by 2 different isozymes: the constitutive PTGS1 and the inducible PTGS2. PTGS1 is expressed constitutively and generally produces prostanoids acutely in response to hormonal stimuli to fine-tune physiological processes requiring instantaneous, continuous regulation (e.g. hemostasis). PTGS2 is inducible and typically produces prostanoids that mediate responses to physiological stresses such as infection and inflammation.MISCELLANEOUS PTGS1 and PTGS2 are the targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin and ibuprofen. Aspirin is able to produce an irreversible inactivation of the enzyme through a serine acetylation. Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. PTGS2 is the principal isozyme responsible for production of inflammatory prostaglandins. New generation PTGSs inhibitors strive to be selective for PTGS2, to avoid side effects such as gastrointestinal complications and ulceration.SIMILARITY Belongs to the prostaglandin G/H synthase family. UniProt P23219 24 EQUAL 599 EQUAL Reactome Database ID Release 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 Reactome DB_ID: 2314693 1 acetylsalicylate [ChEBI:13719] acetylsalicylate ChEBI 13719 Reactome DB_ID: 2314695 1 Ac-PTGS1 dimer [endoplasmic reticulum membrane] Ac-PTGS1 dimer Reactome DB_ID: 2311355 1 Reactome DB_ID: 428931 1 24 EQUAL 599 EQUAL Reactome DB_ID: 2314694 1 O-acetyl-L-serine at 529 529 EQUAL O-acetyl-L-serine 24 EQUAL 599 EQUAL Reactome Database ID Release 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 Reactome DB_ID: 2314690 1 salicylate [ChEBI:30762] salicylate o-hydroxybenzoate 2-hydroxybenzoic acid ion(1-) sal ChEBI 30762 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 ASA- acetylates PTGS2 ASA- acetylates PTGS2 The ionized form of aspirin, acetylsalicylate (ASA-) reacts spontaneously with one subunit of PTGS2 dimer (Dong et al. 2011) to acetylate serine residue 516 (Lecomte et al. 1994). The modified enzyme is no longer capable of catalyzing the conversion of arachidonic acid to PGH2, but acquires the ability to convert it to 15R-HETE. Authored: D'Eustachio, P, 2012-06-07 Reviewed: Rush, MG, 2012-11-10 Edited: D'Eustachio, P, 2012-06-07 Reactome DB_ID: 140491 1 Reactome DB_ID: 2314693 1 Reactome DB_ID: 2314687 1 Ac-PTGS2 dimer [endoplasmic reticulum membrane] Ac-PTGS2 dimer Reactome DB_ID: 2311355 1 Reactome DB_ID: 2161824 1 O-acetyl-L-serine at 516 516 EQUAL 18 EQUAL 604 EQUAL Reactome DB_ID: 61605 1 18 EQUAL 604 EQUAL Reactome Database ID Release 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 DB_ID: 2314690 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 1.14.99.1 Arachidonic acid is oxidised to PGG2 by PTGS1 Arachidonic acid is oxidised to PGG2 by PTGS1 Arachidonic acid oxidised to PGG2 Prostaglandin G/H synthase PTGS1 exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The cyclooxygenase function catalyzes the initial conversion of arachidonic acid to an intermediate, prostaglandin G2 (PGG2) (Hamberg et al. 1974, Nugteren 1973). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-05-28 09:06:10 Edited: Jassal, Bijay, 2008-05-19 Reactome DB_ID: 140356 1 Reactome DB_ID: 113534 2 dioxygen [ChEBI:15379] dioxygen ChEBI 15379 Reactome DB_ID: 140357 1 prostaglandin G2 [ChEBI:27647] prostaglandin G2 ChEBI 27647 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 428986 GO 0004666 GO molecular function Reactome Database ID Release 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 PTGS1 dimer binds PTGS1 Inhibitors PTGS1 dimer binds PTGS1 Inhibitors Prostaglandins are involved in physiological functions such as protecting the stomach mucosa, platelet aggregation and regulating kidney function. They also play pathological roles in inflammation, fever and pain (Ricciotti & FitzGerald 2011). Cyclooxygenase enzymes mediate the production of protaglandins. Prostaglandin G/H synthase 1 (PTGS1, cyclooxygenase 1, COX1) is a mainly constitutively expressed enzyme that acts in a 'housekeeping' fashion producing prostaglandins for physiological functions whereas prostaglandin G/H synthase 2 (PTGS2, cyclooxygenase 2, COX2) is an inducible form which mediates protaglandin production for inflammation.<br><br>In 1971, John R Vane showed that the pharmacological actions of aspirin and similar nonsteroid anti-inflammatory drugs (NSAIDs) were due to the inhibition of cyclooxygenase (Vane 1971). Thus, aspirin-like drugs exert their anti-inflammatory, antipyretic and analgesic effects by the inhibition of cyclooxygenase (Vane & Botting 1997, Botting 2006). The beneficial actions of NSAIDs can be associated with inhibition of COX2 whereas their harmful side effects are associated with inhibition of COX1 therefore developing drugs with a high COX2 specificity is advantageous (Cryer & Feldman 1998, Warner et al. 1999, García-Rayado et al. 2018, Saad & Matthew 2020).<br><br>Most NSAIDs possess some or all of antipyretic, analgesic and anti-inflammatory properties and are used to treat rheumatic and osteoarthritic conditions, pain, inflammation and fever (Botting 2006, Crofford 2013). Authored: Jassal, Bijay, 2020-03-05 Reviewed: Huddart, Rachel, 2022-03-01 Edited: Jassal, Bijay, 2020-03-05 Edited: Matthews, Lisa, 2022-05-10 Converted from EntitySet in Reactome Reactome DB_ID: 9677343 1 PTGS1 Inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity indomethacin [cytosol] APAP [cytosol] meloxicam [cytosol] nimesulide [cytosol] fenoprofen [cytosol] bromfenac [cytosol] Guide to Pharmacology 1909 Guide to Pharmacology 5239 Guide to Pharmacology 7220 Guide to Pharmacology 7401 Guide to Pharmacology 4820 Guide to Pharmacology 7131 Reactome DB_ID: 428986 1 Reactome DB_ID: 9677354 1 PTGS1 dimer:PTGS1 Inhibitors [endoplasmic reticulum membrane] PTGS1 dimer:PTGS1 Inhibitors Converted from EntitySet in Reactome Reactome DB_ID: 9677343 1 Reactome DB_ID: 428986 1 Reactome Database ID Release 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 1.14.99.1 Arachidonic acid is oxidised to PGG2 by PTGS2 Arachidonic acid is oxidised to PGG2 by PTGS2 Arachidonic acid oxidised to PGG2 Prostaglandin G/H synthase PTGS2 exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The cyclooxygenase function catalyzes the initial conversion of arachidonic acid to an intermediate, prostaglandin G2 (PGG2) (Hamberg et al. 1974, Nugteren 1973). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-05-28 09:06:10 Edited: Jassal, Bijay, 2008-05-19 Reactome DB_ID: 140356 1 Reactome DB_ID: 113534 2 Reactome DB_ID: 140357 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 140491 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 1.11.1.7 PGG2 is reduced to PGH2 by PTGS1 PGG2 is reduced to PGH2 by PTGS1 Peroxidative reduction of PGG2 to PGH2 Prostaglandin G/H synthase 1 (PTGS1) exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The peroxidase function converts prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) via a two-electron reduction (Hamberg et al. 1973, Hla & Neilson 1992, Swinney et al. 1997, Barnett et al. 1994). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 Reactome DB_ID: 156540 2 hydron [ChEBI:15378] hydron ChEBI 15378 Reactome DB_ID: 76342 2 electron [ChEBI:10545] electron ChEBI 10545 Reactome DB_ID: 140357 1 Reactome DB_ID: 113519 1 Reactome DB_ID: 30138 1 prostaglandin H2 [ChEBI:15554] prostaglandin H2 ChEBI 15554 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 428986 GO 0004601 GO molecular function 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 1.11.1.7 PGG2 is reduced to PGH2 by PTGS2 PGG2 is reduced to PGH2 by PTGS2 Peroxidative reduction of PGG2 to PGH2 Prostaglandin G/H synthase 2 (PTGS2) exhibits a dual catalytic activity, a cyclooxygenase and a peroxidase. The peroxidase function converts prostaglandin G2 (PGG2) to prostaglandin H2 (PGH2) via a two-electron reduction (Hamberg et al. 1973, Hla & Neilson 1992, Swinney et al. 1997, Barnett et al. 1994). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 Reactome DB_ID: 156540 2 Reactome DB_ID: 76342 2 Reactome DB_ID: 140357 1 Reactome DB_ID: 113519 1 Reactome DB_ID: 30138 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 140491 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 Reactome DB_ID: 549282 1-methylnicotinamide [ChEBI:16797] 1-methylnicotinamide ChEBI 16797 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 Reactome DB_ID: 2309778 PGH2 diffuses from the endoplasmic reticulum lumen to the cytosol PGH2 diffuses from the endoplasmic reticulum lumen to the cytosol PGH2 moves from the endoplasmic reticulum to the cytosol. The mechanism of this movement has not been determined and could could simply be diffusion through the ER membrane. Authored: D'Eustachio, P, 2012-06-04 Reviewed: Rush, MG, 2012-11-10 Reactome DB_ID: 30138 1 Reactome DB_ID: 265283 1 Reactome Database ID Release 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 PGH2 is reduced to PGF2a by AKR1C3 PGH2 is reduced to PGF2a by AKR1C3 Aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS is responsible for the reduction of prostaglandin H2 (PGH2) to prostaglandin F2alpha (PGF2a) (Suzuki-Yamamoto et al. 1999, Komoto et al. 2004, Komoto et al. 2006). There is an additional way of achieving this reaction involving the prostamide/prostaglandin F synthase, FAM213B and thioredoxin (TRX). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 265283 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 29364 1 NADPH(4-) [ChEBI:57783] NADPH(4-) NADPH 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH tetraanion ChEBI 57783 Reactome DB_ID: 879535 1 prostaglandin F2alpha [ChEBI:15553] prostaglandin F2alpha ChEBI 15553 Reactome DB_ID: 29366 1 NADP(3-) [ChEBI:58349] NADP(3-) NADP(+) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADP trianion ChEBI 58349 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142714 UniProt:P42330 AKR1C3 AKR1C3 PGFS KIAA0119 DDH1 AKR1C3 HSD17B5 FUNCTION Cytosolic aldo-keto reductase that catalyzes the NADH and NADPH-dependent reduction of ketosteroids to hydroxysteroids. Acts as a NAD(P)(H)-dependent 3-, 17- and 20-ketosteroid reductase on the steroid nucleus and side chain and regulates the metabolism of androgens, estrogens and progesterone (PubMed:10622721, PubMed:11165022, PubMed:7650035, PubMed:9415401, PubMed:9927279). Displays the ability to catalyze both oxidation and reduction in vitro, but most probably acts as a reductase in vivo since the oxidase activity measured in vitro is inhibited by physiological concentration of NADPH (PubMed:14672942, PubMed:11165022). Acts preferentially as a 17-ketosteroid reductase and has the highest catalytic efficiency of the AKR1C enzyme for the reduction of delta4-androstenedione to form testosterone (PubMed:20036328). Reduces prostaglandin (PG) D2 to 11beta-prostaglandin F2, progesterone to 20alpha-hydroxyprogesterone and estrone to 17beta-estradiol (PubMed:15047184, PubMed:20036328, PubMed:10622721, PubMed:11165022, PubMed:10998348, PubMed:19010934). Catalyzes the transformation of the potent androgen dihydrotestosterone (DHT) into the less active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol) (PubMed:10998348, PubMed:14672942, PubMed:11165022, PubMed:7650035, PubMed:9415401, PubMed:10557352). 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 GO 0036130 GO molecular function 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 1.11.1 PGH2 is reduced to PGF2a by FAM213B PGH2 is reduced to PGF2a by FAM213B Prostamide/prostaglandin F synthase, FAM213B and thioredoxin (TXN) are the proteins involved in the reduction of prostaglandin H2 (PGH2) to prostaglandin F2alpha (PGF2a) (Moriuchi et al. 2008, Yoshikawa et al. 2011). This reaction has been inferred from an event in mice. An additional way of achieving this reaction involves the protein aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 265283 1 Reactome DB_ID: 2142774 1 thioredoxin dithiol [ChEBI:15967] thioredoxin dithiol ChEBI 15967 Reactome DB_ID: 879535 1 Reactome DB_ID: 2142833 1 thioredoxin disulfide [ChEBI:18191] thioredoxin disulfide ChEBI 18191 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142703 UniProt:Q8TBF2 PRXL2B PRXL2B FAM213B PRXL2B C1orf93 FUNCTION Catalyzes the reduction of prostaglandin-ethanolamide H(2) (prostamide H(2)) to prostamide F(2alpha) with NADPH as proton donor. Also able to reduce prostaglandin H(2) to prostaglandin F(2alpha) (By similarity).SIMILARITY Belongs to the peroxiredoxin-like PRXL2 family. Prostamide/prostaglandin F synthase subfamily. UniProt Q8TBF2 1 EQUAL 198 EQUAL GO 0008379 GO molecular function Reactome Database ID Release 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 5.3.99.3 PGH2 is isomerised to PGE2 by PTGES PGH2 is isomerised to PGE2 by PTGES Prostaglandin E synthase (PTGES) requires glutathione (GSH) as an essential cofactor for its enzymatic activity, and together they isomerise prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2) (Jegerschold et al. 2008). After PGH2 has been produced by the prostaglandin G/H synthases (PTGS1 and 2) on the lumenal side of the endoplasmic reticulum, it diffuses through the membrane to the active site of PTGES located on the cytoplasmic side. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 265283 1 Reactome DB_ID: 265287 1 prostaglandin E2 [ChEBI:15551] prostaglandin E2 ChEBI 15551 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142686 PTGES trimer [endoplasmic reticulum membrane] PTGES trimer Prostaglandin E synthase homotrimer Reactome DB_ID: 2142717 3 UniProt:O14684 PTGES PTGES PGES MPGES1 PIG12 MGST1L1 PTGES FUNCTION Terminal enzyme of the cyclooxygenase (COX)-2-mediated prostaglandin E2 (PGE2) biosynthetic pathway. Catalyzes the glutathione-dependent oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2) in response to inflammatory stimuli (PubMed:18682561, PubMed:10377395, PubMed:12672824, PubMed:12460774, PubMed:10869354, PubMed:12244105). Plays a key role in inflammation response, fever and pain (By similarity). Catalyzes also the oxidoreduction of endocannabinoids into prostaglandin glycerol esters and PGG2 into 15-hydroperoxy-PGE2 (PubMed:12244105, PubMed:12672824). In addition, displays low glutathione transferase and glutathione-dependent peroxidase activities, toward 1-chloro-2,4-dinitrobenzene and 5-hydroperoxyicosatetraenoic acid (5-HPETE), respectively (PubMed:12672824).ACTIVITY REGULATION Induced by interleukin IL1B.PATHWAY Lipid metabolism; prostaglandin biosynthesis.SUBUNIT Homotrimer.INDUCTION Induced by the interleukin IL1B (PubMed:10377395, PubMed:10760517). Induced By p53/TP53 (PubMed:9305847).SIMILARITY Belongs to the MAPEG family. UniProt O14684 1 EQUAL 152 EQUAL Reactome DB_ID: 2239524 3 glutathione [ChEBI:16856] glutathione ChEBI 16856 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 GO 0050220 GO molecular function 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 5.3.99.3 Prostaglandin E synthase isomerizes PGH2 to PGE2 Prostaglandin E synthase isomerizes PGH2 to PGE2 Prostaglandin E2 (PGE2) is the most abundant prostanoid in the body and is a major mediator of inflammation in diseases such as osteoarthritis and rheumatoid arthritis. The product of arachidonic acid, prostaglandin H2 (PGH2) serves as the substrate for the isomerization to PGE2. The conversion is carried out by prostaglandin E synthases. Of the three forms, two are predominanly cytosolic. Prostaglandin E synthase 3 (PTGES3) is also called cytosolic prostaglandin E2 synthase (cPGES). Prostaglandin E synthase 2 (mPGES-2, PTGES2) is synthesized as a Golgi membrane-associated protein which undergoes a spontaneous cleavage of the N-terminal hydrophobic domain leading to a truncated mature cytosolic protein. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Reactome DB_ID: 265283 1 Reactome DB_ID: 265287 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 8864254 PTGES2(88-377), PTGES3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PTGES3 [cytosol] PTGES2(88-377) [cytosol] UniProt Q15185 UniProt Q9H7Z7 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 1.1.1.189 PGE2 is converted to PGF2a by CBR1 PGE2 is converted to PGF2a by CBR1 Carbonyl reductase (CBR1) aka prostaglandin 9-keto reductase inactivates prostaglandin E2 (PGE2) by converting it to prostaglandin F2alpha (PGF2a) (Wermuth 1981, Miura et al. 2008). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 70106 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 265287 1 Reactome DB_ID: 879535 1 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142784 UniProt:P16152 CBR1 CBR1 CBR1 CBR SDR21C1 CRN FUNCTION NADPH-dependent reductase with broad substrate specificity. Catalyzes the reduction of a wide variety of carbonyl compounds including quinones, prostaglandins, menadione, plus various xenobiotics. Catalyzes the reduction of the antitumor anthracyclines doxorubicin and daunorubicin to the cardiotoxic compounds doxorubicinol and daunorubicinol (PubMed:18449627, PubMed:15799708, PubMed:17912391, PubMed:7005231). 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 GO 0050221 GO molecular function 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 PGE2 is dehydrated to PGA2 PGE2 is dehydrated to PGA2 Cyclopentenone prostaglandins comprise a family of molecules that are formed by dehydration of hydroxyl moieties in prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Dehydration of PGE2 leads to prostaglandin A2 (PGA2) (Hamberg & Samuelsson B 1966, Amin 1989). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 265287 1 Reactome DB_ID: 2299726 1 prostaglandin A2 [ChEBI:27820] prostaglandin A2 ChEBI 27820 Reactome DB_ID: 29356 1 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 PGA2 is isomerised to PGC2 PGA2 is isomerised to PGC2 Dehydration in the cyclopentane ring of prostaglandin E2 (PGE2) yields prostaglandin A2 (PGA2) followed by isomerization of the double bond to yield the unstable compound prostaglandin C2 (PGC2) (Straus & Glass, 2001). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2299726 1 Reactome DB_ID: 2299724 1 prostaglandin C2 [ChEBI:27555] prostaglandin C2 ChEBI 27555 Reactome Database ID Release 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 PGC2 is isomerised to PGB2 PGC2 is isomerised to PGB2 Isomerization of the double bond in prostaglandin A2 (PGA2) forms prostaglandin C2 (PGC2). This is an unstable compound which undergoes a second isomerization to yield prostaglandin B2 (PGB2) (Straus & Glass, 2001). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2299724 1 Reactome DB_ID: 2299721 1 prostaglandin B2 [ChEBI:28099] prostaglandin B2 ChEBI 28099 Reactome Database ID Release 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 PGA2 is dehydrated to 15d-PGA2 PGA2 is dehydrated to 15d-PGA2 The non-enzymatic dehydration of prostaglandin A2 (PGA2) into 15-deoxy prostaglandin A2 (15d-PGA2) which occurs in mice (Petrova et al. 1999) is inferred in humans. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2299726 1 Reactome DB_ID: 2299722 1 15-deoxy-Delta(12,14)-prostaglandin A2 [ChEBI:63975] 15-deoxy-Delta(12,14)-prostaglandin A2 ChEBI 63975 Reactome DB_ID: 29356 1 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 5.3.99.2 PGH2 is isomerised to PGD2 by PTGDS PGH2 is isomerised to PGD2 by PTGDS Prostaglandin D2 (PGD2) is a structural isomer of prostaglandin E2 (PGE2). There is a 9-keto and 11-hydroxy group on PGE2 with these substituents reversed on PGD2. PGD2 is formed by two evolutionarily distinct, but functionally convergent, prostaglandin D synthases: lipocalin-type prostaglandin-D synthase aka Prostaglandin-H2 D-isomerase (PTDGS) and hematopoietic prostaglandin D synthase (HPGDS). One of the main differences between these two proteins is that HPGDS requires glutathione (GSH) for catalysis while PTDGS can function without this cofactor. Here, PTDGS promotes the isomerisation of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2) (Zhou et al. 2010). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 30138 1 Reactome DB_ID: 2161634 1 prostaglandin D2 [ChEBI:15555] prostaglandin D2 ChEBI 15555 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142814 UniProt:P41222 PTGDS PTGDS PTGDS PDS FUNCTION Catalyzes the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation (PubMed:20667974). Involved in a variety of CNS functions, such as sedation, NREM sleep and PGE2-induced allodynia, and may have an anti-apoptotic role in oligodendrocytes. Binds small non-substrate lipophilic molecules, including biliverdin, bilirubin, retinal, retinoic acid and thyroid hormone, and may act as a scavenger for harmful hydrophobic molecules and as a secretory retinoid and thyroid hormone transporter. Possibly involved in development and maintenance of the blood-brain, blood-retina, blood-aqueous humor and blood-testis barrier. It is likely to play important roles in both maturation and maintenance of the central nervous system and male reproductive system (PubMed:20667974, PubMed:9475419). Involved in PLA2G3-dependent maturation of mast cells. PLA2G3 is secreted by immature mast cells and acts on nearby fibroblasts upstream to PTDGS to synthesize PGD2, which in turn promotes mast cell maturation and degranulation via PTGDR (By similarity).SUBUNIT Monomer.TISSUE SPECIFICITY Abundant in the brain and CNS, where it is expressed in tissues of the blood-brain barrier and secreted into the cerebro-spinal fluid. Abundantly expressed in the heart. In the male reproductive system, it is expressed in the testis, epididymis and prostate, and is secreted into the seminal fluid. Expressed in the eye and secreted into the aqueous humor. Lower levels detected in various tissue fluids such as serum, normal urine, ascitic fluid and tear fluid. Also found in a number of other organs including ovary, fimbriae of the fallopian tubes, kidney, leukocytes.DEVELOPMENTAL STAGE Expression in the amniotic fluid increases dramatically during weeks 12 to 25 of pregnancy. Levels decrease slowly after 25 weeks.INDUCTION By IL1B/interleukin-1 beta and thyroid hormone. Probably induced by dexamethasone, dihydrotestosterone (DHT), progesterone, retinoic acid and retinal. Repressed by the Notch-Hes signaling pathway.DOMAIN Forms a beta-barrel structure that accommodates hydrophobic ligands in its interior.PTM N- and O-glycosylated. Both N-glycosylation recognition sites are almost quantitatively occupied by N-glycans of the biantennary complex type, with a considerable proportion of structures bearing a bisecting GlcNAc. N-glycan at Asn-78: dHex1Hex5HexNAc4. Agalacto structure as well as sialylated and nonsialylated oligosaccharides bearing alpha2-3- and/or alpha2-6-linked NeuNAc are present.MISCELLANEOUS It has been proposed that the urinary and serum levels may provide a sensitive indicator of renal damage in diabetes mellitus and hypertension. Elevated levels in the coronary circulation may also be associated with angina. Changes in charge and molecular weight microheterogeneity, due to modification of the N-linked oligosaccharides, may be associated with neurodegenerative disease and multiple sclerosis. Detected in meningioma but not in other brain tumors and may be considered a specific cell marker for meningioma. Expression levels in amniotic fluid are altered in abnormal pregnancies. Levels are lower in pregnancies with trisomic fetuses and fetuses with renal abnormalities.SIMILARITY Belongs to the calycin superfamily. Lipocalin family. UniProt P41222 23 EQUAL 190 EQUAL GO 0004667 GO molecular function Reactome Database ID Release 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 5.3.99.2 PGH2 is isomerised to PGD2 by HPGDS PGH2 is isomerised to PGD2 by HPGDS Prostaglandin D2 (PGD2) is a structural isomer of prostaglandin E2 (PGE2). There is a 9-keto and 11-hydroxy group on PGE2 with these substituents reversed on PGD2. PGD2 is formed by two evolutionarily distinct, but functionally convergent, prostaglandin D synthases: lipocalin-type prostaglandin-D synthase aka Prostaglandin-H2 D-isomerase (PTDGS) and hematopoietic prostaglandin D synthase (HPGDS). One of the main differences between these two proteins is that HPGDS requires glutathione (GSH) for catalysis while PTDGS can function without this cofactor. Here, HPGDS with GSH promotes the isomerisation of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2) (Jowsey et al. 2001, Inoue et al. 2003). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 265283 1 Reactome DB_ID: 879629 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142683 HPGDS dimer [cytosol] HPGDS dimer Reactome DB_ID: 29450 2 glutathionate(1-) [ChEBI:57925] glutathionate(1-) glutathionate anion glutathionate ion glutathione glutathionate ChEBI 57925 Reactome DB_ID: 2142706 2 UniProt:O60760 HPGDS HPGDS HPGDS PGDS PTGDS2 GSTS FUNCTION Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjugation of glutathione with a wide range of aryl halides and organic isothiocyanates. Also exhibits low glutathione-peroxidase activity towards cumene hydroperoxide.ACTIVITY REGULATION Prostaglandin PGD2 synthesis is stimulated by calcium and magnesium ions. One calcium or magnesium ion is bound between the subunits of the homodimer. The interactions with the protein are for the most part mediated via water molecules. Magnesium increases the affinity for glutathione, while calcium has no effect on the affinity for glutathione.SUBUNIT Homodimer.TISSUE SPECIFICITY Expressed in a number of megakaryocytic cell lines but not in platelets. Highly expressed in adipose tissue, macrophages and placenta. Also expressed at lower levels in lung, heart, lymph nodes, appendix, bone marrow and fetal liver.DEVELOPMENTAL STAGE Highest levels in immature megakaryocytic cells. Disappears after final differentiation to platelets.INDUCTION By 12-O-tetradecanoylphorbol-13-acetate (TPA).SIMILARITY Belongs to the GST superfamily. Sigma family. UniProt O60760 2 EQUAL 199 EQUAL Reactome 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 PGD2 is dehydrated to PGJ2 PGD2 is dehydrated to PGJ2 Analogous to prostaglandin E2 (PGE2), dehydration of the prostaglandin D2 (PGD2) prostane ring forms prostaglandin J2 (PGJ2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2161634 1 Reactome DB_ID: 2142674 1 prostaglandin J2 [ChEBI:27485] prostaglandin J2 ChEBI 27485 Reactome DB_ID: 113519 1 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 PGJ2 is isomerised to delta12-PGJ2 PGJ2 is isomerised to delta12-PGJ2 Delta-12-prostaglandin J2 (delta12-PGJ2) is an isomerisation product of prostaglandin J2 (PGJ2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2142674 1 Reactome DB_ID: 2142821 1 13,14-dihydro-Delta(12)-prostaglandin J2 [ChEBI:28130] 13,14-dihydro-Delta(12)-prostaglandin J2 ChEBI 28130 Reactome Database ID Release 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 Delta12-PGJ2 is dehydrated to 15d-PGJ2 Delta12-PGJ2 is dehydrated to 15d-PGJ2 15-Deoxy-delta(12,14)-PDJ2 (15d-PGJ2) is a dehydration product of delta-12-prostaglandin J2 (delta12-PGJ2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2142821 1 Reactome DB_ID: 2142702 1 15-deoxy-Delta(12,14)-prostaglandin J2 [ChEBI:34159] 15-deoxy-Delta(12,14)-prostaglandin J2 15-Deoxy-delta-12,14-PGJ2 15-Deoxy-delta-12,14-prostaglandin J2 15-Deoxy-PGJ2 ChEBI 34159 Reactome DB_ID: 113519 1 Reactome Database ID Release 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 PGD2 is dehydrated to 15d-PGD2 PGD2 is dehydrated to 15d-PGD2 15-Deoxy-delta 12,14-prostaglandins D2 (15d-PGD2) is a dehydrated form of prostaglandin D2 (PGD2) (Monneret et al. 2002). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2161634 1 Reactome DB_ID: 2142817 1 15-deoxy-Delta(12,14)-prostaglandin D2 [ChEBI:63999] 15-deoxy-Delta(12,14)-prostaglandin D2 ChEBI 63999 Reactome DB_ID: 113519 1 Reactome Database ID Release 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 1.1.1.188 PGD2 is reduced to 11-epi-PGF2a by AKRIC3 PGD2 is reduced to 11-epi-PGF2a by AKRIC3 Aldo-keto reductase family 1 member C3 (AKR1C3) aka PGFS is the enzyme involved in NADPH-dependent prostaglandin D2 11-keto reductase activity of reducing prostaglandin D2 (PGD2) to 11-epi-Prostaglandin F2alpha (11-epi-PGF2a) (Liston & Roberts 1985, Koda et al. 2004). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 70106 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 879629 1 Reactome DB_ID: 2142710 1 11-epi-prostaglandin F2alpha [ChEBI:27595] 11-epi-prostaglandin F2alpha ChEBI 27595 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142714 1 EQUAL 323 EQUAL GO 0036131 GO molecular function Reactome Database ID Release 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 1.1.1.141 PGD2/E2/F2a is oxidised to 15k-PGD2/E2/F2a by HPGD PGD2/E2/F2a is oxidised to 15k-PGD2/E2/F2a by HPGD 15-Hydroxyprostaglandin dehydrogenase (HPGD) oxidises prostaglandins D2 (PGD2), E2 (PGE2), and F2alpha (PGF2a) to 15-keto-prostaglandin D2 (15k-PGD2), E2 (15k-PGE2), and F2alpha (15k-PGF2a) respectively (Cho et al. 2006). This reaction is inferred from rabbits (Bergholte & Okita 1986). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29360 1 NAD(1-) [ChEBI:57540] NAD(1-) NAD(+) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD anion ChEBI 57540 Converted from EntitySet in Reactome Reactome DB_ID: 2161661 1 PGD2/E2/F2a [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PGF2a [cytosol] PGD2 [cytosol] PGE2 [cytosol] Reactome DB_ID: 70106 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161597 1 15k-PGD2,15k-PGE2,15k-PGF2a [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 15k-PGE2 [cytosol] 15k-PGF2a [cytosol] 15k-PGD2 [cytosol] ChEBI 15547 ChEBI 28442 ChEBI 15557 Reactome DB_ID: 73473 1 NADH(2-) [ChEBI:57945] NADH(2-) NADH dianion adenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADH ChEBI 57945 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142778 HPGD dimer [cytosol] HPGD dimer Reactome DB_ID: 2142677 2 UniProt:P15428 HPGD HPGD HPGD SDR36C1 PGDH1 FUNCTION Catalyzes the NAD-dependent dehydrogenation (oxidation) of a broad array of hydroxylated polyunsaturated fatty acids (mainly eicosanoids and docosanoids, including prostaglandins, lipoxins and resolvins), yielding their corresponding keto (oxo) metabolites (PubMed:8086429, PubMed:10837478, PubMed:16828555, PubMed:16757471, PubMed:21916491, PubMed:25586183). Decreases the levels of the pro-proliferative prostaglandins such as prostaglandin E2 (whose activity is increased in cancer because of an increase in the expression of cyclooxygenase 2) and generates oxo-fatty acid products that can profoundly influence cell function by abrogating 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 2142778 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142778 Reactome R-HSA-2142778 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142778.1 GO 0016404 GO molecular function Reactome Database ID Release 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 1.3.1.48 15k-PGE2/F2a is reduced to dhk-PGE2/F2a by PTGR1 15k-PGE2/F2a is reduced to dhk-PGE2/F2a by PTGR1 Prostaglandin reductase 2 (PTGR2) is a 13-prostaglandin reductase which metabolises eicosanoids by catalysing NADH/NADPH-dependant double bond reduction in 15-keto-prostaglandin E2 (15k-PGE2) and F2alpha (15k-PGF2a) to produce 13,14-dihydro-15-keto-prostaglandin E2 (dhk-PGE2) and F2alpha (dhk-PGF2a) respectively (Wu et al. 2008). This has been inferred from the reaction event in mice involving prostaglandin reductase 2 (Ptgr2) (Chou et al. 2007). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 70106 1 Reactome DB_ID: 29364 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161650 1 15k-PGE2,15k-PGF2a [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 15k-PGE2 [cytosol] 15k-PGF2a [cytosol] Reactome DB_ID: 29366 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161684 1 dhk-PGE2,dhk-PGF2a [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity dhk-PGF2a [cytosol] dhk-PGE2 [cytosol] ChEBI 63976 ChEBI 15550 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 8940670 UniProt:Q8N8N7 PTGR2 PTGR2 ZADH1 PTGR2 FUNCTION Functions as 15-oxo-prostaglandin 13-reductase and acts on 15-keto-PGE1, 15-keto-PGE2, 15-keto-PGE1-alpha and 15-keto-PGE2-alpha with highest activity towards 15-keto-PGE2 (PubMed:19000823). Overexpression represses transcriptional activity of PPARG and inhibits adipocyte differentiation (By similarity).SUBUNIT Monomer.TISSUE SPECIFICITY Widely expressed.SIMILARITY Belongs to the NADP-dependent oxidoreductase L4BD family. UniProt Q8N8N7 1 EQUAL 351 EQUAL GO 0036132 GO molecular function Reactome Database ID Release 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 5.3.99.4 PTGIS, CYP8A1 isomerise PGH2 to PGI2 PTGIS, CYP8A1 isomerise PGH2 to PGI2 Prostacyclin synthase (CYP8A1) mediates the isomerization of prostaglandin H2 to prostaglandin I2 Prostacyclin synthase (PTGIS) aka CYP8A1 mediates the isomerisation of prostaglandin H2 (PGH2) to prostaglandin I2 (PGI2) aka prostacyclin (Wada et al. 2004). This reaction is not coupled with any P450 reductase proteins nor consumes NADPH. Experiments on rats with thrombolytic models suggest endogenous MNA could be a stimulator of the COX2/PGI2 pathway and thus regulate an anti-thrombotic effect (Chlopicki et al. 2007). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 Reactome DB_ID: 30138 1 Reactome DB_ID: 31593 1 prostaglandin I2 [ChEBI:15552] prostaglandin I2 ChEBI 15552 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 3222410 PTGIS,CYP8B1 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PTGIS [endoplasmic reticulum membrane] UniProt Q16647 GO 0008116 GO molecular function Reactome Database ID Release 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 PGI2 is hydrolysed to 6k-PGF1a PGI2 is hydrolysed to 6k-PGF1a The ring in prostaglandin I2 (PGI2) aka prostacyclin is highly labile and rapidly hydolyses to form the stable but biologically inactive 6-keto-prostaglandin F1alpha (6k-PGF1a) (Wada et al. 2004). PGI2 and 6k-PGF1a are often used interchangeably in the literature. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 31593 1 Reactome DB_ID: 113519 1 Reactome DB_ID: 2142786 1 6-oxoprostaglandin F1alpha [ChEBI:28158] 6-oxoprostaglandin F1alpha ChEBI 28158 Reactome Database ID Release 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 5.3.99.5 TBXAS1 isomerises PGH2 to TXA2 TBXAS1 isomerises PGH2 to TXA2 Thromboxane synthase (CYP5A1) mediates the isomerization of prostaglandin H2 to thromboxane A2 Thromboxane synthase (TBXAS1) aka CYP5A1 mediates the isomerisation of prostaglandin H2 (PGH2) to thromboxane A2 (TXA2) (Miyata et al. 2001, Chevalier et al. 2001). This reaction is not coupled with any P450 reductase proteins nor consumes NADPH. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 Reactome DB_ID: 30138 1 Reactome DB_ID: 32879 1 thromboxane A2 [ChEBI:15627] thromboxane A2 ChEBI 15627 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 65976 UniProt:P24557 TBXAS1 TBXAS1 TXAS CYP5 TBXAS1 CYP5A1 FUNCTION Catalyzes the conversion of prostaglandin H2 (PGH2) to thromboxane A2 (TXA2), a potent inducer of blood vessel constriction and platelet aggregation (PubMed:8436233, PubMed:11297515, PubMed:9873013, PubMed:11097184, PubMed:24009185, PubMed:22735388). Cleaves also PGH2 to 12-hydroxy-heptadecatrienoicacid (12-HHT) and malondialdehyde, which is known to act as a mediator of DNA damage. 12-HHT and malondialdehyde are formed stoichiometrically in the same amounts as TXA2 (PubMed:11297515, PubMed:9873013, PubMed:22735388). Additionally, displays dehydratase activity, toward (15S)-hydroperoxy-(5Z,8Z,11Z,13E)-eicosatetraenoate (15(S)-HPETE) producing 15-KETE and 15-HETE (PubMed:17459323).PATHWAY Lipid metabolism; fatty acid metabolism.SUBUNIT Monomer.TISSUE SPECIFICITY Platelets, lung, kidney, spleen, macrophages and lung fibroblasts.DISEASE Thromboxane synthetase deficiency has been detected in some patients with a bleeding disorder due to platelet dysfunction.SIMILARITY Belongs to the cytochrome P450 family.CAUTION It is uncertain whether Met-1 is the initiator. An alternative upstream Met is found in primates, but not in other mammals. UniProt P24557 1 EQUAL 533 EQUAL GO 0004796 GO molecular function Reactome Database ID Release 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 TXA2 is hydrolysed to TXB2 TXA2 is hydrolysed to TXB2 Thromboxane A2 degenerates to thromboxane B2 Thromboxane A2 (TXA2) contains an unstable ether linkage that is rapidly hydrolysed under aqueous conditions to form the biologically inert thromboxane B2 (TXB2) (Wang et al. 2001, Hamberg et al. 1975), which is excreted. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 32879 1 Reactome DB_ID: 113519 1 Reactome DB_ID: 443890 1 thromboxane B2 [ChEBI:28728] thromboxane B2 ChEBI 28728 Reactome Database ID Release 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 TXB2 is converted to 11dh-TXB2 by TXDH TXB2 is converted to 11dh-TXB2 by TXDH Thromboxane B2 (TXB2) undergoes dehydrogenation at C-11 to form 11-dehydro-thromboxane B2 (11dh-TXB2). The enzyme responsible for catalysis has been termed 11-dehydroxythromboxane B2 dehydrogenase (TXDH) (Kumlin & Granström 1986, Catella et al. 1986, Westlund et al. 1994). The human TXDH isoform has not been cloned but 11dh-TXB2 has been detected in various experiments. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 443890 1 Reactome DB_ID: 194653 1 Reactome DB_ID: 2142828 1 11-dehydro-thromboxane B2 [ChEBI:28667] 11-dehydro-thromboxane B2 ChEBI 28667 Reactome DB_ID: 156540 1 Reactome DB_ID: 194697 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2161595 TXDH [endoplasmic reticulum lumen] TXDH 11-dehydroxythromboxane B2 dehydrogenase 11-Hydroxythromboxane B2 reductase GO 0036133 GO molecular function Reactome Database ID Release 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 PGH2 is degraded to 12S-HHT and MDA by TBXAS1 PGH2 is degraded to 12S-HHT and MDA by TBXAS1 Thromboxane synthase (TBXAS1) aka CYP5A1 facilitates rearrangement of the PGH2 endoperoxide bridge by a complementary mechanism to prostacyclin synthase, interacting with the C-9 oxygen to promote endoperoxide bond cleavage. The C-11 oxygen radical initiates intramolecular rearrangement, resulting in either the formation of thromboxane A2 (TXA2) or 12-hydroxyheptadecatrienoic acid (12S-HHT) and malonaldehyde (MDA) (Wang et al. 2001). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 30138 1 Reactome DB_ID: 2142797 1 12S-HHTrE [ChEBI:63977] 12S-HHTrE ChEBI 63977 Reactome DB_ID: 2161562 1 malonaldehyde [ChEBI:566274] malonaldehyde 1,3-Propanedialdehyde Malonodialdehyde 1,3-Propanedione Malonic dialdehyde MDA Malonyldialdehyde MDD Malondialdehyde 1,3-Propanedial Malonic aldehyde ChEBI 566274 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 65976 1 EQUAL 533 EQUAL GO 0036134 GO molecular function 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 GO 0019371 GO biological process Synthesis of Leukotrienes (LT) and Eoxins (EX) Synthesis of Leukotrienes (LT) and Eoxins (EX) Leukotrienes (LTs) are biologically active molecules formed in response to inflammatory stimuli. They cause contraction of bronchial smooth muscles, stimulation of vascular permeability, and attraction and activation of leukocytes. LTs were discovered in 1938 and were termed the "slow release substance" (SRS) until their structures were determined in 1979 and they were then renamed to leukotrienes. LTs are derived from arachidonic acid through action by arachidonate 5-lipoxygenase (ALOX5). Cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are generated as products derived from leukotriene A4 (LTA4). Eoxins are generated from leukotrienes (LTs) and resemble cysteinyl leukotrienes but have a different three-dimensional structure (Murphy & Gijon 2007, Hammarstrom 1983, MA.Claesson 2009, Vance & Vance 2008, Buczynski et al. 2009). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 2.7.11.1 ALOX5 is phosphorylated by MAPKAP2 ALOX5 is phosphorylated by MAPKAP2 Arachidonate 5-lipoxygenase (ALOX5) catalyzes the first step in leukotriene biosynthesis and has a key role in inflammatory processes. ALOX5 is phosphorylated by MAPKAPK2; MAPKAPK2 is stimulated by arachidonic acid. Authored: Jupe, S, 2009-07-14 Reviewed: Rush, MG, 2012-11-10 Edited: Jupe, S, 2010-05-06 Reactome DB_ID: 2237880 1 ALOX5:Ca2+:Fe2+ [cytosol] ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 429010 1 UniProt:P09917 ALOX5 ALOX5 LOG5 ALOX5 FUNCTION Catalyzes the oxygenation of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) to 5-hydroperoxyeicosatetraenoate (5-HPETE) followed by the dehydration to 5,6- epoxyeicosatetraenoate (Leukotriene A4/LTA4), the first two steps in the biosynthesis of leukotrienes, which are potent mediators of inflammation (PubMed:8631361, PubMed:21233389, PubMed:22516296, PubMed:24282679, PubMed:19022417, PubMed:23246375, PubMed:8615788, PubMed:24893149, PubMed:31664810). Also catalyzes the oxygenation of arachidonate into 8-hydroperoxyicosatetraenoate (8-HPETE) and 12-hydroperoxyicosatetraenoate (12-HPETE) (PubMed:23246375). Displays lipoxin synthase activity being able to convert (15S)-HETE into a conjugate tetraene (PubMed:31664810). Although arachidonate is the preferred substrate, this enzyme can also metabolize oxidized fatty acids derived from arachidonate such as (15S)-HETE, eicosapentaenoate (EPA) such as (18R)- and (18S)-HEPE or docosahexaenoate (DHA) which lead to the formation of specialized pro-resolving mediators (SPM) lipoxin and resolvins E and D respectively, therefore it participates in anti-inflammatory responses (PubMed:21206090, PubMed:31664810, PubMed:8615788, PubMed:17114001, PubMed:32404334). Oxidation of DHA directly inhibits endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor gamma (PPARgamma) (By similarity). It does not catalyze the oxygenation of linoleic acid and does not convert (5S)-HETE to lipoxin isomers (PubMed:31664810). In addition to inflammatory processes, it participates in dendritic cell migration, wound healing through an antioxidant mechanism based on heme oxygenase-1 (HO-1) regulation expression, monocyte adhesion to the endothelium via ITGAM expression on monocytes (By similarity). Moreover, it helps establish an adaptive humoral immunity by regulating primary resting B cells and follicular helper T cells and participates in the CD40-induced production of reactive oxygen species (ROS) after CD40 ligation in B cells through interaction with PIK3R1 that bridges ALOX5 with CD40 (PubMed:21200133). 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 DB_ID: 71067 1 iron(2+) [ChEBI:29033] iron(2+) FE (II) ION Fe(2+) Fe(II) Ferrous ion Fe2+ iron ion(2+) ChEBI 29033 Reactome DB_ID: 74016 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 Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 265277 1 p-S272-ALOX5:Ca2+:Fe2+ [cytosol] p-S272-ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 265276 1 O-phospho-L-serine at 272 272 EQUAL 2 EQUAL 674 EQUAL Reactome DB_ID: 71067 1 Reactome DB_ID: 74016 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 187760 UniProt:P49137 MAPKAPK2 MAPKAPK2 MAPKAPK2 FUNCTION Stress-activated serine/threonine-protein kinase involved in cytokine production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, CEP131, ELAVL1, HNRNPA0, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Phosphorylates HSF1; leading to the interaction with HSP90 proteins and inhibiting HSF1 homotrimerization, DNA-binding and transactivation activities (PubMed:16278218). Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to the dissociation of HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impairment of their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to the regulation of the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity, leading to inhibition of dependent degradation of ARE-containing transcripts. Phosphorylates CEP131 in response to cellular stress induced by ultraviolet irradiation which promotes binding of CEP131 to 14-3-3 proteins and inhibits formation of novel centriolar satellites (PubMed:26616734). Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilization of GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3.ACTIVITY REGULATION Activated following phosphorylation by p38-alpha/MAPK14 following various stresses. Inhibited following sumoylation. Specifically inhibited by pyrrolopyridine inhibitors.SUBUNIT Heterodimer with p38-alpha/MAPK14; this heterodimer forms a stable complex: molecules are positioned 'face to face' so that the ATP-binding sites of both kinases are at the heterodimer interface (PubMed:12171911, PubMed:17576063, PubMed:17255097, PubMed:17480064, PubMed:17449059, PubMed:17395714). Interacts with PHC2 (PubMed:15094067). Interacts with HSF1 (PubMed:16278218).TISSUE SPECIFICITY Expressed in all tissues examined.PTM Sumoylation inhibits the protein kinase activity.PTM Phosphorylated and activated by MAP kinase p38-alpha/MAPK14 at Thr-222, Ser-272 and Thr-334.SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. UniProt P49137 O-phospho-L-threonine at 222 222 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-serine at 272 272 EQUAL O-phospho-L-threonine at 334 334 EQUAL 1 EQUAL 400 EQUAL GO 0004674 GO molecular function Reactome Database ID Release 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 1.13.11.34 Arachidonic acid is oxidised to 5S-HpETE by ALOX5 Arachidonic acid is oxidised to 5S-HpETE by ALOX5 Oxidation of arachidonic acid to 5-HpETE Arachidonate 5-lipoxygenase (ALOX5) catalyzes the formation of leukotriene A4 (LTA4) from arachidonic acid in a two-step process. First, arachidonic acid AA is oxidized to form 5S-hydroperoxyeicosatetranoic acid (5S-HpETE) (Rouzer et al. 1988, Rouzer & Samuelsson 1987, Rouzer et al. 1986). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 29768 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 266010 1 5(S)-HPETE [ChEBI:15632] 5(S)-HPETE ChEBI 15632 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318764 nuclear envelope GO 0005635 ALOX5:ALOX5AP:LTC4S [nuclear envelope] ALOX5:ALOX5AP:LTC4S ALOX5:FLAP:LTC4S Reactome DB_ID: 2318769 1 p-S272-ALOX5:Ca2+:Fe2+ [nuclear envelope] p-S272-ALOX5:Ca2+:Fe2+ ALOX5 (iron, calcium cofactors) Reactome DB_ID: 2318766 1 Reactome DB_ID: 2318765 1 O-phospho-L-serine at 272 272 EQUAL 2 EQUAL 674 EQUAL Reactome DB_ID: 2318767 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 Reactome DB_ID: 2318770 1 ALOX5AP trimer [nuclear envelope] ALOX5AP trimer FLAP trimer Reactome DB_ID: 2318768 3 UniProt:P20292 ALOX5AP ALOX5AP FLAP ALOX5AP FUNCTION Required for leukotriene biosynthesis by ALOX5 (5-lipoxygenase). Anchors ALOX5 to the membrane. Binds arachidonic acid, and could play an essential role in the transfer of arachidonic acid to ALOX5. Binds to MK-886, a compound that blocks the biosynthesis of leukotrienes.SUBUNIT Homotrimer. Interacts with LTC4S and ALOX5.DOMAIN The C-terminal part after residue 140 is mostly unstructured.DISEASE Genetic variations in ALOX5AP may be associated with susceptibility to myocardial infarction. Involvement in myocardial infarction is however unclear: according to some authors (PubMed:14770184), a 4-SNP haplotype in ALOX5AP confers risk of myocardial infarction, while according to other (PubMed:17304054) ALOX5AP is not implicated in this condition.SIMILARITY Belongs to the MAPEG family. UniProt P20292 1 EQUAL 161 EQUAL Reactome Database ID Release 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 Reactome DB_ID: 2142729 1 LTC4S trimer [nuclear envelope] LTC4S trimer LTC4 synthase homotrimer Reactome DB_ID: 266025 3 UniProt:Q16873 LTC4S LTC4S LTC4S FUNCTION Catalyzes the conjugation of leukotriene A4 with reduced glutathione (GSH) to form leukotriene C4 with high specificity (PubMed:7937884, PubMed:27791009, PubMed:27365393, PubMed:9153254, PubMed:23409838). Can also 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 2142729 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142729 Reactome R-HSA-2142729 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142729.1 Reactome Database ID Release 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 GO 0004051 GO molecular function 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 ALOX5 binds ALOX5 inhibitors ALOX5 binds ALOX5 inhibitors Eicosanoids, oxygenated, 20-carbon fatty acids, are autocrine and paracrine signaling molecules that modulate physiological processes including pain, fever, inflammation, blood clot formation, smooth muscle contraction and relaxation, and the release of gastric acid. Eicosanoids are synthesized in humans primarily from arachidonic acid (AA) that is released from membrane phospholipids. Once released, AA can be acted on by various enzymes to form different eicosanoids. Arachidonate lipoxygenase 5 (ALOX)5 form leukotrienes (LTs) and eicosatetraenoic acids (ETEs) from AA. LTs and ETEs are biologically active molecules formed in response to inflammatory stimuli. They cause contraction of bronchial smooth muscles, stimulation of vascular permeability, and attraction and activation of leukocytes. When produced in excess, these molecules may contribute to a wide range of pathological inflammatory responses.<br><br>ALOX5 inhibitors are compounds that slow or stop the action of the ALOX5 enzyme, which is responsible for the production of inflammatory LTs and ETEs. Zileuton blocks the activity of ALOX5 (Carter et al. 1991). Zileuton is used in the treatment of acne vulgaris (Zouboulis 2005, Zouboulis et al. 2009) and for the prophylaxis and chronic treatment of allergic asthma (Bruno et al. 2018, Morina et al. 2016). Meclofenamic acid is a non-steroidal anti-inflammatory drug (NSAID) used for the relief of mild to moderate pain, for the treatment of primary dysmenorrhea and for the treatment of idiopathic heavy menstrual blood loss. It is also used for relief of the signs and symptoms of acute and chronic rheumatoid arthritis and osteoarthritis. In vitro meclofenamic acid was found to be an inhibitor of human ALOX5 activity (Boctor et al. 1986). Balsalazide, olsalazine and sulfasalazine are all pro-drugs that are enzymatically cleaved in the colon to produce the anti-inflammatory agent mesalazine (5-aminosalicylic acid, 5-ASA, mesalazine (Klotz 1985, Selby et al. 1985, Sharon et al. 1978, Hawkey et al. 1985, Neilsen et al. 1987). Once metabolised, 5-ASA acts locally in the colon to reduce inflammation in conditions such as inflammatory bowel disease and ulcerative colitis (Wiggins & Rajapakse 2009, Rask-Madsen et al. 1992, Singer et al. 2006, Hoult 1986, Feagan & Macdonald 2012). Authored: Jassal, Bijay, 2021-03-25 Reviewed: Huddart, Rachel, 2022-03-01 Edited: Jassal, Bijay, 2021-10-27 Edited: Matthews, Lisa, 2022-05-10 Converted from EntitySet in Reactome Reactome DB_ID: 9707237 1 ALOX5 inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity meclofenamic acid [cytosol] zileuton [cytosol] balsalazide [cytosol] olsalazine [cytosol] sulfasalazine [cytosol] Guide to Pharmacology 7219 Guide to Pharmacology 5297 Guide to Pharmacology 11569 Guide to Pharmacology 11578 Guide to Pharmacology 4840 Reactome DB_ID: 2318764 1 Reactome DB_ID: 9707188 1 ALOX5:ALOX5 inhibitors [nuclear envelope] ALOX5:ALOX5 inhibitors Converted from EntitySet in Reactome Reactome DB_ID: 9707237 1 Reactome DB_ID: 2318764 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 1.13.11.34 5S-HpETE is dehydrated to LTA4 by ALOX5 5S-HpETE is dehydrated to LTA4 by ALOX5 Dehydration of 5-HpETE to leukotriene A4 In the second step of the formation of leukotriene A4 (LTA4) from arachidonic acid, arachidonate 5-lipoxygenase (ALOX5) converts 5S-hydroperoxyeicosatetranoic acid (5S-HpETE) to an allylic epoxide, leukotriene A4 (LTA4) (Rouzer et al. 1988, Rouzer & Samuelsson 1987, Rouzer et al. 1986). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Reviewed: Hansen, Trond Vidar, 2018-02-21 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 266010 1 Reactome DB_ID: 265281 1 leukotriene A4 [ChEBI:15651] leukotriene A4 ChEBI 15651 Reactome DB_ID: 29356 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318764 Reactome Database ID Release 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 3.3.2.6 LTA4 is hydolysed to LTB4 by LTA4H LTA4 is hydolysed to LTB4 by LTA4H LTA4 is hydrolyzed to LTB4 Leukotriene A4 hydrolase (LTA4H) is a monomeric, soluble enzyme that catalyzes the hydrolysis of the allylic epoxide leukotriene A4 (LTA4) to the dihydroxy acid leukotriene B4 (LTB4) (Radmark et al. 1984, McGee & Fitzpatrick 1985). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 265281 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 266056 1 leukotriene B4 [ChEBI:15647] leukotriene B4 ChEBI 15647 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 266038 LTA4H:Zn2+ [cytosol] LTA4H:Zn2+ LTA4 hydrolase (Zinc cofactor) Reactome DB_ID: 266022 1 UniProt:P09960 LTA4H LTA4H LTA4 LTA4H FUNCTION Bifunctional zinc metalloenzyme that comprises both epoxide hydrolase (EH) and aminopeptidase activities. Acts as an epoxide hydrolase to catalyze the conversion of LTA4 to the 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 DB_ID: 29426 1 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 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 GO 0004463 GO molecular function 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 LTB4 is oxidised to 12-oxoLTB4 by PTGR1 LTB4 is oxidised to 12-oxoLTB4 by PTGR1 Prostaglandin reductase 1 (PTGR1) aka LTB4DH metabolizes eicosanoids by catalysing the oxidation of leukotriene B4 (LTB4) to form 12-oxo-Leukotriene B4 (12-oxoLTB4) aka 12-Keto-LTB4. The gene was originally cloned as leukotriene B4 12-hydroxydehydrogenase (LTB4DH) but was later discovered to have dual functionality as a prostaglandin reductase (Yokomizo et al. 1996). This reaction has been inferred from a reaction in pigs (Yokomizo et al. 1993, Ensor et al. 1998). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 266056 1 Reactome DB_ID: 29366 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 2142810 1 12-dehydro-leukotriene B4 [ChEBI:27814] 12-dehydro-leukotriene B4 ChEBI 27814 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142671 UniProt:Q14914 PTGR1 PTGR1 LTB4DH PTGR1 FUNCTION NAD(P)H-dependent oxidoreductase involved in metabolic inactivation of pro- and anti-inflammatory eicosanoids: prostaglandins (PG), leukotrienes (LT) and lipoxins (LX) (PubMed:25619643). Catalyzes with high efficiency the reduction of the 13,14 double bond of 15-oxoPGs, including 15-oxo-PGE1, 15-oxo-PGE2, 15-oxo-PGF1-alpha and 15-oxo-PGF2-alpha (PubMed:25619643). Catalyzes with lower efficiency the oxidation of the hydroxyl group at C12 of LTB4 and its derivatives, converting them into biologically less active 12-oxo-LTB4 metabolites (PubMed:25619643) (By similarity). Reduces 15-oxo-LXA4 to 13,14 dihydro-15-oxo-LXA4, enhancing neutrophil recruitment at the inflammatory site (By similarity). May play a role in metabolic detoxification of alkenals and ketones. Reduces alpha,beta-unsaturated alkenals and ketones, particularly those with medium-chain length, showing highest affinity toward (2E)-decenal and (3E)-3-nonen-2-one (PubMed:25619643). May inactivate 4-hydroxy-2-nonenal, a cytotoxic lipid constituent of oxidized low-density lipoprotein particles (By similarity).SUBUNIT Monomer or homodimer.TISSUE SPECIFICITY High expression in the kidney, liver, and intestine but not in leukocytes.SIMILARITY Belongs to the NADP-dependent oxidoreductase L4BD family. UniProt Q14914 1 EQUAL 329 EQUAL GO 0097257 GO molecular function Reactome Database ID Release 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 1.14.14.94 CYP4F2, 4F3 20-hydroxylate LTB4 CYP4F2, 4F3 20-hydroxylate LTB4 CYP4F2 omega-hydroxylates leukotriene B4, thus inactivating it Leukotriene B4 (LTB4) is formed from arachidonic acid and is a potent inflammatory mediator. LTB4's activity is terminated by formation of its omega hydroxylated metabolite, 20-hydroxyleukotriene B4 (20OH-LTB4), catalysed by CYP4F2 primarily in human liver (Jin et al. 1998) and also by CYP4F3 (Kikuta et al. 1998). Authored: Jassal, Bijay, 2008-05-19 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, Bijay, 2008-05-19 Reactome DB_ID: 70106 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 266056 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 2161636 1 20-hydroxy-leukotriene B4 [ChEBI:15646] 20-hydroxy-leukotriene B4 ChEBI 15646 Reactome DB_ID: 29366 1 Reactome DB_ID: 29356 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161611 Cytochrome P450 (CYP4F2/4F3 based) [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP4F2 [endoplasmic reticulum membrane] CYP4F3 [endoplasmic reticulum membrane] UniProt P78329 UniProt Q08477 GO 0050051 GO molecular function Reactome Database ID Release 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 20oh-LTB4 is oxidised to 20cho-LTB4 by CYP4F2/4F3 20oh-LTB4 is oxidised to 20cho-LTB4 by CYP4F2/4F3 The cytochrome P450s 4F2 (CYP4F2) and F3 (CYP4F3) oxidise the omega hydroxylated metabolite, 20-hydroxyleukotriene B4 (20oh-LTB4) to form 20-aldehyde leukotriene B4 (20cho-LTB4) (Soberman et al. 1988). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 70106 1 Reactome DB_ID: 2161636 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 2142740 1 20-oxoleukotriene B4 [ChEBI:63979] 20-oxoleukotriene B4 ChEBI 63979 Reactome DB_ID: 29366 1 Reactome DB_ID: 29356 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161611 GO 0097258 GO molecular function 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 20cho-LTB4 is oxidised to 20cooh-LTB4 by CYP4F2/4F3 20cho-LTB4 is oxidised to 20cooh-LTB4 by CYP4F2/4F3 The cytochrome P450s 4F2 (CYP4F2) and F3 (CYP4F3) oxidise 20-aldehyde leukotriene B4 (20cho-LTB4) to form 20-carboxy leukotriene B4 (20cooh-LTB4) (Soberman et al. 1988). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 70106 1 Reactome DB_ID: 2142740 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 2161582 1 20-hydroxy-20-oxoleukotriene B4 [ChEBI:27562] 20-hydroxy-20-oxoleukotriene B4 ChEBI 27562 Reactome DB_ID: 29366 1 Reactome DB_ID: 29356 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161611 GO 0097259 GO molecular function 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 20cho-LTB4 is oxidised to 20cooh-LTB4 by ALDH 20cho-LTB4 is oxidised to 20cooh-LTB4 by ALDH An aldehyde dehydrogenase (ALDH) yet to be cloned in humans has been observed to oxidise 20-aldehyde leukotriene B4 (20cho-LTB4) to form 20-carboxy leukotriene B4 (20cooh-LTB4) (Sutyak et al. 1989). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 70106 1 Reactome DB_ID: 2142740 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 2161582 1 Reactome DB_ID: 29366 1 Reactome DB_ID: 29356 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2161598 ALDH [cytosol] ALDH Aldehyde dehydrogenase 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 20cooh-LTB4 is converted to 18cooh-LTB4 20cooh-LTB4 is converted to 18cooh-LTB4 Once omega-oxidation has occurred, 20-carboxy leukotriene B4 (20cooh-LTB4) can be further metabolized by beta-oxidation at its omega end into 18-carboxy-LTB4 (18cooh-LTB4) (Berry et al. 2003, Wheelan et al. 1999). The actual human enzyme or enzymes involved have yet to be identified. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2161582 1 Reactome DB_ID: 2142676 1 18-hydroxy-18-oxo-dinorleukotriene B4 [ChEBI:63980] 18-hydroxy-18-oxo-dinorleukotriene B4 ChEBI 63980 Reactome Database ID Release 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 4.4.1.20 LTA4 is converted to LTC4 by LTC4S LTA4 is converted to LTC4 by LTC4S LTA4 conjugates with glutathione to form LTC4 Leukotriene A4 conjugates with reduced glutathione (GSH) to produce leukotriene C4 (LTC4). This conjugation is mediated by the homodimeric, perinuclear membrane-bound enzyme leukotriene C4 synthase (LTC4S) (Lam et al. 1994, Welsch et al. 1994). LTC4S differs from cytosolic and microsomal GSH-S-transferases by having a very narrow substrate specificity and the inability to conjugate xenobiotics. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 29450 1 Reactome DB_ID: 265281 1 Reactome DB_ID: 266066 1 leukotriene C4 [ChEBI:16978] leukotriene C4 ChEBI 16978 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318764 GO 0004464 GO molecular function Reactome Database ID Release 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 LTC4 is exported from the cytosol by ABCC1 LTC4 is exported from the cytosol by ABCC1 ABCC1 mediates LTC4 export from the cell On formation, leukotriene C4 (LTC4) is exported to the extracellular region by the ABCC1 transporter (Sjolinder et al. 1999, Lam et al. 1989) and processed further by cleavage reactions. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 266066 1 Reactome DB_ID: 266013 1 extracellular region GO 0005576 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 266068 plasma membrane GO 0005886 UniProt:P33527 ABCC1 ABCC1 ABCC1 MRP1 MRP FUNCTION Mediates export of organic anions and drugs from the cytoplasm (PubMed:7961706, PubMed:16230346, PubMed:9281595, PubMed:10064732, PubMed:11114332). Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotrexate, antiviral drugs and other xenobiotics (PubMed:7961706, PubMed:16230346, PubMed:9281595, PubMed:10064732, PubMed:11114332). Confers resistance to anticancer drugs by decreasing accumulation of drug in cells, and by mediating ATP- and GSH-dependent drug export (PubMed:9281595). Hydrolyzes ATP with low efficiency (PubMed:16230346). Catalyzes the export of sphingosine 1-phosphate from mast cells independently of their degranulation (PubMed:17050692). Participates in inflammatory response by allowing export of leukotriene C4 from leukotriene C4-synthezing cells (By similarity).ACTIVITY REGULATION MK 571 inhibits sphingosine 1-phosphate and leukotriene C4 export.TISSUE SPECIFICITY Lung, testis and peripheral blood mononuclear cells.SIMILARITY Belongs to the ABC transporter superfamily. ABCC family. Conjugate transporter (TC 3.A.1.208) subfamily. UniProt P33527 1 EQUAL 1531 EQUAL GO 0140359 GO molecular function Reactome Database ID Release 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 3.4.19.13 GGT1, 5 dimers hydrolyse LTC4 to LTD4 GGT1, 5 dimers hydrolyse LTC4 to LTD4 Cleavage of the gamma-glutamyl bond of LTC4 forms LTD4 The reversible conversion of leukotriene C4 (LTC4) to leukotriene D4 (LTD4) is catalysed by gamma-glutamyl transferases 1 (GGT1) and 5 (GGT5). GGTs are present on the outer surface of plasma membranes and are a heterodimer of a heavy and a light chain. Its action involves the hydrolysis of the gamma-glutamyl peptide bond of glutathione and glutathione conjugates, releasing glutamate. In this example, LTC4 is a glutathione conjugate that is hydrolysed to LTD4 (Anderson et al. 1982, Wickham et al. 2011). Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 266013 1 Reactome DB_ID: 109276 1 Reactome DB_ID: 210382 1 L-glutamate(1-) [ChEBI:29985] L-glutamate(1-) C5H8NO4 WHUUTDBJXJRKMK-VKHMYHEASA-M (2S)-2-ammoniopentanedioate 146.12136 L-glutamate hydrogen L-glutamate InChI=1S/C5H9NO4/c6-3(5(9)10)1-2-4(7)8/h3H,1-2,6H2,(H,7,8)(H,9,10)/p-1/t3-/m0/s1 L-glutamic acid, ion(1-) [NH3+][C@@H](CCC([O-])=O)C([O-])=O L-glutamic acid monoanion ChEBI 29985 Reactome DB_ID: 266074 1 leukotriene D4 [ChEBI:28666] leukotriene D4 ChEBI 28666 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2162130 GGT1, 5 dimers [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0036374 GO molecular function Reactome Database ID Release 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 3.4.13.21 3.4.13.18 LTD4 is converted to LTE4 by DPEP1/2 LTD4 is converted to LTE4 by DPEP1/2 Further cleavage of LTD4 forms LTE4 Another outer surface membrane-bound, homodimeric enzyme, dipeptidase, existing in two forms DPEP1 (Adachi et al. 1989) and DPEP2 (Lee et al. 1983, Raulf et al. 1987), further hydrolyses leukotriene D4 (LTD4) to leukotriene E4 (LTE4), cleaving a glycine residue in the process. Authored: Jassal, Bijay, 2008-10-01 Reviewed: Rush, MG, 2012-11-10 Edited: Jassal, B, 2008-04-21 14:30:22 Reactome DB_ID: 266074 1 Reactome DB_ID: 109276 1 Reactome DB_ID: 266033 1 leukotriene E4 [ChEBI:15650] leukotriene E4 ChEBI 15650 Reactome DB_ID: 266029 1 glycine zwitterion [ChEBI:57305] glycine zwitterion glycine DHMQDGOQFOQNFH-UHFFFAOYSA-N C2H5NO2 2-azaniumylacetate [NH3+]CC([O-])=O InChI=1S/C2H5NO2/c3-1-2(4)5/h1,3H2,(H,4,5) 75.06660 ChEBI 57305 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2162149 DPEP1,2,3 dimers [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0016805 GO molecular function 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 LTA4 is hydrolysed to 6t-/6t,12epi-LTB4 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 Reactome DB_ID: 265281 1 Reactome DB_ID: 29356 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161801 1 6t/6t,12epi-LTB4 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 6t,12epi-LTB4 [cytosol] 6t-LTB4 [cytosol] ChEBI 63982 ChEBI 63981 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 LTA4 is converted to EXA4 by ALOX15 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 Reactome DB_ID: 265281 1 Reactome DB_ID: 2142772 1 eoxin A4 [ChEBI:63983] eoxin A4 ChEBI 63983 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142744 ALOX15:Fe2+ [cytosol] ALOX15:Fe2+ Reactome DB_ID: 71067 1 Reactome DB_ID: 2142838 1 UniProt:P16050 ALOX15 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 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 GO 0097260 GO molecular function 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 EXA4 is converted to EXC4 by LTC4S 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 Reactome DB_ID: 29450 1 Reactome DB_ID: 2142772 1 Reactome DB_ID: 2142726 1 eoxin C4 [ChEBI:63984] eoxin C4 ChEBI 63984 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2318764 GO 0097261 GO molecular function 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 EXC4 is converted to EXD4 by GGT 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 Reactome DB_ID: 2142726 1 Reactome DB_ID: 29404 1 Reactome DB_ID: 2142758 1 eoxin D4 [ChEBI:63985] eoxin D4 ChEBI 63985 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2161915 GGT [cytosol] GGT gamma-glutamyltransferase GO 0097262 GO molecular function 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 EXD4 is converted to EXE4 by DPEP 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 Reactome DB_ID: 2142758 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 29424 1 Reactome DB_ID: 2142730 1 eoxin E4 [ChEBI:63986] eoxin E4 ChEBI 63986 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2161751 DPEP [cytosol] DPEP Dipeptidase GO 0097263 GO molecular function 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 GO 0006691 GO biological process Synthesis of 5-eicosatetraenoic acids 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 1.11.1.9 5S-HpETE is reduced to 5S-HETE by GPX1/2/4 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 Reactome DB_ID: 29450 2 Reactome DB_ID: 266010 1 Reactome DB_ID: 2142733 1 5(S)-HETE [ChEBI:28209] 5(S)-HETE ChEBI 28209 Reactome DB_ID: 29356 1 Reactome DB_ID: 111745 1 glutathione disulfide(2-) [ChEBI:58297] glutathione disulfide(2-) glutathione disulfide (2S,2'S)-5,5'-[disulfanediylbis({(2R)-3-[(carboxylatomethyl)amino]-3-oxopropane-1,2-diyl}imino)]bis(2-azaniumyl-5-oxopentanoate) glutathione disulfide dianion ChEBI 58297 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161954 GPX1/2/4 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity L-selenocysteine-residue-GPX4(?-197) [cytosol] UniProt P36969 GO 0004602 GO molecular function 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 5S-HETE is oxidised to 5-oxoETE by 5-HEDH 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 Reactome DB_ID: 2142733 1 Reactome DB_ID: 29366 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 2161921 1 5-oxo-ETE [ChEBI:52449] 5-oxo-ETE ChEBI 52449 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2161764 5-HEDH [cytosol] 5-HEDH 5-hydroxy-eicosatetraenoic acid dehydrogenase GO 0097265 GO molecular function 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 3.1.1.81 PON1,2,3:Ca2+ dimers hydrolyse 5-HETEL to 5-HETE PON1,2,3:Ca2+ dimers hydrolyse 5-HETEL to 5-HETE Serum paraoxonase/arylesterases 1, 2 and 3 (PON1,2 and 3) are extracellular lactonases/lactonysing enzymes with overlapping, but also distinct substrate specificity. PONs are homodimeric proteins which bind 2 Ca2+ ions per subunit, necessary for enzyme stability and enzymatic activity. All three PONs can efficiently metabolise 5-hydroxy-eicosatetraenoic acid 1,5-lactone (5-HETEL), a product of both enzymatic and nonenzymatic oxidation of arachidonic acid and may represent one of the PONs' endogenous substrates (Draganov et al. 2005). Authored: Jassal, Bijay, 2016-07-27 Reviewed: D'Eustachio, Peter, 2016-08-12 Edited: Jassal, Bijay, 2016-07-27 Reactome DB_ID: 109276 1 Reactome DB_ID: 8932801 1 meadowlactone [ChEBI:132873] meadowlactone ChEBI 132873 Reactome DB_ID: 8932804 1 5-HETE [ChEBI:60943] 5-HETE 5-hydroxy,6E,8Z,11Z,14Z-eicosatetraenoic acid 5-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid (6E,8Z,11Z,14Z)-5-hydroxyeicosa-6,8,11,14-tetraenoic acid InChI=1S/C20H32O3/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-16-19(21)17-15-18-20(22)23/h6-7,9-10,12-14,16,19,21H,2-5,8,11,15,17-18H2,1H3,(H,22,23)/b7-6-,10-9-,13-12-,16-14+ 5-hydroxy-6E,8Z,11Z,14Z-icosatetraenoic acid 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (6E,8Z,11Z,14Z)-5-hydroxyicosa-6,8,11,14-tetraenoic acid 5-OH 6t,8c,11c,14c-20:4 C20H32O3 KGIJOOYOSFUGPC-XTDASVJISA-N (6E,8Z,11Z,14Z)-5-hydroxy-6,8,11,14-eicosatetraenoic acid 5-hydroxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid CCCCC\C=C/C\C=C/C\C=C/C=C/C(O)CCCC(O)=O ChEBI 60943 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 8932645 PON1,2,3:2xCa2+ dimers [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0102007 GO molecular function Reactome Database ID Release 81 8932640 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8932640 Reactome Database ID Release 81 8932633 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8932633 Reactome R-HSA-8932633 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8932633.1 15772423 Pubmed 2005 Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities Draganov, Dragomir I Teiber, John F Speelman, Audrey Osawa, Yoichi Sunahara, Roger La Du, Bert N J. Lipid Res. 46:1239-47 19082953 Pubmed 2008 Paraoxonases (PON1, PON2, PON3) analyses in vitro and in vivo in relation to cardiovascular diseases Aviram, Michael Rosenblat, Mira Methods Mol. Biol. 477:259-76 Reactome Database ID Release 81 2142688 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142688 Reactome R-HSA-2142688 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-2142688.2 GO 0019372 GO biological process Synthesis of 15-eicosatetraenoic acid derivatives Synthesis of 15-eicosatetraenoic acid derivatives The 15-eicosatetraenoic acids: 15-hydroperoxy-eicosatetraenoic acid (15-HpETE), 15-hydroxyeicosatetraenoic acid (15-HETE) and 15-oxo-eicosatetraenoic acid (15-oxoETE) are formed after the initial step of arachidonic acid oxidation by the arachidonate 15-lipoxygenases (ALOX15 and ALOX15B) (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 1.13.11.33 Arachidonic acid is oxidised to 15S-HpETE by ALOX15/15B Arachidonic acid is oxidised to 15S-HpETE by ALOX15/15B Arachidonate 15-lipoxygenase (ALOX15) (Gulliksson et al. 2007, Kuhn et al. 1993, Izumi et al. 1991) and arachidonate 15-lipoxygenase B (ALOX15B) (Tang et al. 2002, Wecksler et al. 2008) are lipid peroxidising enzymes mainly expressed in airway epithelial cells, eosinophils, reticulocytes and in macrophages. They insert molecular oxygen at C-6 from the omega-end of arachidonic acid with formation of the unstable intermediate 15S-hydroperoxyeicosatetraenoic acid (15S-HpETE) which can be further converted, enzymatically or non-enzymatically, to 15S-hydroxyeicosatetraenoic acid (15S-HETE). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29768 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 2142718 1 15(S)-HPETE [ChEBI:15628] 15(S)-HPETE ChEBI 15628 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161783 ALOX15/15B [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0050473 GO molecular function Reactome Database ID Release 81 2161832 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161832 Reactome Database ID Release 81 2162002 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162002 Reactome R-HSA-2162002 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-2162002.2 18570379 Pubmed 2008 Substrate specificity changes for human reticulocyte and epithelial 15-lipoxygenases reveal allosteric product regulation Wecksler, AT Kenyon, V Deschamps, JD Holman, TR Biochemistry 47:7364-75 8334154 Pubmed 1993 Overexpression, purification and characterization of human recombinant 15-lipoxygenase Kühn, H Barnett, J Grunberger, D Baecker, P Chow, J Nguyen, B Bursztyn-Pettegrew, H Chan, H Sigal, E Biochim Biophys Acta 1169:80-9 17662651 Pubmed 2007 Expression of 15-lipoxygenase type-1 in human mast cells Gulliksson, M Brunnström, A Johannesson, M Backman, L Nilsson, G Harvima, I Dahlén, B Kumlin, M Claesson, HE Biochim Biophys Acta 1771:1156-65 11839751 Pubmed 2002 Evidence that arachidonate 15-lipoxygenase 2 is a negative cell cycle regulator in normal prostate epithelial cells Tang, S Bhatia, B Maldonado, CJ Yang, P Newman, RA Liu, J Chandra, D Traag, J Klein, RD Fischer, SM Chopra, D Shen, Jinlong Zhau, HE Chung, LW Tang, DG J Biol Chem 277:16189-201 1662607 Pubmed 1991 Purification of two forms of arachidonate 15-lipoxygenase from human leukocytes Izumi, T Rådmark, O Jörnvall, H Samuelsson, B Eur J Biochem 202:1231-8 1.11.1.9 15S-HpETE is reduced to 15S-HETE by GPX1/2/4 15S-HpETE is reduced to 15S-HETE by GPX1/2/4 Glutathione peroxidases (GPXs) in human platelets (either GPX1, GPX2, or GPX4 are present in the cytosol) are involved in reducing 15S-hydroperoxyeicosatetraenoic acid (15S-HpETE) to 15S-hydroxyeicosatetraenoic acid (15S-HETE) (Hill et al. 1989). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2142718 1 Reactome DB_ID: 29450 2 Reactome DB_ID: 2142707 1 15(S)-HETE [ChEBI:15558] 15(S)-HETE ChEBI 15558 Reactome DB_ID: 29356 1 Reactome DB_ID: 111745 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161766 GPX1/2/4 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 81 2161937 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161937 Reactome Database ID Release 81 2161791 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161791 Reactome R-HSA-2161791 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-2161791.2 2501828 Pubmed 1989 Role of glutathione and glutathione peroxidase in human platelet arachidonic acid metabolism Hill, TD White, JG Rao, GH Prostaglandins 38:21-32 1.1.1.232 15S-HETE is oxidised to 15-oxoETE by 15-HEDH 15S-HETE is oxidised to 15-oxoETE by 15-HEDH A 15-hydroxy-eicosatetraenoic acid dehydrogenase (15-HEDH) oxidises 15S-hydroxyeicosatetraenoic acid (15S-HETE) to 15-oxo-eicosatetraenoic acid (15-oxoETE) (Gulliksson et al. 2007). The actual human 15-HEDH has yet to be cloned. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2142707 1 Converted from EntitySet in Reactome Reactome DB_ID: 428218 1 NAD(P)+ [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NADP+ [cytosol] NAD+ [cytosol] Reactome DB_ID: 2142747 1 15-oxo-ETE [ChEBI:15559] 15-oxo-ETE ChEBI 15559 Reactome DB_ID: 70106 1 Converted from EntitySet in Reactome Reactome DB_ID: 428206 1 NAD(P)H [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NADPH [cytosol] NADH [cytosol] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2161674 15-HEDH [cytosol] 15-HEDH 15-hydroxy-eicosatetraenoic acid dehydrogenase GO 0047034 GO molecular function Reactome Database ID Release 81 2161741 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161741 Reactome Database ID Release 81 2161789 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161789 Reactome R-HSA-2161789 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-2161789.2 1.13.11.33 Arachidonic acid is oxidised to 15R-HETE by Acetyl-PTGS2 Arachidonic acid is oxidised to 15R-HETE by Acetyl-PTGS2 Aspirin acetylates the cyclooxygenase, prostaglandin G/H synthase 2 (PTGS2) aka COX2. The acetylated PTGS2 triggers the formation of 15R-hydroxyeicosatetraenoic acid (15R-HETE) from arachidonic acid (Claria & Serhan 1995). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 70106 1 Reactome DB_ID: 29768 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 2142738 1 15(R)-HETE [ChEBI:63989] 15(R)-HETE ChEBI 63989 Reactome DB_ID: 29366 1 Reactome DB_ID: 29356 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2314687 Reactome Database ID Release 81 2161919 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161919 Reactome Database ID Release 81 2161951 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161951 Reactome R-HSA-2161951 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-2161951.2 7568157 Pubmed 1995 Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions Clària, J Serhan, Charles N Proc Natl Acad Sci U S A 92:9475-9 Reactome Database ID Release 81 2142770 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142770 Reactome R-HSA-2142770 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142770.1 Synthesis of 12-eicosatetraenoic acid derivatives Synthesis of 12-eicosatetraenoic acid derivatives The 12-eicosatetraenoic acids: 12-hydroperoxy-eicosatetraenoic acid (12-HpETE), 12-hydroxyeicosatetraenoic acid (12-HETE) and 12-oxo-eicosatetraenoic acid (12-oxoETE) are formed after the initial step of arachidonic acid oxidation by the arachidonate 12 and 15 lipoxygenases (ALOX12, ALOX12B and ALOX15 respectively). This part of the pathway is bifurcated at the level of 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE), which can either be reduced to 12S-hydro-eicosatetraenoic acid (12S-HETE) or converted to hepoxilins (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 1.13.11.31 Arachidonic acid is oxidised to 12R-HpETE by ALOX12B Arachidonic acid is oxidised to 12R-HpETE by ALOX12B The arachidonate 12-lipoxygenase, 12R-type (ALOX12B) oxidises arachidonic acid to 12R-hydroperoxy-eicosatetraenoic acid (12R-HpETE) (Boeglin et al. 1998). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29768 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 2142790 1 12(R)-HPETE [ChEBI:34145] 12(R)-HPETE (5Z,8Z,10E,14Z)-(12R)-12-Hydroperoxyicosa-5,8,10,14-tetraenoic acid (5Z,8Z,10E,14Z)-(12R)-12-Hydroperoxyeicosa-5,8,10,14-tetraenoic acid ChEBI 34145 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142822 ALOX12B:Fe2+ [cytosol] ALOX12B:Fe2+ Reactome DB_ID: 2142832 1 UniProt:O75342 ALOX12B ALOX12B ALOX12B FUNCTION Catalyzes the regio and stereo-specific incorporation of a single molecule of dioxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species (PubMed:9837935, PubMed:9618483, PubMed:21558561). In the skin, acts upstream of ALOXE3 on the lineolate moiety of esterified omega-hydroxyacyl-sphingosine (EOS) ceramides to produce an epoxy-ketone derivative, a crucial step in the conjugation of omega-hydroxyceramide to membrane proteins (PubMed:21558561). Therefore plays a crucial role in the synthesis of corneocytes lipid envelope and the establishment of the skin barrier to water loss (PubMed:21558561). May also play a role in the regulation of the expression of airway mucins (PubMed:22441738).ACTIVITY REGULATION Increased by calcium.PATHWAY Lipid metabolism; hydroperoxy eicosatetraenoic acid biosynthesis.PATHWAY Lipid metabolism; sphingolipid metabolism.TISSUE SPECIFICITY Expressed in B-cells, hair follicles, foreskin keratinocytes and adult skin. Also expressed in psoriatic tissue.SIMILARITY Belongs to the lipoxygenase family. UniProt O75342 1 EQUAL 701 EQUAL Reactome DB_ID: 71067 1 Reactome Database ID Release 81 2142822 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142822 Reactome R-HSA-2142822 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142822.1 GO 0004052 GO molecular function Reactome Database ID Release 81 2161752 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161752 Reactome Database ID Release 81 2161950 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161950 Reactome R-HSA-2161950 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-2161950.2 9618483 Pubmed 1998 A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expression Boeglin, WE Kim, RB Brash, AR Proc Natl Acad Sci U S A 95:6744-9 1.11.1.9 12R-HpETE is reduced to 12R-HETE by GPX1/2/4 12R-HpETE is reduced to 12R-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) are involved in converting 12R-hydroperoxy-eicosatetraenoic acid (12R-HpETE) to 12R-hydro-eicosatetraenoic acid (12R-HETE). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 2142790 1 Reactome DB_ID: 29450 2 Reactome DB_ID: 2142716 1 12(R)-HETE [ChEBI:34144] 12(R)-HETE 12R-HETE 12(R)-hydroxyeicosatetraenoic acid (5Z,8Z,10E,12R,14Z)-12-hydroxyeicosa-5,8,10,14-tetraenoic acid (5Z,8Z,10E,14Z)-(12R)-12-Hydroxyicosa-5,8,10,14-tetraenoic acid (5Z,8Z,10E,14Z)-(12R)-12-Hydroxyeicosa-5,8,10,14-tetraenoic acid 12(R)-hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid (5Z,8Z,10E,12R,14Z)-12-hydroxy-5,8,10,14-eicosatetraenoic acid 12(R)-hydroxy-5,8,14-cis-10-trans-eicosatetraenoic acid ChEBI 34144 Reactome DB_ID: 29356 1 Reactome DB_ID: 111745 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161954 Reactome Database ID Release 81 2161959 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161959 Reactome R-HSA-2161959 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-2161959.2 ALOXE3 isomerises 12R-HpETE to HXA3 ALOXE3 isomerises 12R-HpETE to HXA3 Hydroperoxide isomerase (ALOXE3, e-LOX-3) is a non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced dioxygenase activity compared to other lipoxygenases. The hydroperoxide isomerase activity catalyses the isomerisation of hydroperoxides, derived from arachidonic and linoleic acid by ALOX12B, into epoxyalcohols (Yu et al. 2003).<br>In the skin, ALOXE3 acts downstream of ALOX12B on the linoleate moiety of esterified omega-hydroxyacyl-sphingosine (EOS) ceramides to produce an epoxy-ketone derivative, a crucial step in the conjugation of omega-hydroxyceramide to membrane proteins, important for the maintenance of the skin permeability barrier and protection against water loss. Loss-of-function mutations in ALOX12B and ALOXE3 represent the second most common cause of autosomal recessive congenital ichthyosis, a hereditary disorder of keratinization (Yu et al. 2005, Wang et al. 2015). Targeted disruption of these genes in mice resulted in neonatal death due to a severely impaired permeability barrier function (Zheng et al. 2011). Authored: Jassal, Bijay, 2016-10-11 Reviewed: D'Eustachio, Peter, 2017-01-06 Edited: Jassal, Bijay, 2016-10-11 Reactome DB_ID: 2142790 1 Reactome DB_ID: 8942209 1 hepoxilin A3 [ChEBI:36190] hepoxilin A3 ChEBI 36190 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 8942204 UniProt:Q9BYJ1 ALOXE3 ALOXE3 ALOXE3 FUNCTION Non-heme iron-containing lipoxygenase which is atypical in that it displays a prominent hydroperoxide isomerase activity and a reduced lipoxygenases activity (PubMed:12881489, PubMed:17045234, PubMed:20921226, PubMed:20923767). The hydroperoxide isomerase activity catalyzes the isomerization of hydroperoxides, derived from arachidonic and linoleic acid by ALOX12B, into hepoxilin-type epoxyalcohols and ketones (PubMed:12881489, PubMed:17045234, PubMed:20923767). In presence of oxygen, oxygenates polyunsaturated fatty acids, including arachidonic acid, to produce fatty acid hydroperoxides (PubMed:20921226). In the skin, acts downstream of ALOX12B on the linoleate moiety of esterified omega-hydroxyacyl-sphingosine (EOS) ceramides to produce an epoxy-ketone derivative, a crucial step in the conjugation of omega-hydroxyceramide to membrane proteins (PubMed:21558561). Therefore plays a crucial role in the synthesis of corneocytes lipid envelope and the establishment of the skin barrier to water loss (PubMed:21558561). In parallel, it may have a signaling function in barrier formation through the production of hepoxilins metabolites (PubMed:21558561). Plays also a role in adipocyte differentiation through hepoxilin A3 and hepoxilin B3 production which in turn activate PPARG (By similarity). Through the production of hepoxilins in the spinal cord, it may regulate inflammatory tactile allodynia (By similarity).ACTIVITY REGULATION Lipoxygenase activity is activated by 13(S)-HPODE leading to an active free ferric enzyme (PubMed:20921226). The lipoxygenase and hydroperoxide isomerase activities are in competition and are reciprocally regulated by oxygen (PubMed:20923767). The oxygen reacts with an epoxyallylic radical intermediate leading to an epoxyallylic peroxyl radical, which, due to its limited reactivity within the enzyme active site, it dissociates and leaves the enzyme in the activated free ferric state (PubMed:20923767).PATHWAY Lipid metabolism; hydroperoxy eicosatetraenoic acid biosynthesis.PATHWAY Lipid metabolism; sphingolipid metabolism.TISSUE SPECIFICITY Predominantly expressed in skin.SIMILARITY Belongs to the lipoxygenase family. UniProt Q9BYJ1 1 EQUAL 711 EQUAL GO 0051120 GO molecular function Reactome Database ID Release 81 8942207 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8942207 Reactome Database ID Release 81 8942208 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8942208 Reactome R-HSA-8942208 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8942208.1 15629692 Pubmed 2005 Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12R-LOX and eLOX3 Yu, Zheyong Schneider, Claus Boeglin, William E Brash, Alan R Biochim. Biophys. Acta 1686:238-47 21558561 Pubmed 2011 Lipoxygenases mediate the effect of essential fatty acid in skin barrier formation: a proposed role in releasing omega-hydroxyceramide for construction of the corneocyte lipid envelope Zheng, Yuxiang Yin, Huiyong Boeglin, William E Elias, Peter M Crumrine, Debra Beier, David R Brash, Alan R J. Biol. Chem. 286:24046-56 12881489 Pubmed 2003 The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomerase Yu, Zheyong Schneider, Claus Boeglin, William E Marnett, Lawrence J Brash, Alan R Proc. Natl. Acad. Sci. U.S.A. 100:9162-7 26370990 Pubmed 2015 Homozygous ALOXE3 Nonsense Variant Identified in a Patient with Non-Bullous Congenital Ichthyosiform Erythroderma Complicated by Superimposed Bullous Majocchi's Granuloma: The Consequences of Skin Barrier Dysfunction Wang, Tao Xu, Chenchen Zhou, Xiping Li, Chunjia Zhang, Hongbing Lian, Bill Q Lee, Jonathan J Shen, Jun Liu, Yuehua Lian, Christine Guo Int J Mol Sci 16:21791-801 1.13.11.31 Arachidonic acid is oxidised to 12S-HpETE by ALOX12/15 Arachidonic acid is oxidised to 12S-HpETE by ALOX12/15 Arachidonate 12-lipoxygenase, 12S-type (ALOX12) (Funk et al. 1990, Izumi et al. 1990) and arachidonate 15-lipoxygenase (ALOX15) (Kuhn et al. 1993, Sigal et al. 1990) convert arachidonic acid into 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29768 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 2142811 1 12(S)-HPETE [ChEBI:15626] 12(S)-HPETE ChEBI 15626 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161958 ALOX12/15 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 81 2162014 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162014 Reactome Database ID Release 81 2161964 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161964 Reactome R-HSA-2161964 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-2161964.2 2377602 Pubmed 1990 Molecular cloning, primary structure, and expression of the human platelet/erythroleukemia cell 12-lipoxygenase Funk, CD Furci, L FitzGerald, GA Proc Natl Acad Sci U S A 87:5638-42 2217179 Pubmed 1990 Cloning of the cDNA for human 12-lipoxygenase Izumi, T Hoshiko, S Rådmark, O Samuelsson, B Proc Natl Acad Sci U S A 87:7477-81 2318885 Pubmed 1990 Expression of cloned human reticulocyte 15-lipoxygenase and immunological evidence that 15-lipoxygenases of different cell types are related Sigal, E Grunberger, D Highland, E Gross, C Dixon, RA Craik, CS J Biol Chem 265:5113-20 1.11.1.9 12S-HpETE is reduced to 12S-HETE by GPX1/2/4 12S-HpETE is reduced to 12S-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) are involved in converting 12S-hydroperoxy-eicosatetraenoic acid (12S-HpETE) to 12S-hydro-eicosatetraenoic acid (12S-HETE). GPXs are selenoenzymes that are responsible for reducing the cellular peroxide. Cellular GPXs compete with hepoxilins A3 (HXA3) synthase for 12S-HpETE as substrate either to produce 12S-HETE or to convert to HXA3, respectively. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29450 2 Reactome DB_ID: 2142811 1 Reactome DB_ID: 2142678 1 12(S)-HETE [ChEBI:34146] 12(S)-HETE (12S)-12-hydroxy-5,8,14-cis-10-trans-eicosatetraenoic acid (5Z,8Z,10E,14Z)-(12S)-12-Hydroxyicosa-5,8,10,14-tetraenoic acid 12(S)-hydroxy-5,8,14(Z),10(E)-eicosatetraenoic acid 12(S)-hydroxyeicosatetraenoic acid 12S-HETE 12(S)-hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid (5Z,8Z,10E,14Z)-(12S)-12-Hydroxyeicosa-5,8,10,14-tetraenoic acid (5Z,8Z,10E,12S,14Z)-12-hydroxyeicosa-5,8,10,14-tetraenoic acid ChEBI 34146 Reactome DB_ID: 29356 1 Reactome DB_ID: 111745 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161954 Reactome Database ID Release 81 2161999 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161999 Reactome R-HSA-2161999 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-2161999.2 1.13.11.31 Arachidonic acid is converted to 12-oxoETE by ALOX12 Arachidonic acid is converted to 12-oxoETE by ALOX12 Arachidonate 12-lipoxygenase, 12S-type (ALOX12) catalyses the formation of 12-oxo-eicosatetraenoic acid (12-oxoETE) from arachidonic acid. This conversion has been observed when normal human epidermis is exposed to arachidonic acid and with the purified recombinant enzyme in vitro (Anton & Vila 2000). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29768 1 Reactome DB_ID: 2142745 1 12-oxo-ETE [ChEBI:34151] 12-oxo-ETE (5Z,8Z,10E,14Z)-12-Oxoicosa-5,8,10,14-tetraenoic acid 12-ketoeicosatetraenoic acid 12-OxoETE (5Z,8Z,10E,14Z)-12-Oxoeicosa-5,8,10,14-tetraenoic acid 12-keto-ETE 12-KETE 12-oxo, 5c,8c,10t,14c-20:4 (5Z,8Z,10E,14Z)-12-oxoeicosa-5,8,10,14-tetraenoic acid ChEBI 34151 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142793 ALOX12:Fe2+ [cytosol] ALOX12:Fe2+ Reactome DB_ID: 71067 1 Reactome DB_ID: 2142768 1 UniProt:P18054 ALOX12 ALOX12 12LO LOG12 ALOX12 FUNCTION Catalyzes the regio and stereo-specific incorporation of molecular oxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species (PubMed:17493578, PubMed:1851637, PubMed:8319693, PubMed:8500694, PubMed:18311922, PubMed:32404334). Mainly converts arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) to the specific bioactive lipid (12S)-hydroperoxyeicosatetraenoate/(12S)-HPETE (PubMed:17493578, PubMed:22984144, PubMed:24282679, PubMed:8319693, PubMed:8500694). Through the production of bioactive lipids like (12S)-HPETE it regulates different biological processes including platelet activation (PubMed:8319693, PubMed:8500694). It can also catalyze the epoxidation of double bonds of polyunsaturated fatty acids such as (14S)-hydroperoxy-docosahexaenoate/(14S)-HPDHA resulting in the formation of (13S,14S)-epoxy-DHA (PubMed:23504711). Furthermore, it 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). An additional function involves a multistep process by which it transforms leukotriene A4/LTA4 into the bioactive lipids lipoxin A4/LXA4 and lipoxin B4/LXB4, both are vasoactive and LXA4 may regulate neutrophil function via occupancy of specific recognition sites (PubMed:8250832). Can also peroxidize linoleate ((9Z,12Z)-octadecadienoate) to (13S)-hydroperoxyoctadecadienoate/ (13S-HPODE) (By similarity). Due to its role in regulating both the expression of the vascular endothelial growth factor (VEGF, an angiogenic factor involved in the survival and metastasis of solid tumors) and the expression of integrin beta-1 (known to affect tumor cell migration and proliferation), it can be regarded as protumorigenic (PubMed:9751607, PubMed:16638750, PubMed:22237009). Important for cell survival, as it may play a role not only in proliferation but also in the prevention of apoptosis in vascular smooth muscle cells (PubMed:23578768).ACTIVITY REGULATION Activated by EGF (PubMed:8912711). Arachidonic acid conversion is inhibited by (13S,14S)-epoxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate (13S,14S-epoxy-DHA) (PubMed:23504711). Arachidonate 12-lipoxygenase activity is decreased when PH decreases from 7.4 to 6 (By similarity).PATHWAY Lipid metabolism; hydroperoxy eicosatetraenoic acid biosynthesis.TISSUE SPECIFICITY Expressed in vascular smooth muscle cells.INDUCTION Down-regulated upon starvation, by UV-irradiation and 15-lipoxygenase metabolites.SIMILARITY Belongs to the lipoxygenase family. UniProt P18054 2 EQUAL 663 EQUAL Reactome Database ID Release 81 2142793 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142793 Reactome R-HSA-2142793 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142793.1 Reactome Database ID Release 81 2161926 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161926 Reactome Database ID Release 81 2161948 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161948 Reactome R-HSA-2161948 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-2161948.2 10692117 Pubmed 2000 Stereoselective biosynthesis of hepoxilin B3 in human epidermis Antón, R Vila, L J Invest Dermatol 114:554-9 Reactome Database ID Release 81 2142712 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142712 Reactome R-HSA-2142712 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-2142712.2 Synthesis of Hepoxilins (HX) and Trioxilins (TrX) Synthesis of Hepoxilins (HX) and Trioxilins (TrX) Hepoxilins are biologically relevant signalling molecules produced by certain arachidonate 12-lipoxygenase (ALOX12s). Hepoxilin A3 (HXA3) and B3 (HXB3) have been identified, both of which incorporate an epoxide across the C-11 and C-12 double bond, as well as an additional hydroxyl moiety. HXA3 has a C-8 hydroxyl, whereas the HXB3 hydroxyl occurs at C-10. The epoxy moiety is labile and can be hydrolyzed either by a hepoxilin specific epoxide hydrolase (HXEH) or in acidic aqueous solution to form the corresponding diol metabolites trioxilin A3 (TrXA3) and B3 (TrXB3) (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 Arachidonic acid is converted to HXA3/B3 by ALOX12 Arachidonic acid is converted to HXA3/B3 by ALOX12 Arachidonate 12-lipoxygenase, 12S-type (ALOX12) converts arachidonic acid to both hepoxilin A3 (HXA3) and B3 (HXB3). They both incorporate an epoxide across the C-11 and C-12 double bond, as well as an additional hydroxyl moiety with HXA3 having a C-8 hydroxyl, whereas the HXB3 hydroxyl occurs at C-10 (Sutherland et al. 2001, Nigam et al. 2004). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29768 1 Reactome DB_ID: 29368 1 Converted from EntitySet in Reactome Reactome DB_ID: 2162031 1 HXA3/B3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity HXA3 [cytosol] HXB3 [cytosol] ChEBI 34784 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142793 Reactome Database ID Release 81 2161887 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161887 Reactome Database ID Release 81 2161794 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161794 Reactome R-HSA-2161794 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-2161794.2 15123652 Pubmed 2004 The rat leukocyte-type 12-lipoxygenase exhibits an intrinsic hepoxilin A3 synthase activity Nigam, S Patabhiraman, S Ciccoli, R Ishdorj, G Schwarz, K Petrucev, B Kühn, H Haeggström, Jesper Z J Biol Chem 279:29023-30 3.3.2.7 HXA3/B3 is hydrolysed to TrXA3/B3 by HXEH HXA3/B3 is hydrolysed to TrXA3/B3 by HXEH The epoxy moiety of hepoxilin A3 (HXA3) and B3 (HXB3) is labile and can be hydrolysed either by a hepoxilin specific epoxide hydrolase (HXEH) or in acidic aqueous solution to form the corresponding diol metabolites trioxilin A3 (TrXA3) and B3 (TrXB3) (Anton et al. 1995, Anton et al. 1998, Pace-Asciak et al. 1983, Pace-Asciak & Lee 1989). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29356 1 Converted from EntitySet in Reactome Reactome DB_ID: 2162031 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161985 1 TrXA3/B3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TrXA3 [cytosol] TrXB3 [cytosol] ChEBI 15630 ChEBI 35032 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2161957 HXEH [cytosol] HXEH hepoxilin specific epoxide hydrolase GO 0047977 GO molecular function Reactome Database ID Release 81 2161802 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161802 Reactome Database ID Release 81 2161949 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161949 Reactome R-HSA-2161949 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-2161949.2 6406490 Pubmed 1983 Arachidonic acid epoxides. Isolation and structure of two hydroxy epoxide intermediates in the formation of 8,11,12- and 10,11,12-trihydroxyeicosatrienoic acids Pace-Asciak, CR Granström, E Samuelsson, B J Biol Chem 258:6835-40 8829479 Pubmed 1995 Characterization of arachidonic acid metabolites through the 12-lipoxygenase pathway in human epidermis by high-performance liquid chromatography and gas chromatography/mass spectrometry Antón, R Abián, J Vila, L Rapid Commun Mass SpectromS169-82 2722835 Pubmed 1989 Purification of hepoxilin epoxide hydrolase from rat liver Pace-Asciak, CR Lee, WS J Biol Chem 264:9310-3 9540966 Pubmed 1998 Occurrence of hepoxilins and trioxilins in psoriatic lesions Antón, R Puig, L Esgleyes, T de Moragas, JM Vila, L J Invest Dermatol 110:303-10 Reactome Database ID Release 81 2142696 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142696 Reactome R-HSA-2142696 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142696.1 GO 0051121 GO biological process Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE) Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE) Similar to the lipoxygenases, cytochrome P450 (CYP) enzymes catalyse the hydroxylation and epoxygenation of arachidonic acid. However, whereas lipoxygenases use an active non-heme iron to abstract hydrogen directly from arachidonic acid, CYPs contain a heme-iron active site that oxidizes its substrate by a different mechanism. They hydroxylate arachidonic acid between C-5 and C-15 to produce lipoxygenase-like hydroxyeicosatetraenoic acids (HETEs) and add a hydroxyl moiety to the sp3-hybridized omega-carbons to form a unique class of HETEs. The transfer of oxygen to the unstable arachidonic acid intermediate terminates the reaction by forming HETE or epoxy-eicosatrienoic acid (EETs), respectively (Capdevila et al. 2000, 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 Arachidonic acid is hydroxylated to 16/17/18-HETE by CYP(1) Arachidonic acid is hydroxylated to 16/17/18-HETE by CYP(1) Cytochrome P450s 1A1 (CYP1A1), 1A2 (CYP1A2), and 1B1 (CYP1B1) convert arachidonic acid to 16-, 17-, and 18-hydroxyeicosatetraenoic acids (16-, 17-, and 18-HETEs) (Choudhary et al. 2004). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 113601 1 NADPH [ChEBI:16474] NADPH TPNH ChEBI 16474 Reactome DB_ID: 140356 1 Reactome DB_ID: 156540 1 Reactome DB_ID: 113534 1 Reactome DB_ID: 113564 1 NADP(+) [ChEBI:18009] NADP(+) ChEBI 18009 Reactome DB_ID: 113519 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161639 1 16/17/18-HETE [endoplasmic reticulum lumen] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 18-HETE [endoplasmic reticulum lumen] 17-HETE [endoplasmic reticulum lumen] 16-HETE [endoplasmic reticulum lumen] ChEBI 63579 ChEBI 63995 ChEBI 63994 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2162028 CYP(1) [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP1A2 [endoplasmic reticulum membrane] CYP1A1 [endoplasmic reticulum membrane] CYP1B1 [endoplasmic reticulum membrane] UniProt P05177 UniProt P04798 UniProt Q16678 GO 0004497 GO molecular function Reactome Database ID Release 81 2161998 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161998 Reactome Database ID Release 81 2161795 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161795 Reactome R-HSA-2161795 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-2161795.2 15258110 Pubmed 2004 Metabolism of retinoids and arachidonic acid by human and mouse cytochrome P450 1b1 Choudhary, D Jansson, I Stoilov, I Sarfarazi, M Schenkman, JB Drug Metab Dispos 32:840-7 Arachidonic acid is hydroxylated to 19-HETE by CYP(2) Arachidonic acid is hydroxylated to 19-HETE by CYP(2) Several cytochrome P450s (CYPs) convert arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE). The CYPs and their references are as follows: CYP2C8 (Bylund et al. 1998); CYP2C9 (Bylund et al. 1998); CYP2C19 (Bylund et al. 1998); CYP4A11 (Gainer et al. 2005); CYP2U1 (Chuang et al. 2004); CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 113601 1 Reactome DB_ID: 140356 1 Reactome DB_ID: 156540 1 Reactome DB_ID: 113534 1 Reactome DB_ID: 2142836 1 19-HETE [ChEBI:63998] 19-HETE ChEBI 63998 Reactome DB_ID: 113564 1 Reactome DB_ID: 113519 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161767 CYP(2) [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP4A11 [endoplasmic reticulum membrane] CYP1A2 [endoplasmic reticulum membrane] CYP2C9 [endoplasmic reticulum membrane] CYP2C8 [endoplasmic reticulum membrane] CYP2C19 [endoplasmic reticulum membrane] CYP1A1 [endoplasmic reticulum membrane] CYP1B1 [endoplasmic reticulum membrane] CYP2U1 [endoplasmic reticulum membrane] UniProt Q02928 UniProt P11712 UniProt P10632 UniProt P33261 UniProt Q7Z449 Reactome Database ID Release 81 2162026 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162026 Reactome Database ID Release 81 2161814 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161814 Reactome R-HSA-2161814 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-2161814.2 14660610 Pubmed 2004 CYP2U1, a novel human thymus- and brain-specific cytochrome P450, catalyzes omega- and (omega-1)-hydroxylation of fatty acids Chuang, SS Helvig, C Taimi, M Ramshaw, HA Collop, AH Amad, M White, JA Petkovich, M Jones, G Korczak, B J Biol Chem 279:6305-14 9435160 Pubmed 1998 Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomes Bylund, J Kunz, T Valmsen, K Oliw, EH J Pharmacol Exp Ther 284:51-60 15611369 Pubmed 2005 Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertension Gainer, JV Bellamine, A Dawson, EP Womble, KE Grant, SW Wang, Y Cupples, LA Guo, CY Demissie, S O'Donnell, CJ Brown, NJ Waterman, MR Capdevila, JH Circulation 111:63-9 Arachidonic acid is hydroxylated to 20-HETE by CYP(3) Arachidonic acid is hydroxylated to 20-HETE by CYP(3) Several cytochrome P450s (CYPs) convert arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE). The CYPs and their references are as follows: CYP4A11 (Gainer et al. 2005, Powell 1998); CYP4F2 (Powell et al. 1998, Kikuta et al. 2002); CYP2U1 (Chuang et al. 2004); CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 113601 1 Reactome DB_ID: 140356 1 Reactome DB_ID: 156540 1 Reactome DB_ID: 113534 1 Reactome DB_ID: 113564 1 Reactome DB_ID: 113519 1 Reactome DB_ID: 2142780 1 20-HETE [ChEBI:34306] 20-HETE 20-Hydroxyicosatetraenoic acid 20-Hydroxyeicosatetraenoic acid (5Z,8Z,11Z,14Z)-20-Hydroxyicosa-5,8,11,14-tetraenoic acid 20-Hydroxy arachidonic acid ChEBI 34306 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161816 CYP(3) [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP4A11 [endoplasmic reticulum membrane] CYP1A2 [endoplasmic reticulum membrane] CYP4F2 [endoplasmic reticulum membrane] CYP1A1 [endoplasmic reticulum membrane] CYP1B1 [endoplasmic reticulum membrane] CYP2U1 [endoplasmic reticulum membrane] Reactome Database ID Release 81 2161836 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161836 Reactome Database ID Release 81 2161940 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161940 Reactome R-HSA-2161940 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-2161940.2 12432928 Pubmed 2002 Prostaglandin and leukotriene omega-hydroxylases Kikuta, Y Kusunose, E Kusunose, M Prostaglandins Other Lipid Mediat 68:345-62 9618440 Pubmed 1998 Metabolism of arachidonic acid to 20-hydroxy-5,8,11, 14-eicosatetraenoic acid by P450 enzymes in human liver: involvement of CYP4F2 and CYP4A11 Powell, PK Wolf, I Jin, R Lasker, JM J Pharmacol Exp Ther 285:1327-36 Reactome Database ID Release 81 2142816 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142816 Reactome R-HSA-2142816 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142816.1 10681399 Pubmed 2000 Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase Capdevila, JH Falck, JR Harris, RC J Lipid Res 41:163-81 GO 0097267 GO biological process Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) The epoxidation of arachidonic acid by cytochrome P450s (CYPs) results in the formation of unique bioactive lipid mediators termed epoxyeicosatrienoic acids (EETs). Each double bond has been shown to be susceptible to oxidation, resulting in 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. The majority of the EET biological activities are diminished by the hydrolysis to the corresponding dihydroxyeicosatrienoic acids (DHET) (Capdevila et al. 2000, 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 Arachidonic acid is epoxidated to 5,6-EET by CYP(4) Arachidonic acid is epoxidated to 5,6-EET by CYP(4) Several cytochrome P450s (CYPs) convert arachidonic acid to 5,6-epoxyeicosatrienoic acid (5,6-EET). The CYPs and their references are as follows: CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004); CYP2J2 (Wu et al. 1996). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 70106 1 Reactome DB_ID: 29768 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 2142739 1 5,6-EET [ChEBI:34450] 5,6-EET ChEBI 34450 Reactome DB_ID: 29366 1 Reactome DB_ID: 29356 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161805 CYP(4) [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP1A2 [endoplasmic reticulum membrane] CYP2J2 [endoplasmic reticulum membrane] CYP1A1 [endoplasmic reticulum membrane] CYP1B1 [endoplasmic reticulum membrane] UniProt P51589 Reactome Database ID Release 81 2161927 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161927 Reactome Database ID Release 81 2161890 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161890 Reactome R-HSA-2161890 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-2161890.2 8631948 Pubmed 1996 Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart Wu, S Moomaw, CR Tomer, KB Falck, JR Zeldin, DC J Biol Chem 271:3460-8 Arachidonic acid is epoxidated to 8,9/11,12/14,15-EET by CYP(5) Arachidonic acid is epoxidated to 8,9/11,12/14,15-EET by CYP(5) Several cytochrome P450s (CYPs) convert arachidonic acid to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (8,9-, 11,12-, 14,15-EETs). The CYPs and their references are as follows: CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004); CYP2C8, CYP2C9 (Rifkind et al. 1995); CYP2C19 (Bylund et al. 1998, Rifkind et al. 1995); CYP2J2 (Wu et al. 1996). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 70106 1 Reactome DB_ID: 29768 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 29368 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161753 1 8,9/11,12/14,15-EET [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 8,9-EET [cytosol] 11,12-EET [cytosol] 14,15-EET [cytosol] ChEBI 34490 ChEBI 34130 ChEBI 34157 Reactome DB_ID: 29366 1 Reactome DB_ID: 29356 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161990 CYP(5) [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP1A2 [endoplasmic reticulum membrane] CYP2C9 [endoplasmic reticulum membrane] CYP2J2 [endoplasmic reticulum membrane] CYP2C8 [endoplasmic reticulum membrane] CYP2C19 [endoplasmic reticulum membrane] CYP1A1 [endoplasmic reticulum membrane] CYP1B1 [endoplasmic reticulum membrane] Reactome Database ID Release 81 2161882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161882 Reactome Database ID Release 81 2161899 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161899 Reactome R-HSA-2161899 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-2161899.2 9866708 Pubmed 1998 Analysis of cytochrome P450 metabolites of arachidonic and linoleic acids by liquid chromatography-mass spectrometry with ion trap MS Bylund, J Ericsson, J Oliw, EH Anal Biochem 265:55-68 7625847 Pubmed 1995 Arachidonic acid metabolism by human cytochrome P450s 2C8, 2C9, 2E1, and 1A2: regioselective oxygenation and evidence for a role for CYP2C enzymes in arachidonic acid epoxygenation in human liver microsomes Rifkind, AB Lee, C Chang, TK Waxman, DJ Arch Biochem Biophys 320:380-9 3.3.2.10 EET(1) is hydrolysed to DHET(1) by EPHX2 EET(1) is hydrolysed to DHET(1) by EPHX2 Epoxide hydrolase 2 (EPHX2) hydrolyses 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids ("EET(1)") to their corresponding dihydroxyeicosatrienoic acids ("DHET(1)") (Werner et al. 2002; Gomez et al. 2004). The majority of the EET biological activities are diminished by this hydrolysis. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Converted from EntitySet in Reactome Reactome DB_ID: 2161818 1 EET(1) [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 8,9-EET [cytosol] 5,6-EET [cytosol] 11,12-EET [cytosol] 14,15-EET [cytosol] Reactome DB_ID: 29356 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161883 1 DHET(1) [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 5,6-DHET [cytosol] (5Z,8Z,14Z)-11,12-dihydroxyicosatrienoic acid [cytosol] (5Z,8Z,11Z)-14,15-dihydroxyicosatrienoic acid [cytosol] (5Z,11Z,14Z)-8,9-dihydroxyicosatrienoic acid [cytosol] ChEBI 63974 ChEBI 63969 ChEBI 63966 ChEBI 63970 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142777 EPHX2 dimer [cytosol] EPHX2 dimer Reactome DB_ID: 2142819 2 UniProt:P34913 EPHX2 EPHX2 EPHX2 FUNCTION Bifunctional enzyme (PubMed:12574510). The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides (PubMed:12869654, PubMed:12574510, PubMed:22798687). Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides (By similarity). Also determines steady-state levels of physiological mediators (PubMed:12869654, PubMed:12574510, PubMed:22798687, PubMed:21217101).FUNCTION Bifunctional enzyme (PubMed:12574510). The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid and 12-phosphonooxy-octadec-9E-enoic acid (PubMed:12574510). Has phosphatase activity toward lyso-glycerophospholipids with also some lower activity toward lysolipids of sphingolipid and isoprenoid phosphates (PubMed:22217705, PubMed:22387545).ACTIVITY REGULATION Inhibited by 1-(1-acetylpiperidin-4-yl)-3-(4-(trifl uoromethoxy)phenyl)urea (TPAU), 1-cyclohexyl-3-dodecylurea (CDU), 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), 1-((3S, 5S, 7S)-adamantan-1-yl)-3-(5-(2-(2-ethoxyethoxy) ethoxy)pentyl)urea (AEPU), N-adamantyl-N[']-cyclohexyl urea (ACU), 4-(((1S, 4S)-4-(3-((3S, 5S, 7S)-adamantan-1-yl) ureido)cyclohexyl)oxy)benzoic acid (c-AUCB), 4-(((1R, 4R)-4-(3-((3S, 5S, 7S)-adamantan-1-yl)ureido)cyclohexyl)oxy)benzoic acid (t-AUCB), 4-(((1R, 4R)-4-(3-(4(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid (t-TAUCB) and to a lesser extent by 8-(3-((3S, 5S, 7S)-adamantan-1-yl)ureido) octanoic acid (AUOA). Phosphatase activity is inhibited by dodecyl-phosphate, phospholipids such as phospho-lysophosphatidic acids and fatty acids such as palmitic acid and lauric acid (PubMed:22217705, PubMed:22387545).SUBUNIT Homodimer.INDUCTION By compounds that cause peroxisome proliferation such as clofibrate, tiadenol and fenofibrate.DOMAIN The N-terminal domain has phosphatase activity. The C-terminal domain has epoxide hydrolase activity.PTM The N-terminus is blocked.PTM The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation (Probable).SIMILARITY Belongs to the AB hydrolase superfamily. Epoxide hydrolase family. UniProt P34913 1 EQUAL 555 EQUAL Reactome DB_ID: 29926 2 magnesium(2+) [ChEBI:18420] magnesium(2+) ChEBI 18420 Reactome Database ID Release 81 2142777 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142777 Reactome R-HSA-2142777 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142777.1 GO 0004301 GO molecular function Reactome Database ID Release 81 2161846 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161846 Reactome Database ID Release 81 2161961 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161961 Reactome R-HSA-2161961 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-2161961.2 12468260 Pubmed 2002 Characterization and identification of cytochrome P450 metabolites of arachidonic acid released by human peritoneal macrophages obtained from the pouch of Douglas Werner, K Schaefer, WR Schweer, H Deppert, WR Karck, U Zahradnik, HP Prostaglandins Leukot Essent Fatty Acids 67:397-404 15096040 Pubmed 2004 Structure of human epoxide hydrolase reveals mechanistic inferences on bifunctional catalysis in epoxide and phosphate ester hydrolysis Gomez, GA Morisseau, C Hammock, BD Christianson, DW Biochemistry 43:4716-23 Reactome Database ID Release 81 2142670 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142670 Reactome R-HSA-2142670 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142670.1 GO 0019373 GO biological process Reactome Database ID Release 81 2142753 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142753 Reactome R-HSA-2142753 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142753.5 GO 0019369 GO biological process