BioPAX pathway converted from "Arachidonic acid metabolism" in the Reactome database.Arachidonic acid metabolismArachidonic acid metabolismEicosanoids, 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Hydrolysis of phosphatidylcholineHydrolysis of phosphatidylcholineOnce 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 12:22:05Reviewed: Rush, MG, 2012-11-10Edited: Jassal, Bijay, 2008-11-06Reactome DB_ID: 4269251endoplasmic reticulum membraneGO00057891,2-diacyl-sn-glycero-3-phosphocholine(1+) [ChEBI:16110]1,2-diacyl-sn-glycero-3-phosphocholine(1+)Reactomehttp://www.reactome.orgChEBI16110Reactome DB_ID: 293561cytosolGO0005829water [ChEBI:15377]waterChEBI15377Reactome DB_ID: 1403561endoplasmic reticulum lumenGO0005788arachidonic acid [ChEBI:15843]arachidonic acidChEBI15843Reactome DB_ID: 42898111-O-acyl-sn-glycero-3-phosphocholine(1+) [ChEBI:17504]1-O-acyl-sn-glycero-3-phosphocholine(1+)ChEBI17504PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 111860Active PLA2:phosphatidylcholine [endoplasmic reticulum membrane]Active PLA2:phosphatidylcholineReactome DB_ID: 4269251Reactome DB_ID: 1118591UniProt:P47712 PLA2G4APLA2G4ACPLA2PLA2G4APLA2G4FUNCTION 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 sapiensNCBI Taxonomy9606UniProtP47712O-phospho-L-serine at 505505EQUALO-phospho-L-serine [MOD:00046]O-phospho-L-serine at 727727EQUALChain Coordinates1EQUAL749EQUALReactome DB_ID: 740161calcium(2+) [ChEBI:29108]calcium(2+)ChEBI29108Reactome Database ID Release 74111860Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111860ReactomeR-HSA-1118601Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-111860.1GO0047498GO molecular functionReactome Database ID Release 74111882Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111882Reactome Database ID Release 74111883Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111883ReactomeR-HSA-1118833Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-111883.321247147Pubmed2011Functional characterization of mutations in inherited human cPLA? deficiencyReed, Kathleen ATucker, Dawn EAloulou, AhmedAdler, DavidGhomashchi, FaridehGelb, Michael HLeslie, Christina COates, John ABoutaud, OlivierBiochemistry 50:1731-821746768Pubmed2011Secreted phospholipase A2 revisitedMurakami, MakotoTaketomi, YoshitakaSato, HiroyasuYamamoto, KeiJ. Biochem. 150:233-55Arachidonate diffuses across the ER membraneArachidonate diffuses across the ER membraneArachidonate 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, 2009-07-14Reviewed: Rush, MG, 2012-11-10Edited: Jupe, S, 2009-07-14Reactome DB_ID: 1403561Reactome DB_ID: 297681Reactome Database ID Release 74428990Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428990ReactomeR-HSA-4289903Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428990.36810878Pubmed1982How is the level of free arachidonic acid controlled in mammalian cells?Irvine, RFBiochem J 204:3-166146314Pubmed1984Inositol trisphosphate and diacylglycerol as second messengersBerridge, MJBiochem J 220:345-602.3.1.75AWAT1 transfers acyl group from acyl-CoA to ARACOH, forming wax estersAWAT1 transfers acyl group from acyl-CoA to ARACOH, forming wax estersArachidyl 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, 2015-05-29Reviewed: D'Eustachio, Peter, 2015-06-26Edited: Jassal, Bijay, 2015-05-29Reactome DB_ID: 1921721acyl-CoA [ChEBI:17984]acyl-CoAChEBI17984Reactome DB_ID: 56964261icosan-1-ol [ChEBI:75627]icosan-1-olarachidyl alcoholeicosyl alcoholeicosan-1-olarachidic alcohol1-eicosanolChEBI75627Reactome DB_ID: 56964121wax ester [ChEBI:10036]wax esterWax estersChEBI10036Reactome DB_ID: 1627431coenzyme A [ChEBI:15346]coenzyme AChEBI15346PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 5696425UniProt:Q58HT5 AWAT1AWAT1AWAT1DGAT2L3DGA2FUNCTION 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.UniProtQ58HT51EQUAL328EQUALGO0047196GO molecular functionReactome Database ID Release 745696418Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696418Reactome Database ID Release 745696424Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5696424ReactomeR-HSA-56964242Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5696424.215671038Pubmed2005Identification of two novel human acyl-CoA wax alcohol acyltransferases: members of the diacylglycerol acyltransferase 2 (DGAT2) gene superfamilyTurkish, Aaron RHenneberry, Annette LCromley, DebraPadamsee, MahajabeenOelkers, PBazzi, HishamChristiano, Angela MBillheimer, JTSturley, Stephen LJ. Biol. Chem. 280:14755-64FAAH hydrolyses AEA to AA and ETAFAAH hydrolyses AEA to AA and ETAFatty 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, 2015-05-18Reviewed: D'Eustachio, Peter, 2015-06-26Edited: Jassal, Bijay, 2015-05-18Reactome DB_ID: 56937541anandamide [ChEBI:2700]anandamideChEBI2700Reactome DB_ID: 293561Reactome DB_ID: 297681Reactome DB_ID: 14987511ethanolamine [ChEBI:16000]ethanolamineChEBI16000PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 5693746UniProt:O00519 FAAHFAAHFAAHFAAH1FUNCTION 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). Also catalyzes the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-glycerol) (PubMed:21049984).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.UniProtO005191EQUAL579EQUALGO0017064GO molecular functionReactome Database ID Release 745693749Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693749Reactome Database ID Release 745693742Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693742ReactomeR-HSA-56937421Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5693742.117015445Pubmed2006A second fatty acid amide hydrolase with variable distribution among placental mammalsWei, Binqing QMikkelsen, Tarjei SMcKinney, Michele KLander, Eric SCravatt, BFJ. Biol. Chem. 281:36569-7819926788Pubmed2010Lipid droplets are novel sites of N-acylethanolamine inactivation by fatty acid amide hydrolase-2Kaczocha, MartinGlaser, Sherrye TChae, JaniperBrown, Deborah ADeutsch, Dale GJ. Biol. Chem. 285:2796-806FAAH2 hydrolyses AEA to AA and ETAFAAH2 hydrolyses AEA to AA and ETAFatty 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, 2015-05-18Reviewed: D'Eustachio, Peter, 2015-06-26Edited: Jassal, Bijay, 2015-05-18Reactome DB_ID: 56937471lipid dropletGO0005811Reactome DB_ID: 56937521Reactome DB_ID: 56937361Reactome DB_ID: 56937331PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 5693745UniProt:Q6GMR7 FAAH2FAAH2AMDDFAAH2FUNCTION 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.UniProtQ6GMR71EQUAL532EQUALReactome Database ID Release 745693738Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693738Reactome Database ID Release 745693751Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693751ReactomeR-HSA-56937511Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5693751.1Synthesis 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24PTGS2 dimer binds celecoxibPTGS2 dimer binds celecoxibWhile 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 celecoxib (Luong et al. 1996; Smith et al. 2000; Dong et al. 2011).Authored: D'Eustachio, P, 2012-06-05Reviewed: Rush, MG, 2012-11-10Edited: D'Eustachio, P, 2012-06-05Reactome DB_ID: 96774321celecoxib [IUPHAR:2892]celecoxibCelecox&reg;SC-58635SC58635Onsenal&reg;IUPHAR2892Reactome DB_ID: 1404911PTGS2 dimer [endoplasmic reticulum membrane]PTGS2 dimerPGHS2 dimerReactome DB_ID: 616052UniProt:P35354 PTGS2PTGS2COX2PTGS2FUNCTION 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. PGHS1 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). PGHS2 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.UniProtP3535418EQUAL604EQUALReactome DB_ID: 23113551heme b [ChEBI:26355]heme bprotohemeheme[3,7,12,17-tetramethyl-8,13-divinylporphyrin-2,18-dipropanoato(2-)]ironhaem bPROTOPORPHYRIN IX CONTAINING FEprotoheme IX(7,12-diethenyl-3,8,13,17-tetramethylporphyrin-2,18-dipropanoato)ironChEBI26355Reactome Database ID Release 74140491Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140491ReactomeR-HSA-1404911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-140491.1Reactome DB_ID: 23097781PTGS2:celecoxib [endoplasmic reticulum membrane]PTGS2:celecoxibReactome DB_ID: 96774321Reactome DB_ID: 1404911Reactome Database ID Release 742309778Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309778ReactomeR-HSA-23097782Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2309778.2Reactome Database ID Release 742309779Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309779ReactomeR-HSA-23097793Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2309779.38901870Pubmed1996Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2Luong, ChristineMiller, AaronBarnett, JimChow, JoanRamesha, ChakkBrowner, Michelle FNat. Struct. Biol. 3:927-3310966456Pubmed2000Cyclooxygenases: structural, cellular, and molecular biologySmith, William LDeWitt, David LGaravito, R MichaelAnnu Rev Biochem 69:145-8221467029Pubmed2011Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimerDong, LiangVecchio, Alex JSharma, Narayan PJurban, Brice JMalkowski, Michael GSmith, William LJ. Biol. Chem. 286:19035-46Aspirin acetylates PTGS1Aspirin acetylates PTGS1Aspirin (acetylsalicylate) 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, 2012-06-07Reviewed: Rush, MG, 2012-11-10Edited: D'Eustachio, P, 2012-06-07Reactome DB_ID: 4289861PTGS1 dimer [endoplasmic reticulum membrane]PTGS1 dimerPGHS1 homodimerCOX1Reactome DB_ID: 23113551Reactome DB_ID: 4289312UniProt:P23219 PTGS1PTGS1COX1PTGS1FUNCTION Converts arachidonate to prostaglandin H2 (PGH2), a committed step in prostanoid synthesis. 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.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. PGHS1 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). PGHS2 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.UniProtP2321924EQUAL599EQUALReactome Database ID Release 74428986Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=428986ReactomeR-HSA-4289861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-428986.1Reactome DB_ID: 23146931acetylsalicylate [ChEBI:13719]acetylsalicylateChEBI13719Reactome DB_ID: 23146901salicylate [ChEBI:30762]salicylateo-hydroxybenzoate2-hydroxybenzoic acid ion(1-)salChEBI30762Reactome DB_ID: 23146951Ac-PTGS1 dimer [endoplasmic reticulum membrane]Ac-PTGS1 dimerReactome DB_ID: 23146941O-acetyl-L-serine at 529529EQUALO-acetyl-L-serine24EQUAL599EQUALReactome DB_ID: 23113551Reactome DB_ID: 428931124EQUAL599EQUALReactome Database ID Release 742314695Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314695ReactomeR-HSA-23146951Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314695.1Reactome Database ID Release 742314678Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314678ReactomeR-HSA-23146783Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314678.37552725Pubmed1995The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthaseLoll, Patrick JPicot, DanielGaravito, R MichaelNat. Struct. Biol. 2:637-438175750Pubmed1994Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirinLecomte, MarcLaneuville, OdetteJi, ChuanDeWitt, David LSmith, William LJ. Biol. Chem. 269:13207-15Aspirin acetylates PTGS2Aspirin acetylates PTGS2Aspirin (acetylsalicylate) 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, 2012-06-07Reviewed: Rush, MG, 2012-11-10Edited: D'Eustachio, P, 2012-06-07Reactome DB_ID: 1404911Reactome DB_ID: 23146931Reactome DB_ID: 23146901Reactome DB_ID: 23146871Ac-PTGS2 dimer [endoplasmic reticulum membrane]Ac-PTGS2 dimerReactome DB_ID: 61605118EQUAL604EQUALReactome DB_ID: 23113551Reactome DB_ID: 21618241O-acetyl-L-serine at 516516EQUAL18EQUAL604EQUALReactome Database ID Release 742314687Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314687ReactomeR-HSA-23146871Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314687.1Reactome Database ID Release 742314686Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2314686ReactomeR-HSA-23146862Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2314686.21.14.99.1Arachidonic acid is oxidised to PGG2 by PTGS1Arachidonic acid is oxidised to PGG2 by PTGS1Arachidonic acid oxidised to PGG2Prostaglandin 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Edited: Jassal, B, 2008-05-28 09:06:10Edited: Jassal, Bijay, 2008-05-19Reactome DB_ID: 1403561Reactome DB_ID: 1135342dioxygen [ChEBI:15379]dioxygenChEBI15379Reactome DB_ID: 1403571prostaglandin G2 [ChEBI:27647]prostaglandin G2ChEBI27647PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 428986GO0004666GO molecular functionReactome Database ID Release 74140354Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140354Reactome Database ID Release 74140355Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140355ReactomeR-HSA-1403551Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-140355.14521806Pubmed1974Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregationHamberg, MSvensson, JWakabayashi, TSamuelsson, BProc Natl Acad Sci U S A 71:345-94776443Pubmed1973Isolation and properties of intermediates in prostaglandin biosynthesisNugteren, DHHazelhof, EBiochim Biophys Acta 326:448-611.14.99.1Arachidonic acid is oxidised to PGG2 by PTGS2Arachidonic acid is oxidised to PGG2 by PTGS2Arachidonic acid oxidised to PGG2Prostaglandin 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Edited: Jassal, B, 2008-05-28 09:06:10Edited: Jassal, Bijay, 2008-05-19Reactome DB_ID: 1403561Reactome DB_ID: 1135342Reactome DB_ID: 1403571PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 140491Reactome Database ID Release 742309772Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309772Reactome Database ID Release 742309787Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309787ReactomeR-HSA-23097871Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2309787.11.11.1.7PGG2 is reduced to PGH2 by PTGS1PGG2 is reduced to PGH2 by PTGS1Peroxidative reduction of PGG2 to PGH2Prostaglandin 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Edited: Jassal, Bijay, 2008-05-19Reactome DB_ID: 1565402hydron [ChEBI:15378]hydronChEBI15378Reactome DB_ID: 1403571Reactome DB_ID: 763422electron [ChEBI:10545]electronChEBI10545Reactome DB_ID: 301381prostaglandin H2 [ChEBI:15554]prostaglandin H2ChEBI15554Reactome DB_ID: 1135191PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 428986GO0004601GO molecular functionReactome Database ID Release 74140358Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140358Reactome Database ID Release 74140359Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=140359ReactomeR-HSA-1403591Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-140359.14514999Pubmed1973Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesisHamberg, MSamuelsson, BProc Natl Acad Sci U S A 70:899-9039139685Pubmed1997Differential allosteric regulation of prostaglandin H synthase 1 and 2 by arachidonic acidSwinney, DCMak, AYBarnett, JRamesha, CSJ Biol Chem 272:12393-87947975Pubmed1994Purification, characterization and selective inhibition of human prostaglandin G/H synthase 1 and 2 expressed in the baculovirus systemBarnett, JChow, JIves, DChiou, MMackenzie, ROsen, ENguyen, BTsing, SBach, CFreire, JBiochim Biophys Acta 1209:130-91380156Pubmed1992Human cyclooxygenase-2 cDNAHla, TNeilson, KProc Natl Acad Sci U S A 89:7384-81.11.1.7PGG2 is reduced to PGH2 by PTGS2PGG2 is reduced to PGH2 by PTGS2Peroxidative reduction of PGG2 to PGH2Prostaglandin 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Edited: Jassal, Bijay, 2008-05-19Reactome DB_ID: 1565402Reactome DB_ID: 1403571Reactome DB_ID: 763422Reactome DB_ID: 301381Reactome DB_ID: 1135191PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 140491Reactome Database ID Release 742309777Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309777Reactome Database ID Release 742309773Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2309773ReactomeR-HSA-23097735Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2309773.5ACTIVATIONReactome Database ID Release 745362144Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5362144ReactomeR-HSA-53621441Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5362144.1Reactome DB_ID: 5492821-methylnicotinamide [ChEBI:16797]1-methylnicotinamideChEBI16797INHIBITIONReactome Database ID Release 749677534Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9677534Reactome DB_ID: 2309778PGH2 diffuses from the endoplasmic reticulum lumen to the cytosolPGH2 diffuses from the endoplasmic reticulum lumen to the cytosolPGH2 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, 2012-06-04Reviewed: Rush, MG, 2012-11-10Reactome DB_ID: 301381Reactome DB_ID: 2652831Reactome Database ID Release 742299725Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2299725ReactomeR-HSA-22997253Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2299725.320346915Pubmed2010The prostaglandin transporter PGT transports PGH(2)Chi, YulingSchuster, Victor LBiochem. Biophys. Res. Commun. 395:168-72PGH2 is reduced to PGF2a by AKR1C3PGH2 is reduced to PGF2a by AKR1C3Aldo-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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 701061Reactome DB_ID: 293641NADPH [ChEBI:16474]NADPHTPNHChEBI16474Reactome DB_ID: 2652831Reactome DB_ID: 293661NADP(+) [ChEBI:18009]NADP(+)ChEBI18009Reactome DB_ID: 8795351prostaglandin F2alpha [ChEBI:15553]prostaglandin F2alphaChEBI15553PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142714UniProt:P42330 AKR1C3AKR1C3PGFSKIAA0119DDH1AKR1C3HSD17B5FUNCTION Catalyzes the conversion of aldehydes and ketones to alcohols. Catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ) and the oxidation of 9-alpha,11-beta-PGF2 to PGD2. Functions as a bi-directional 3-alpha-, 17-beta- and 20-alpha HSD. Can interconvert active androgens, estrogens and progestins with their cognate inactive metabolites. Preferentially transforms androstenedione (4-dione) to testosterone.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).TISSUE SPECIFICITY Expressed in many tissues including adrenal gland, brain, kidney, liver, lung, mammary gland, placenta, small intestine, colon, spleen, prostate and testis. The dominant HSD 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.UniProtP423301EQUAL323EQUALGO0036130GO molecular functionReactome Database ID Release 742161558Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161558Reactome Database ID Release 742161549Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161549ReactomeR-HSA-21615492Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161549.216475787Pubmed2006Prostaglandin F2alpha formation from prostaglandin H2 by prostaglandin F synthase (PGFS): crystal structure of PGFS containing bimatoprostKomoto, JYamada, TWatanabe, KWoodward, DFTakusagawa, FBiochemistry 45:1987-9610622721Pubmed1999cDNA cloning, expression and characterization of human prostaglandin F synthaseSuzuki-Yamamoto, TNishizawa, MFukui, MOkuda-Ashitaka, ENakajima, TIto, SWatanabe, KFEBS Lett 462:335-4014979715Pubmed2004Crystal structure of human prostaglandin F synthase (AKR1C3)Komoto, JYamada, TWatanabe, KTakusagawa, FBiochemistry 43:2188-981.11.1PGH2 is reduced to PGF2a by FAM213BPGH2 is reduced to PGF2a by FAM213BProstamide/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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 2652831Reactome DB_ID: 21427741thioredoxin dithiol [ChEBI:15967]thioredoxin dithiolChEBI15967Reactome DB_ID: 21428331thioredoxin disulfide [ChEBI:18191]thioredoxin disulfideChEBI18191Reactome DB_ID: 8795351PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142703UniProt:Q8TBF2 PRXL2BPRXL2BFAM213BPRXL2BC1orf93FUNCTION 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.UniProtQ8TBF21EQUAL198EQUALGO0008379GO molecular functionReactome Database ID Release 742161731Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161731Reactome Database ID Release 742161612Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161612ReactomeR-HSA-21616122Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161612.218006499Pubmed2008Molecular characterization of a novel type of prostamide/prostaglandin F synthase, belonging to the thioredoxin-like superfamilyMoriuchi, HKoda, NOkuda-Ashitaka, EDaiyasu, HOgasawara, KToh, HIto, SWoodward, DFWatanabe, KJ Biol Chem 283:792-80120950588Pubmed2011Preferential localization of prostamide/prostaglandin F synthase in myelin sheaths of the central nervous systemYoshikawa, KTakei, SHasegawa-Ishii, SChiba, YFurukawa, AKawamura, NHosokawa, MWoodward, DFWatanabe, KShimada, ABrain Res 1367:22-325.3.99.3PGH2 is isomerised to PGE2 by PTGESPGH2 is isomerised to PGE2 by PTGESProstaglandin 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 2652831Reactome DB_ID: 2652871prostaglandin E2 [ChEBI:15551]prostaglandin E2ChEBI15551PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142686PTGES trimer [endoplasmic reticulum membrane]PTGES trimerProstaglandin E synthase homotrimerReactome DB_ID: 21427173UniProt:O14684 PTGESPTGESPGESMPGES1PIG12MGST1L1PTGESFUNCTION Catalyzes the oxidoreduction of prostaglandin endoperoxide H2 (PGH2) to prostaglandin E2 (PGE2).SUBUNIT Homotrimer.INDUCTION By p53/TP53.SIMILARITY Belongs to the MAPEG family.UniProtO146841EQUAL152EQUALReactome DB_ID: 22395243glutathione [ChEBI:16856]glutathioneChEBI16856Reactome Database ID Release 742142686Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142686ReactomeR-HSA-21426861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142686.1GO0050220GO molecular functionReactome Database ID Release 742161577Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161577Reactome Database ID Release 742161660Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161660ReactomeR-HSA-21616603Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161660.318682561Pubmed2008Structural basis for induced formation of the inflammatory mediator prostaglandin E2Jegerschöld, CPawelzik, SCPurhonen, PBhakat, PGheorghe, KRGyobu, NMitsuoka, KMorgenstern, RJakobsson, PJHebert, HProc Natl Acad Sci U S A 105:11110-55.3.99.3Prostaglandin E synthase isomerizes PGH2 to PGE2Prostaglandin E synthase isomerizes PGH2 to PGE2Prostaglandin 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Reactome DB_ID: 2652831Reactome DB_ID: 2652871PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 8864254PTGES2(88-377), PTGES3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPTGES3 [cytosol]PTGES2(88-377) [cytosol]UniProtQ15185UniProtQ9H7Z7Reactome Database ID Release 74265290Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265290Reactome Database ID Release 74265295Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265295ReactomeR-HSA-2652952Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265295.212835322Pubmed2003Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2Murakami, MakotoNakashima, KarinKamei, DaisukeMasuda, SeikoIshikawa, YukioIshii, ToshiharuOhmiya, YoshihiroWatanabe, KikukoKudo, IchiroJ. Biol. Chem. 278:37937-4710922363Pubmed2000Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesisTanioka, TNakatani, YSemmyo, NMurakami, MKudo, IJ Biol Chem 275:32775-821.1.1.189PGE2 is converted to PGF2a by CBR1PGE2 is converted to PGF2a by CBR1Carbonyl 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 2652871Reactome DB_ID: 701061Reactome DB_ID: 293641Reactome DB_ID: 293661Reactome DB_ID: 8795351PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142784UniProt:P16152 CBR1CBR1CBR1CBRSDR21C1CRNFUNCTION 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.UniProtP161522EQUAL277EQUALGO0050221GO molecular functionReactome Database ID Release 742161655Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161655Reactome Database ID Release 742161651Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161651ReactomeR-HSA-21616512Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161651.218493841Pubmed2008Different functions between human monomeric carbonyl reductase 3 and carbonyl reductase 1Miura, TNishinaka, TTerada, TMol Cell Biochem 315:113-217005231Pubmed1981Purification and properties of an NADPH-dependent carbonyl reductase from human brain. Relationship to prostaglandin 9-ketoreductase and xenobiotic ketone reductaseWermuth, BJ Biol Chem 256:1206-13PGE2 is dehydrated to PGA2PGE2 is dehydrated to PGA2Cyclopentenone 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 2652871Reactome DB_ID: 293561Reactome DB_ID: 22997261prostaglandin A2 [ChEBI:27820]prostaglandin A2ChEBI27820Reactome Database ID Release 742161659Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161659ReactomeR-HSA-21616592Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161659.22717650Pubmed1989Simultaneous determination of prostaglandins (PG) E2, A2 and B2 and stability studies of PGE2 in pharmaceutical preparations by ion-pair reversed phase HPLCAmin, MPharm Acta Helv 64:45-505903721Pubmed1966Prostaglandins in human seminal plasma. Prostaglandins and related factors 46Hamberg, MSamuelsson, BJ Biol Chem 241:257-63PGA2 is isomerised to PGC2PGA2 is isomerised to PGC2Dehydration 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 22997261Reactome DB_ID: 22997241prostaglandin C2 [ChEBI:27555]prostaglandin C2ChEBI27555Reactome Database ID Release 742161666Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161666ReactomeR-HSA-21616662Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161666.211301410Pubmed2001Cyclopentenone prostaglandins: new insights on biological activities and cellular targetsStraus, DSGlass, CKMed Res Rev 21:185-210PGC2 is isomerised to PGB2PGC2 is isomerised to PGB2Isomerization 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 22997241Reactome DB_ID: 22997211prostaglandin B2 [ChEBI:28099]prostaglandin B2ChEBI28099Reactome Database ID Release 742161735Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161735ReactomeR-HSA-21617352Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161735.2PGA2 is dehydrated to 15d-PGA2PGA2 is dehydrated to 15d-PGA2The 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 22997261Reactome DB_ID: 293561Reactome DB_ID: 2299722115-deoxy-Delta(12,14)-prostaglandin A2 [ChEBI:63975]15-deoxy-Delta(12,14)-prostaglandin A2ChEBI63975Reactome Database ID Release 742161668Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161668ReactomeR-HSA-21616682Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161668.210200320Pubmed1999Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta12,14-prostaglandin J2Petrova, TVAkama, KTVan Eldik, LJProc Natl Acad Sci U S A 96:4668-735.3.99.2PGH2 is isomerised to PGD2 by PTGDSPGH2 is isomerised to PGD2 by PTGDSProstaglandin 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 301381Reactome DB_ID: 21616341prostaglandin D2 [ChEBI:15555]prostaglandin D2ChEBI15555PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142814UniProt:P41222 PTGDSPTGDSPTGDSPDSFUNCTION Catalyzes the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation. 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.UniProtP4122223EQUAL190EQUALGO0004667GO molecular functionReactome Database ID Release 742161647Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161647Reactome Database ID Release 742161620Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161620ReactomeR-HSA-21616202Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161620.220667974Pubmed2010Structure-function analysis of human l-prostaglandin D synthase bound with fatty acid moleculesZhou, YShaw, NLi, YZhao, YZhang, RLiu, ZJFASEB J 24:4668-775.3.99.2PGH2 is isomerised to PGD2 by HPGDSPGH2 is isomerised to PGD2 by HPGDSProstaglandin 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 2652831Reactome DB_ID: 8796291PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142683HPGDS dimer [cytosol]HPGDS dimerReactome DB_ID: 21427062UniProt:O60760 HPGDSHPGDSHPGDSPGDSPTGDS2GSTSFUNCTION 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.UniProtO607602EQUAL199EQUALReactome DB_ID: 294502Reactome Database ID Release 742142683Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142683ReactomeR-HSA-21426831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142683.1Reactome Database ID Release 742161729Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161729Reactome Database ID Release 742161701Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161701ReactomeR-HSA-21617013Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161701.311672424Pubmed2001Mammalian class Sigma glutathione S-transferases: catalytic properties and tissue-specific expression of human and rat GSH-dependent prostaglandin D2 synthasesJowsey, IRThomson, AMFlanagan, JUMurdock, PRMoore, GBMeyer, DJMurphy, GJSmith, SAHayes, JDBiochem J 359:507-1612627223Pubmed2003Mechanism of metal activation of human hematopoietic prostaglandin D synthaseInoue, TIrikura, DaisukeOkazaki, NKinugasa, SMatsumura, HUodome, NYamamoto, MKumasaka, TMiyano, MKai, YUrade, YNat Struct Biol 10:291-6PGD2 is dehydrated to PGJ2PGD2 is dehydrated to PGJ2Analogous to prostaglandin E2 (PGE2), dehydration of the prostaglandin D2 (PGD2) prostane ring forms prostaglandin J2 (PGJ2) (Monneret et al. 2002).Authored: Williams, MG, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 21616341Reactome DB_ID: 21426741prostaglandin J2 [ChEBI:27485]prostaglandin J2ChEBI27485Reactome DB_ID: 1135191Reactome Database ID Release 742161733Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161733ReactomeR-HSA-21617332Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161733.211907120Pubmed200215-Deoxy-delta 12,14-prostaglandins D2 and J2 are potent activators of human eosinophilsMonneret, GLi, HVasilescu, JRokach, JPowell, WSJ Immunol 168:3563-9PGJ2 is isomerised to delta12-PGJ2PGJ2 is isomerised to delta12-PGJ2Delta-12-prostaglandin J2 (delta12-PGJ2) is an isomerisation product of prostaglandin J2 (PGJ2) (Monneret et al. 2002).Authored: Williams, MG, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 21426741Reactome DB_ID: 2142821113,14-dihydro-Delta(12)-prostaglandin J2 [ChEBI:28130]13,14-dihydro-Delta(12)-prostaglandin J2ChEBI28130Reactome Database ID Release 742161563Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161563ReactomeR-HSA-21615632Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161563.2Delta12-PGJ2 is dehydrated to 15d-PGJ2Delta12-PGJ2 is dehydrated to 15d-PGJ215-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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 21428211Reactome DB_ID: 2142702115-deoxy-Delta(12,14)-prostaglandin J2 [ChEBI:34159]15-deoxy-Delta(12,14)-prostaglandin J215-Deoxy-delta-12,14-PGJ215-Deoxy-delta-12,14-prostaglandin J215-Deoxy-PGJ2ChEBI34159Reactome DB_ID: 1135191Reactome Database ID Release 742161588Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161588ReactomeR-HSA-21615882Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161588.2PGD2 is dehydrated to 15d-PGD2PGD2 is dehydrated to 15d-PGD215-Deoxy-delta 12,14-prostaglandins D2 (15d-PGD2) is a dehydrated form of prostaglandin D2 (PGD2) (Monneret et al. 2002).Authored: Williams, MG, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 21616341Reactome DB_ID: 2142817115-deoxy-Delta(12,14)-prostaglandin D2 [ChEBI:63999]15-deoxy-Delta(12,14)-prostaglandin D2ChEBI63999Reactome DB_ID: 1135191Reactome Database ID Release 742161673Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161673ReactomeR-HSA-21616732Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161673.21.1.1.188PGD2 is reduced to 11-epi-PGF2a by AKRIC3PGD2 is reduced to 11-epi-PGF2a by AKRIC3Aldo-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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 8796291Reactome DB_ID: 701061Reactome DB_ID: 293641Reactome DB_ID: 293661Reactome DB_ID: 2142710111-epi-prostaglandin F2alpha [ChEBI:27595]11-epi-prostaglandin F2alphaChEBI27595PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 21427141EQUAL323EQUALGO0036131GO molecular functionReactome Database ID Release 742161608Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161608Reactome Database ID Release 742161614Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161614ReactomeR-HSA-21616142Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161614.23862115Pubmed1985Transformation 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 humansListon, TERoberts LJ, 2ndProc Natl Acad Sci U S A 82:6030-415047184Pubmed2004Synthesis 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/MSKoda, NTsutsui, YNiwa, HIto, SWoodward, DFWatanabe, KArch Biochem Biophys 424:128-361.1.1.141PGD2/E2/F2a is oxidised to 15k-PGD2/E2/F2a by HPGDPGD2/E2/F2a is oxidised to 15k-PGD2/E2/F2a by HPGD15-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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Converted from EntitySet in ReactomeReactome DB_ID: 21616611PGD2/E2/F2a [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPGE2 [cytosol]PGD2 [cytosol]PGF2a [cytosol]Reactome DB_ID: 293601NAD(1-) [ChEBI:57540]NAD(1-)NAD(+)adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate}NAD anionChEBI57540Converted from EntitySet in ReactomeReactome DB_ID: 2161597115k-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 PhysicalEntity15k-PGF2a [cytosol]15k-PGD2 [cytosol]15k-PGE2 [cytosol]ChEBI28442ChEBI15557ChEBI15547Reactome DB_ID: 734731NADH(2-) [ChEBI:57945]NADH(2-)NADH dianionadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate}NADHChEBI57945Reactome DB_ID: 701061PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142778HPGD dimer [cytosol]HPGD dimerReactome DB_ID: 21426772UniProt:P15428 HPGDHPGDHPGDSDR36C1PGDH1FUNCTION Primary enzyme catalyzing the conversion of hydroxylated arachidonic acid species to their corresponding oxidized metabolites (Probable). Prostaglandin inactivation, catalyzes the first step in the catabolic pathway of the prostaglandins. Contributes to the regulation of events that are under the control of prostaglandin levels (PubMed:15574495, PubMed:16828555, PubMed:8086429). Catalyzes the NAD-dependent dehydrogenation of lipoxin A4 to form 15-oxo-lipoxin A4 (PubMed:10837478). Converts 11(R)-HETE to 11-oxo-5,8,12,14-(Z,Z,E,Z)-eicosatetraenoic acid (ETE) (PubMed:21916491). Has hydroxylated docosahexaenoic acid metabolites as substrates (PubMed:25586183). Converts resolvins E1, D1 and D2 to their oxo products which represents a mode of resolvins inactivation and stabilizes their anti-inflammatory actions (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.UniProtP154281EQUAL266EQUALReactome Database ID Release 742142778Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142778ReactomeR-HSA-21427781Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142778.1GO0016404GO molecular functionReactome Database ID Release 742161623Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161623Reactome Database ID Release 742161662Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161662ReactomeR-HSA-21616622Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161662.216828555Pubmed2006Role of glutamine 148 of human 15-hydroxyprostaglandin dehydrogenase in catalytic oxidation of prostaglandin E2Cho, HHuang, LHamza, AGao, DZhan, CGTai, HHBioorg Med Chem 14:6486-913954355Pubmed1986Isolation and properties of lung 15-hydroxyprostaglandin dehydrogenase from pregnant rabbitsBergholte, JMOkita, RTArch Biochem Biophys 245:308-151.3.1.4815k-PGE2/F2a is reduced to dhk-PGE2/F2a by PTGR115k-PGE2/F2a is reduced to dhk-PGE2/F2a by PTGR1Prostaglandin 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Converted from EntitySet in ReactomeReactome DB_ID: 2161650115k-PGE2,15k-PGF2a [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity15k-PGF2a [cytosol]15k-PGE2 [cytosol]Reactome DB_ID: 701061Reactome DB_ID: 293641Reactome DB_ID: 293661Converted from EntitySet in ReactomeReactome DB_ID: 21616841dhk-PGE2,dhk-PGF2a [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntitydhk-PGE2 [cytosol]dhk-PGF2a [cytosol]ChEBI15550ChEBI63976PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 8940670UniProt:Q8N8N7 PTGR2PTGR2ZADH1PTGR2FUNCTION 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. 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.UniProtQ8N8N71EQUAL351EQUALGO0036132GO molecular functionReactome Database ID Release 742161566Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161566Reactome Database ID Release 742161692Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161692ReactomeR-HSA-21616922Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161692.217449869Pubmed2007Identification of a novel prostaglandin reductase reveals the involvement of prostaglandin E2 catabolism in regulation of peroxisome proliferator-activated receptor gamma activationChou, WLChuang, LMChou, CCWang, AHLawson, JAFitzGerald, GAChang, ZFJ Biol Chem 282:18162-7219000823Pubmed2008Structural basis for catalytic and inhibitory mechanisms of human prostaglandin reductase PTGR2Wu, Yu-HauhKo, Tzu-PingGuo, Rey-TingHu, Su-MingChuang, Lee-MingWang, Andrew H-JStructure 16:1714-235.3.99.4PTGIS, CYP8A1 isomerise PGH2 to PGI2PTGIS, CYP8A1 isomerise PGH2 to PGI2Prostacyclin synthase (CYP8A1) mediates the isomerization of prostaglandin H2 to prostaglandin I2Prostacyclin 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Edited: Jassal, Bijay, 2008-05-19Reactome DB_ID: 301381Reactome DB_ID: 315931prostaglandin I2 [ChEBI:15552]prostaglandin I2ChEBI15552PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 3222410PTGIS,CYP8B1 [endoplasmic reticulum membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPTGIS [endoplasmic reticulum membrane]UniProtQ16647GO0008116GO molecular functionReactome Database ID Release 7476495Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76495Reactome Database ID Release 7476496Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76496ReactomeR-HSA-764962Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-76496.217641676Pubmed20071-Methylnicotinamide (MNA), a primary metabolite of nicotinamide, exerts anti-thrombotic activity mediated by a cyclooxygenase-2/prostacyclin pathwayChlopicki, SSwies, JMogielnicki, ABuczko, WBartus, MLomnicka, MAdamus, JGebicki, JBr. J. Pharmacol. 152:230-915115769Pubmed2004Purification and characterization of recombinant human prostacyclin synthaseWada, MYokoyama, CHatae, TShimonishi, MNakamura, MImai, YUllrich, VTanabe, TJ Biochem 135:455-63PGI2 is hydrolysed to 6k-PGF1aPGI2 is hydrolysed to 6k-PGF1aThe 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 1135191Reactome DB_ID: 315931Reactome DB_ID: 214278616-oxoprostaglandin F1alpha [ChEBI:28158]6-oxoprostaglandin F1alphaChEBI28158Reactome Database ID Release 742161619Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161619ReactomeR-HSA-21616192Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161619.25.3.99.5TBXAS1 isomerises PGH2 to TXA2TBXAS1 isomerises PGH2 to TXA2Thromboxane synthase (CYP5A1) mediates the isomerization of prostaglandin H2 to thromboxane A2Thromboxane 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Edited: Jassal, Bijay, 2008-05-19Reactome DB_ID: 301381Reactome DB_ID: 328791thromboxane A2 [ChEBI:15627]thromboxane A2ChEBI15627PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 65976UniProt:P24557 TBXAS1TBXAS1CYP5TBXAS1CYP5A1SUBUNIT 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.UniProtP245571EQUAL533EQUALGO0004796GO molecular functionReactome Database ID Release 7476499Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76499Reactome Database ID Release 7476500Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76500ReactomeR-HSA-765001Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-76500.17925341Pubmed1994Characterization of the human gene (TBXAS1) encoding thromboxane synthaseMiyata, AYokoyama, CIhara, HBandoh, STakeda, OTakahashi, ETanabe, TEur J Biochem 224:273-911465543Pubmed2001Identification of genetic variants in the human thromboxane synthase gene (CYP5A1)Chevalier, DLo-Guidice, JMSergent, EAllorge, DDebuysère, HFerrari, NLibersa, CLhermitte, MBroly, FMutat Res 432:61-7TXA2 is hydrolysed to TXB2TXA2 is hydrolysed to TXB2Thromboxane A2 degenerates to thromboxane B2Thromboxane 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 328791Reactome DB_ID: 1135191Reactome DB_ID: 4438901thromboxane B2 [ChEBI:28728]thromboxane B2ChEBI28728Reactome Database ID Release 74443894Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=443894ReactomeR-HSA-4438942Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-443894.21059088Pubmed1975Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxidesHamberg, MSvensson, JSamuelsson, BProc Natl Acad Sci U S A 72:2994-811297515Pubmed2001Substrate binding is the rate-limiting step in thromboxane synthase catalysisWang, LHTsai, ALHsu, PYJ Biol Chem 276:14737-43TXB2 is converted to 11dh-TXB2 by TXDHTXB2 is converted to 11dh-TXB2 by TXDHThromboxane 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 4438901Reactome DB_ID: 1946531Reactome DB_ID: 1565401Reactome DB_ID: 2142828111-dehydro-thromboxane B2 [ChEBI:28667]11-dehydro-thromboxane B2ChEBI28667Reactome DB_ID: 1946971PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2161595TXDH [endoplasmic reticulum lumen]TXDH11-dehydroxythromboxane B2 dehydrogenase11-Hydroxythromboxane B2 reductaseGO0036133GO molecular functionReactome Database ID Release 742161726Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161726Reactome Database ID Release 742161732Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161732ReactomeR-HSA-21617322Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161732.23461463Pubmed198611-Dehydrothromboxane B2: a quantitative index of thromboxane A2 formation in the human circulationCatella, FHealy, DLawson, JAFitzGerald, GAProc Natl Acad Sci U S A 83:5861-58200461Pubmed199411-Hydroxythromboxane B2 dehydrogenase is identical to cytosolic aldehyde dehydrogenaseWestlund, PFylling, ACCederlund, EJörnvall, HFEBS Lett 345:99-1033823488Pubmed1986Radioimmunoassay for 11-dehydro-TXB2: a method for monitoring thromboxane production in vivoKumlin, MGranström, EProstaglandins 32:741-67PGH2 is degraded to 12S-HHT and MDA by TBXAS1PGH2 is degraded to 12S-HHT and MDA by TBXAS1Thromboxane 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 301381Reactome DB_ID: 21615621malonaldehyde [ChEBI:566274]malonaldehyde1,3-PropanedialdehydeMalonodialdehyde1,3-PropanedioneMalonic dialdehydeMDAMalonyldialdehydeMDDMalondialdehyde1,3-PropanedialMalonic aldehydeChEBI566274Reactome DB_ID: 2142797112S-HHTrE [ChEBI:63977]12S-HHTrEChEBI63977PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 659761EQUAL533EQUALGO0036134GO molecular functionReactome Database ID Release 742161594Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161594Reactome Database ID Release 742161613Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161613ReactomeR-HSA-21616132Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161613.2Reactome Database ID Release 742162123Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162123ReactomeR-HSA-21621232Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2162123.219244215Pubmed2009Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biologyBuczynski, MWDumlao, DSDennis, EAJ Lipid Res 50:1015-3820655950Pubmed2011Old and new generation lipid mediators in acute inflammation and resolutionStables, Melanie JGilroy, Derek WProg. Lipid Res. 50:35-51978-0-444-53219-0ISBN2008The eicosanoids: cyclooxygenase, lipoxygenase, and epoxygenase pathwaysSmith, William LMurphy, RCBiochemistry of Lipids, Lipoproteins and Membranes, 5th Edition (Book): 331-362GO0019371GO biological processSynthesis 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-242.7.11ALOX5 is phosphorylated by MAPKAP2ALOX5 is phosphorylated by MAPKAP2Arachidonate 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, 2009-07-14Reviewed: Rush, MG, 2012-11-10Edited: Jupe, S, 2010-05-06Reactome DB_ID: 22378801ALOX5:Ca2+:Fe2+ [cytosol]ALOX5:Ca2+:Fe2+ALOX5 (iron, calcium cofactors)Reactome DB_ID: 4290101UniProt:P09917 ALOX5ALOX5LOG5ALOX5FUNCTION Catalyzes the oxygenation of arachidonic acid to 5-hydroperoxyicosatetraenoic acid (5-HPETE) followed by the dehydration of the hydroperoxide into an epoxide, 5,6- oxidoicosatetraenoic acid (LTA4), thereby participates in the first step in leukotriene biosynthesis and in the inflammatory processes (PubMed:8631361, PubMed:21233389, PubMed:22516296, PubMed:24282679, PubMed:19022417, PubMed:23246375, PubMed:8615788, PubMed:24893149, PubMed:31664810). Also catalyzes the oxygenation of arachidonic acid into 8-hydroperoxyicosatetraenoic acid (8-HPETE) and 12-hydroperoxyicosatetraenoic acid (12-HPETE) (PubMed:23246375). Although arachidonic acid is the preferred substrate, can also metabolize oxidized fatty acids derived from arachidonic acid such as (15S)-HETE, eicosapentaenoic acid (EPA) such as (18R)- and (18S)-HEPE or docosahexaenoic (DHA) acid which leads to the formation of specialized pro-resolving mediators (SPM) lipoxin and resolvins E and D respectively, therefore plays a role in anti-inflammatory response (PubMed:21206090, PubMed:31664810, PubMed:8615788, PubMed:17114001). Also displays lipoxin synthase activity being able to convert (15S)-HETE into a conjugate tetraene (PubMed:31664810). Oxidation of docosahexaenoic acid directly inhibits endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor gamma (PPARgamma) (By similarity). Does not catalyze the oxygenation of linoleic acid and does not convert (5S)-HETE to lipoxins isomers (PubMed:31664810). In addition to inflammatory processes, participates in dendritic cell migration, wound healing through an antioxidant mechanism based on HO1 regulation expression, monocyte adhesion to the endothelium via ITGAM expression on monocytes (By similarity). Moreover, establishes 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 INS 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.UniProtP099172EQUAL674EQUALReactome DB_ID: 740162Reactome DB_ID: 710671iron(2+) [ChEBI:29033]iron(2+)FE (II) IONFe(2+)Fe(II)Ferrous ionFe2+iron ion(2+)ChEBI29033Reactome Database ID Release 742237880Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2237880ReactomeR-HSA-22378801Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2237880.1Reactome DB_ID: 1135921ATP(4-) [ChEBI:30616]ATP(4-)Adenosine 5'-triphosphateatpATPChEBI30616Reactome DB_ID: 293701ADP(3-) [ChEBI:456216]ADP(3-)ADP trianion5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADPChEBI456216Reactome DB_ID: 2652771p-S272-ALOX5:Ca2+:Fe2+ [cytosol]p-S272-ALOX5:Ca2+:Fe2+ALOX5 (iron, calcium cofactors)Reactome DB_ID: 2652761O-phospho-L-serine at 272272EQUAL2EQUAL674EQUALReactome DB_ID: 740162Reactome DB_ID: 710671Reactome Database ID Release 74265277Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265277ReactomeR-HSA-2652771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265277.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 187760UniProt:P49137 MAPKAPK2MAPKAPK2MAPKAPK2FUNCTION 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.UniProtP49137O-phospho-L-threonine at 222222EQUALO-phospho-L-threonine [MOD:00047]O-phospho-L-serine at 272272EQUALO-phospho-L-threonine at 334334EQUAL1EQUAL400EQUALGO0004674GO molecular functionReactome Database ID Release 74429015Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=429015Reactome Database ID Release 74429016Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=429016ReactomeR-HSA-4290162Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-429016.211844797Pubmed2002Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2)Werz, OSzellas, DSteinhilber, DRådmark, OJ Biol Chem 277:14793-80010779545Pubmed20005-lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinasesWerz, OKlemm, JSamuelsson, BRådmark, OProc Natl Acad Sci U S A 97:5261-61.13.11.34Arachidonic acid is oxidised to 5S-HpETE by ALOX5Arachidonic acid is oxidised to 5S-HpETE by ALOX5Oxidation of arachidonic acid to 5-HpETEArachidonate 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Edited: Jassal, B, 2008-04-21 14:30:22Reactome DB_ID: 297681Reactome DB_ID: 293681Reactome DB_ID: 26601015(S)-HPETE [ChEBI:15632]5(S)-HPETEChEBI15632PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2318764nuclear envelopeGO0005635ALOX5:ALOX5AP:LTC4S [nuclear envelope]ALOX5:ALOX5AP:LTC4SALOX5:FLAP:LTC4SReactome DB_ID: 23187691p-S272-ALOX5:Ca2+:Fe2+ [nuclear envelope]p-S272-ALOX5:Ca2+:Fe2+ALOX5 (iron, calcium cofactors)Reactome DB_ID: 23187661Reactome DB_ID: 23187672Reactome DB_ID: 23187651O-phospho-L-serine at 272272EQUAL2EQUAL674EQUALReactome Database ID Release 742318769Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318769ReactomeR-HSA-23187691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318769.1Reactome DB_ID: 23187701ALOX5AP trimer [nuclear envelope]ALOX5AP trimerFLAP trimerReactome DB_ID: 23187683UniProt:P20292 ALOX5APALOX5APFLAPALOX5APFUNCTION 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.UniProtP202921EQUAL161EQUALReactome Database ID Release 742318770Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318770ReactomeR-HSA-23187701Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318770.1Reactome DB_ID: 21427291LTC4S trimer [nuclear envelope]LTC4S trimerLTC4 synthase homotrimerReactome DB_ID: 2660253UniProt:Q16873 LTC4SLTC4SLTC4SFUNCTION 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.UniProtQ168731EQUAL150EQUALReactome Database ID Release 742142729Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142729ReactomeR-HSA-21427291Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142729.1Reactome Database ID Release 742318764Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318764ReactomeR-HSA-23187641Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318764.1GO0004051GO molecular functionReactome Database ID Release 74265275Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265275Reactome Database ID Release 74265296Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=265296ReactomeR-HSA-2652961Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-265296.13006030Pubmed1986Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activitiesRouzer, CAMatsumoto, TSamuelsson, BProc Natl Acad Sci U S A 83:857-613118366Pubmed1987Reversible, calcium-dependent membrane association of human leukocyte 5-lipoxygenaseRouzer, CASamuelsson, BProc Natl Acad Sci U S A 84:7393-73164719Pubmed1988Characterization of cloned human leukocyte 5-lipoxygenase expressed in mammalian cellsRouzer, CARands, EKargman, SJones, RERegister, RBDixon, RAJ Biol Chem 263:10135-401.13.11.345S-HpETE is dehydrated to LTA4 by ALOX55S-HpETE is dehydrated to LTA4 by ALOX5Dehydration of 5-HpETE to leukotriene A4In 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Reviewed: Hansen, Trond Vidar, 2018-02-21Edited: Jassal, B, 2008-04-21 14:30:22Reactome DB_ID: 2660101Reactome DB_ID: 293561Reactome DB_ID: 2652811leukotriene A4 [ChEBI:15651]leukotriene A4ChEBI15651PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2318764Reactome Database ID Release 74266051Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266051ReactomeR-HSA-2660512Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266051.23.3.2.6LTA4 is hydolysed to LTB4 by LTA4HLTA4 is hydolysed to LTB4 by LTA4HLTA4 is hydrolyzed to LTB4Leukotriene 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Edited: Jassal, B, 2008-04-21 14:30:22Reactome DB_ID: 293561Reactome DB_ID: 2652811Reactome DB_ID: 2660561leukotriene B4 [ChEBI:15647]leukotriene B4ChEBI15647PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 266038LTA4H:Zn2+ [cytosol]LTA4H:Zn2+LTA4 hydrolase (Zinc cofactor)Reactome DB_ID: 2660221UniProt:P09960 LTA4HLTA4HLTA4LTA4HFUNCTION Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity.ACTIVITY REGULATION Inhibited by bestatin. Subject to suicide inhibition by leukotriene A4, due to the formation of a covalent adduct at Tyr-379.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 enzymatic activity.SIMILARITY Belongs to the peptidase M1 family.UniProtP099602EQUAL611EQUALReactome DB_ID: 294261zinc(2+) [ChEBI:29105]zinc(2+)ChEBI29105Reactome Database ID Release 74266038Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266038ReactomeR-HSA-2660381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266038.1GO0004463GO molecular functionReactome Database ID Release 74266024Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266024Reactome Database ID Release 74266072Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266072ReactomeR-HSA-2660721Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266072.16490615Pubmed1984Leukotriene A4 hydrolase in human leukocytes. Purification and propertiesRådmark, OShimizu, TJörnvall, HSamuelsson, BJ Biol Chem 259:12339-452995393Pubmed1985Enzymatic hydration of leukotriene A4. Purification and characterization of a novel epoxide hydrolase from human erythrocytesMcGee, JFitzpatrick, FJ Biol Chem 260:12832-7LTB4 is oxidised to 12-oxoLTB4 by PTGR1LTB4 is oxidised to 12-oxoLTB4 by PTGR1Prostaglandin 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 2660561Reactome DB_ID: 293661Reactome DB_ID: 701061Reactome DB_ID: 293641Reactome DB_ID: 2142810112-dehydro-leukotriene B4 [ChEBI:27814]12-dehydro-leukotriene B4ChEBI27814PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142671UniProt:Q14914 PTGR1PTGR1LTB4DHPTGR1FUNCTION Functions as 15-oxo-prostaglandin 13-reductase and acts on 15-oxo-PGE1, 15-oxo-PGE2 and 15-oxo-PGE2-alpha. Has no activity towards PGE1, PGE2 and PGE2-alpha (By similarity). Catalyzes the conversion of leukotriene B4 into its biologically less active metabolite, 12-oxo-leukotriene B4. This is an initial and key step of metabolic inactivation of leukotriene B4.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.UniProtQ149141EQUAL329EQUALGO0097257GO molecular functionReactome Database ID Release 742161632Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161632Reactome Database ID Release 742161567Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161567ReactomeR-HSA-21615672Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161567.29461497Pubmed1998Purification, cDNA cloning and expression of 15-oxoprostaglandin 13-reductase from pig lungEnsor, CMZhang, HTai, HHBiochem J 330:103-88394361Pubmed1993Enzymatic inactivation of leukotriene B4 by a novel enzyme found in the porcine kidney. Purification and properties of leukotriene B4 12-hydroxydehydrogenaseYokomizo, TIzumi, TTakahashi, TKasama, TKobayashi, YSato, FTaketani, YShimizu, TJ Biol Chem 268:18128-358576264Pubmed1996cDNA cloning, expression, and mutagenesis study of leukotriene B4 12-hydroxydehydrogenaseYokomizo, TOgawa, YUozumi, NKume, KIzumi, TShimizu, TJ Biol Chem 271:2844-501.14.14.94CYP4F2, 4F3 20-hydroxylate LTB4CYP4F2, 4F3 20-hydroxylate LTB4CYP4F2 omega-hydroxylates leukotriene B4, thus inactivating itLeukotriene 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, 2008-05-19Reviewed: Rush, MG, 2012-11-10Edited: Jassal, Bijay, 2008-05-19Reactome DB_ID: 2660561Reactome DB_ID: 701061Reactome DB_ID: 293641Reactome DB_ID: 293681Reactome DB_ID: 293661Reactome DB_ID: 293561Reactome DB_ID: 2161636120-hydroxy-leukotriene B4 [ChEBI:15646]20-hydroxy-leukotriene B4ChEBI15646PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161611Cytochrome 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 PhysicalEntityCYP4F3 [endoplasmic reticulum membrane]CYP4F2 [endoplasmic reticulum membrane]UniProtQ08477UniProtP78329GO0050051GO molecular functionReactome Database ID Release 742162138Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162138Reactome Database ID Release 74211873Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211873ReactomeR-HSA-2118731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-211873.19539102Pubmed1998Human leukotriene B4 omega-hydroxylase (CYP4F3) gene: molecular cloning and chromosomal localizationKikuta, YKato, MYamashita, YMiyauchi, YTanaka, KKamada, NKusunose, MDNA Cell Biol 17:221-309799565Pubmed1998Role of human CYP4F2 in hepatic catabolism of the proinflammatory agent leukotriene B4Jin, RKoop, DRRaucy, JLLasker, JMArch Biochem Biophys 359:89-9820oh-LTB4 is oxidised to 20cho-LTB4 by CYP4F2/4F320oh-LTB4 is oxidised to 20cho-LTB4 by CYP4F2/4F3The 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 701061Reactome DB_ID: 293641Reactome DB_ID: 293681Reactome DB_ID: 21616361Reactome DB_ID: 293661Reactome DB_ID: 293562Reactome DB_ID: 2142740120-oxoleukotriene B4 [ChEBI:63979]20-oxoleukotriene B4ChEBI63979PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161611GO0097258GO molecular functionReactome Database ID Release 742161740Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161740Reactome Database ID Release 742161745Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161745ReactomeR-HSA-21617452Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161745.22836406Pubmed1988The identification and formation of 20-aldehyde leukotriene B4Soberman, RJSutyak, JPOkita, RTWendelborn, DFRoberts LJ, 2ndAusten, KFJ Biol Chem 263:7996-800220cho-LTB4 is oxidised to 20cooh-LTB4 by CYP4F2/4F320cho-LTB4 is oxidised to 20cooh-LTB4 by CYP4F2/4F3The 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 701061Reactome DB_ID: 293641Reactome DB_ID: 293681Reactome DB_ID: 21427401Reactome DB_ID: 2161582120-hydroxy-20-oxoleukotriene B4 [ChEBI:27562]20-hydroxy-20-oxoleukotriene B4ChEBI27562Reactome DB_ID: 293661Reactome DB_ID: 293561PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161611GO0097259GO molecular functionReactome Database ID Release 742161602Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161602Reactome Database ID Release 742161792Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161792ReactomeR-HSA-21617922Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161792.220cho-LTB4 is oxidised to 20cooh-LTB4 by ALDH20cho-LTB4 is oxidised to 20cooh-LTB4 by ALDHAn 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 701061Reactome DB_ID: 293641Reactome DB_ID: 293681Reactome DB_ID: 21427401Reactome DB_ID: 21615821Reactome DB_ID: 293661Reactome DB_ID: 293561PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2161598ALDH [cytosol]ALDHAldehyde dehydrogenaseReactome Database ID Release 742161683Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161683Reactome Database ID Release 742161979Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161979ReactomeR-HSA-21619792Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161979.22549038Pubmed1989Identification of an aldehyde dehydrogenase in the microsomes of human polymorphonuclear leukocytes that metabolizes 20-aldehyde leukotriene B4Sutyak, JAusten, KFSoberman, RJJ Biol Chem 264:14818-2320cooh-LTB4 is converted to 18cooh-LTB420cooh-LTB4 is converted to 18cooh-LTB4Once 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 21615821Reactome DB_ID: 2142676118-hydroxy-18-oxo-dinorleukotriene B4 [ChEBI:63980]18-hydroxy-18-oxo-dinorleukotriene B4ChEBI63980Reactome Database ID Release 742161790Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161790ReactomeR-HSA-21617902Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161790.29862787Pubmed1999Metabolic transformations of leukotriene B4 in primary cultures of human hepatocytesWheelan, PHankin, JABilir, BGuenette, DMurphy, RCJ Pharmacol Exp Ther 288:326-3412709426Pubmed2003Urinary metabolites of leukotriene B4 in the human subjectBerry, KABorgeat, PGosselin, JFlamand, LMurphy, RCJ Biol Chem 278:24449-604.4.1.20LTA4 is converted to LTC4 by LTC4SLTA4 is converted to LTC4 by LTC4SLTA4 conjugates with glutathione to form LTC4Leukotriene 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Edited: Jassal, B, 2008-04-21 14:30:22Reactome DB_ID: 294501Reactome DB_ID: 2652811Reactome DB_ID: 2660661leukotriene C4 [ChEBI:16978]leukotriene C4ChEBI16978PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2318764GO0004464GO molecular functionReactome Database ID Release 74266055Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266055Reactome Database ID Release 74266050Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266050ReactomeR-HSA-2660501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266050.18052639Pubmed1994Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4Lam, Bing KPenrose, JFFreeman, GJAusten, KFProc Natl Acad Sci U S A 91:7663-77937884Pubmed1994Molecular cloning and expression of human leukotriene-C4 synthaseWelsch, DJCreely, DPHauser, SDMathis, KJKrivi, GGIsakson, PCProc Natl Acad Sci U S A 91:9745-9LTC4 is exported from the cytosol by ABCC1LTC4 is exported from the cytosol by ABCC1ABCC1 mediates LTC4 export from the cellOn 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Edited: Jassal, B, 2008-04-21 14:30:22Reactome DB_ID: 2660661Reactome DB_ID: 2660131extracellular regionGO0005576PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 266068plasma membraneGO0005886UniProt:P33527 ABCC1ABCC1ABCC1MRP1MRPFUNCTION 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.UniProtP335271EQUAL1531EQUALGO0140359GO molecular functionReactome Database ID Release 74266058Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266058Reactome Database ID Release 74266070Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266070ReactomeR-HSA-2660701Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266070.12753893Pubmed1989The identification of a distinct export step following the biosynthesis of leukotriene C4 by human eosinophilsLam, Bing KOwen WF, JrAusten, KFSoberman, RJJ Biol Chem 264:12885-910064732Pubmed1999Characterization of a leukotriene C4 export mechanism in human platelets: possible involvement of multidrug resistance-associated protein 1Sjölinder, MikaelTornhamre, SClaesson, HEHydman, JLindgren, JJ Lipid Res 40:439-463.4.19.13GGT1, 5 dimers hydrolyse LTC4 to LTD4GGT1, 5 dimers hydrolyse LTC4 to LTD4Cleavage of the gamma-glutamyl bond of LTC4 forms LTD4The 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Edited: Jassal, B, 2008-04-21 14:30:22Reactome DB_ID: 1092761Reactome DB_ID: 2660131Reactome DB_ID: 2660741leukotriene D4 [ChEBI:28666]leukotriene D4ChEBI28666Reactome DB_ID: 2103821L-glutamate(1-) [ChEBI:29985]L-glutamate(1-)C5H8NO4WHUUTDBJXJRKMK-VKHMYHEASA-M(2S)-2-ammoniopentanedioate146.12136L-glutamatehydrogen L-glutamateInChI=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/s1L-glutamic acid, ion(1-)[NH3+][C@@H](CCC([O-])=O)C([O-])=OL-glutamic acid monoanionChEBI29985PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2162130GGT1, 5 dimers [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGO0036374GO molecular functionReactome Database ID Release 74266030Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266030Reactome Database ID Release 74266046Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266046ReactomeR-HSA-2660464Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266046.421447318Pubmed2011Gamma-glutamyl compounds: substrate specificity of gamma-glutamyl transpeptidase enzymesWickham, SWest, MBCook, PFHanigan, MHAnal Biochem 414:208-146122208Pubmed1982Interconversion of leukotrienes catalyzed by purified gamma-glutamyl transpeptidase: concomitant formation of leukotriene D4 and gamma-glutamyl amino acidsAnderson, MEAllison, RDMeister, AltonProc Natl Acad Sci U S A 79:1088-913.4.13LTD4 is converted to LTE4 by DPEP1/2LTD4 is converted to LTE4 by DPEP1/2Further cleavage of LTD4 forms LTE4Another 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, 2008-10-01Reviewed: Rush, MG, 2012-11-10Edited: Jassal, B, 2008-04-21 14:30:22Reactome DB_ID: 2660741Reactome DB_ID: 1092761Reactome DB_ID: 2660331leukotriene E4 [ChEBI:15650]leukotriene E4ChEBI15650Reactome DB_ID: 2660291glycine zwitterion [ChEBI:57305]glycine zwitterionglycineDHMQDGOQFOQNFH-UHFFFAOYSA-NC2H5NO22-azaniumylacetate[NH3+]CC([O-])=OInChI=1S/C2H5NO2/c3-1-2(4)5/h1,3H2,(H,4,5)75.06660ChEBI57305PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2162149DPEP1,2,3 dimers [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGO0016805GO molecular functionReactome Database ID Release 74266039Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266039Reactome Database ID Release 74266012Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266012ReactomeR-HSA-2660123Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-266012.32768222Pubmed1989Purification and characterization of human microsomal dipeptidaseAdachi, HidekiKubota, IOkamura, NIwata, HTsujimoto, MNakazato, HNishihara, TNoguchi, TJ Biochem 105:957-616293969Pubmed1983Conversion of leukotriene D4 to leukotriene E4 by a dipeptidase released from the specific granule of human polymorphonuclear leucocytesLee, CWLewis, RACorey, EJAusten, KFImmunology 48:27-353563417Pubmed1987Release and functional characterization of the leukotriene D4-metabolizing enzyme (dipeptidase) from human polymorphonuclear leucocytesRaulf, MKönig, WKöller, MStüning, MScand J Immunol 25:305-13LTA4 is hydrolysed to 6t-/6t,12epi-LTB4LTA4 is hydrolysed to 6t-/6t,12epi-LTB4Non-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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 293561Reactome DB_ID: 2652811Converted from EntitySet in ReactomeReactome DB_ID: 216180116t/6t,12epi-LTB4 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity6t-LTB4 [cytosol]6t,12epi-LTB4 [cytosol]ChEBI63981ChEBI63982Reactome Database ID Release 742161962Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161962ReactomeR-HSA-21619622Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161962.210741385Pubmed1999Inhibition of calcium ionophore-stimulated leukotriene generation from intact human neutrophils by captoprilMansour, MAgha, ARes Commun Mol Pathol Pharmacol 104:345-602998743Pubmed1985Metabolism of leukotrienes by adult and fetal human lungsSirois, PBrousseau, YChagnon, MGentile, JGladu, MSalari, HBorgeat, PExp Lung Res 9:17-30LTA4 is converted to EXA4 by ALOX15LTA4 is converted to EXA4 by ALOX15Analogous 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 2652811Reactome DB_ID: 21427721eoxin A4 [ChEBI:63983]eoxin A4ChEBI63983PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142744ALOX15:Fe2+ [cytosol]ALOX15:Fe2+Reactome DB_ID: 21428381UniProt:P16050 ALOX15ALOX15ALOX15LOG15FUNCTION 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:23242647, PubMed:25293588, PubMed:1944593, PubMed:17052953, PubMed:8334154, PubMed:24282679). Converts arachidonic acid into 12-hydroperoxyeicosatetraenoic acid/12-HPETE and 15-hydroperoxyeicosatetraenoic acid/15-HPETE (PubMed:1944593, PubMed:17052953, PubMed:8334154, PubMed:24282679). Also converts linoleic acid into 13-hydroperoxyoctadecadienoic acid (PubMed:8334154). Converts epoxy fatty acids to hydroperoxy-epoxides derivatives followed by an intramolecular nucleophilic substitution between hydroperoxy and epoxy moieties leading to the formation of monocyclic endoperoxides (PubMed:25293588). May also act on (12S)-hydroperoxyeicosatetraenoic acid/(12S)-HPETE to produce hepoxilin A3 (By similarity). Probably plays an important role in the immune and inflammatory responses. Through the oxygenation of membrane-bound phosphatidylethanolamine in macrophages may favor clearance of apoptotic cells during inflammation by resident macrophages and prevent an autoimmune response associated with the clearance of apoptotic cells by inflammatory monocytes. In parallel, may regulate actin polymerization which is crucial for several biological processes, including macrophage function. May also regulate macrophage function through regulation of the peroxisome proliferator activated receptor signaling pathway (By similarity). Finally, it is also involved in the cellular response to IL13/interleukin-13 (PubMed:21831839). In addition to its role in the immune and inflammatory responses, may play a role in epithelial wound healing in the cornea maybe through production of lipoxin A4. May also play a role in endoplasmic reticulum stress response and the regulation of bone mass (By similarity).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 variations 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.UniProtP160502EQUAL662EQUALReactome DB_ID: 710671Reactome Database ID Release 742142744Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142744ReactomeR-HSA-21427441Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142744.1GO0097260GO molecular functionReactome Database ID Release 742161993Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161993Reactome Database ID Release 742162019Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162019ReactomeR-HSA-21620192Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2162019.218647347Pubmed2008Hodgkin Reed-Sternberg cells express 15-lipoxygenase-1 and are putative producers of eoxins in vivo: novel insight into the inflammatory features of classical Hodgkin lymphomaClaesson, HEGriffiths, WJBrunnström, ASchain, FAndersson, EFeltenmark, SJohnson, HAPorwit, ASjöberg, JBjörkholm, MFEBS J 275:4222-3418184802Pubmed2008Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cellsFeltenmark, SGautam, NBrunnström, AGriffiths, WBackman, LEdenius, CLindbom, LBjörkholm, MClaesson, HEProc Natl Acad Sci U S A 105:680-5EXA4 is converted to EXC4 by LTC4SEXA4 is converted to EXC4 by LTC4SIn 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 21427721Reactome DB_ID: 294501Reactome DB_ID: 21427261eoxin C4 [ChEBI:63984]eoxin C4ChEBI63984PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2318764GO0097261GO molecular functionReactome Database ID Release 742161978Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161978Reactome Database ID Release 742161768Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161768ReactomeR-HSA-21617682Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161768.2EXC4 is converted to EXD4 by GGTEXC4 is converted to EXD4 by GGTIn 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 21427261Reactome DB_ID: 21427581eoxin D4 [ChEBI:63985]eoxin D4ChEBI63985Reactome DB_ID: 294041PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2161915GGT [cytosol]GGTgamma-glutamyltransferaseGO0097262GO molecular functionReactome Database ID Release 742161784Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161784Reactome Database ID Release 742161945Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161945ReactomeR-HSA-21619452Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161945.2EXD4 is converted to EXE4 by DPEPEXD4 is converted to EXE4 by DPEPIn 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 21427581Reactome DB_ID: 293561Reactome DB_ID: 21427301eoxin E4 [ChEBI:63986]eoxin E4ChEBI63986Reactome DB_ID: 294241PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2161751DPEP [cytosol]DPEPDipeptidaseGO0097263GO molecular functionReactome Database ID Release 742161981Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161981Reactome Database ID Release 742161868Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161868ReactomeR-HSA-21618682Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161868.2Reactome Database ID Release 742142691Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142691ReactomeR-HSA-21426911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142691.117623009Pubmed2007Biosynthesis and metabolism of leukotrienesMurphy, RCGijon, MABiochem J 405:379-956311078Pubmed1983LeukotrienesHammarström, SvenAnnu Rev Biochem 52:355-7719130894Pubmed2009On the biosynthesis and biological role of eoxins and 15-lipoxygenase-1 in airway inflammation and Hodgkin lymphomaClaesson, HEProstaglandins Other Lipid Mediat 89:120-5GO0006691GO biological processSynthesis of 5-eicosatetraenoic acidsSynthesis of 5-eicosatetraenoic acids5-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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-241.11.1.95S-HpETE is reduced to 5S-HETE by GPX1/2/45S-HpETE is reduced to 5S-HETE by GPX1/2/4Glutathione 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 2660101Reactome DB_ID: 294502Reactome DB_ID: 214273315(S)-HETE [ChEBI:28209]5(S)-HETEChEBI28209Reactome DB_ID: 293561Reactome DB_ID: 1117451glutathione disulfide [ChEBI:17858]glutathione disulfideChEBI17858PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161954GPX1/2/4 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGPX4(?-197) [cytosol]UniProtP36969GO0004602GO molecular functionReactome Database ID Release 742161908Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161908Reactome Database ID Release 742161946Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161946ReactomeR-HSA-21619462Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161946.210549853Pubmed1999Cellular glutathione peroxidase as a predominant scavenger of hydroperoxyeicosatetraenoic acids in rabbit alveolar macrophagesChiba, NImai, HNarashima, KArai, MOshima, GKunimoto, MNakagawa, YBiol Pharm Bull 22:1047-518428933Pubmed1993Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GIChu, FFDoroshow, JHEsworthy, RSJ Biol Chem 268:2571-611115402Pubmed2001Evidence 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 metabolismSutherland, MShankaranarayanan, PSchewe, TNigam, SBiochem J 353:91-1006816802Pubmed1982Role of glutathione peroxidase and hexose monophosphate shunt in the platelet lipoxygenase pathwayBryant, RWSimon, TCBailey, JMJ Biol Chem 257:14937-435S-HETE is oxidised to 5-oxoETE by 5-HEDH5S-HETE is oxidised to 5-oxoETE by 5-HEDHCurrent 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 293661Reactome DB_ID: 21427331Reactome DB_ID: 701061Reactome DB_ID: 293641Reactome DB_ID: 216192115-oxo-ETE [ChEBI:52449]5-oxo-ETEChEBI52449PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 21617645-HEDH [cytosol]5-HEDH5-hydroxy-eicosatetraenoic acid dehydrogenaseGO0097265GO molecular functionReactome Database ID Release 742161975Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161975Reactome Database ID Release 742161776Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161776ReactomeR-HSA-21617762Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161776.21326548Pubmed1992Metabolism of 5(S)-hydroxy-6,8,11,14-eicosatetraenoic acid and other 5(S)-hydroxyeicosanoids by a specific dehydrogenase in human polymorphonuclear leukocytesPowell, WSGravelle, FGravel, SJ Biol Chem 267:19233-413.1.1.81PON1,2,3:Ca2+ dimers hydrolyse 5-HETEL to 5-HETEPON1,2,3:Ca2+ dimers hydrolyse 5-HETEL to 5-HETESerum 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, 2016-07-27Reviewed: D'Eustachio, Peter, 2016-08-12Edited: Jassal, Bijay, 2016-07-27Reactome DB_ID: 1092761Reactome DB_ID: 89328011meadowlactone [ChEBI:132873]meadowlactoneChEBI132873Reactome DB_ID: 893280415-HETE [ChEBI:60943]5-HETE5-hydroxy,6E,8Z,11Z,14Z-eicosatetraenoic acid5-hydroxy-6-trans-8,11,14-cis-eicosatetraenoic acid(6E,8Z,11Z,14Z)-5-hydroxyeicosa-6,8,11,14-tetraenoic acidInChI=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 acid5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid(6E,8Z,11Z,14Z)-5-hydroxyicosa-6,8,11,14-tetraenoic acid5-OH 6t,8c,11c,14c-20:4C20H32O3KGIJOOYOSFUGPC-XTDASVJISA-N(6E,8Z,11Z,14Z)-5-hydroxy-6,8,11,14-eicosatetraenoic acid5-hydroxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acidCCCCC\C=C/C\C=C/C\C=C/C=C/C(O)CCCC(O)=OChEBI60943PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 8932645PON1,2,3:2xCa2+ dimers [extracellular region]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGO0102007GO molecular functionReactome Database ID Release 748932640Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8932640Reactome Database ID Release 748932633Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8932633ReactomeR-HSA-89326331Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8932633.115772423Pubmed2005Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificitiesDraganov, Dragomir ITeiber, John FSpeelman, AudreyOsawa, YoichiSunahara, RogerLa Du, Bert NJ. Lipid Res. 46:1239-4719082953Pubmed2008Paraoxonases (PON1, PON2, PON3) analyses in vitro and in vivo in relation to cardiovascular diseasesAviram, MichaelRosenblat, MiraMethods Mol. Biol. 477:259-76Reactome Database ID Release 742142688Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142688ReactomeR-HSA-21426882Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142688.2GO0019372GO biological processSynthesis of 15-eicosatetraenoic acid derivativesSynthesis of 15-eicosatetraenoic acid derivativesThe 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-241.13.11.33Arachidonic acid is oxidised to 15S-HpETE by ALOX15/15BArachidonic acid is oxidised to 15S-HpETE by ALOX15/15BArachidonate 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 297681Reactome DB_ID: 293681Reactome DB_ID: 2142718115(S)-HPETE [ChEBI:15628]15(S)-HPETEChEBI15628PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161783ALOX15/15B [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGO0050473GO molecular functionReactome Database ID Release 742161832Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161832Reactome Database ID Release 742162002Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162002ReactomeR-HSA-21620022Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2162002.211839751Pubmed2002Evidence that arachidonate 15-lipoxygenase 2 is a negative cell cycle regulator in normal prostate epithelial cellsTang, SBhatia, BMaldonado, CJYang, PNewman, RALiu, JChandra, DTraag, JKlein, RDFischer, SMChopra, DShen, JinlongZhau, HEChung, LWTang, DGJ Biol Chem 277:16189-2011662607Pubmed1991Purification of two forms of arachidonate 15-lipoxygenase from human leukocytesIzumi, TRådmark, OJörnvall, HSamuelsson, BEur J Biochem 202:1231-818570379Pubmed2008Substrate specificity changes for human reticulocyte and epithelial 15-lipoxygenases reveal allosteric product regulationWecksler, ATKenyon, VDeschamps, JDHolman, TRBiochemistry 47:7364-758334154Pubmed1993Overexpression, purification and characterization of human recombinant 15-lipoxygenaseKühn, HBarnett, JGrunberger, DBaecker, PChow, JNguyen, BBursztyn-Pettegrew, HChan, HSigal, EBiochim Biophys Acta 1169:80-917662651Pubmed2007Expression of 15-lipoxygenase type-1 in human mast cellsGulliksson, MBrunnström, AJohannesson, MBackman, LNilsson, GHarvima, IDahlén, BKumlin, MClaesson, HEBiochim Biophys Acta 1771:1156-651.11.1.915S-HpETE is reduced to 15S-HETE by GPX1/2/415S-HpETE is reduced to 15S-HETE by GPX1/2/4Glutathione 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 294502Reactome DB_ID: 21427181Reactome DB_ID: 293561Reactome DB_ID: 2142707115(S)-HETE [ChEBI:15558]15(S)-HETEChEBI15558Reactome DB_ID: 1117451PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161766GPX1/2/4 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome Database ID Release 742161937Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161937Reactome Database ID Release 742161791Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161791ReactomeR-HSA-21617912Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161791.22501828Pubmed1989Role of glutathione and glutathione peroxidase in human platelet arachidonic acid metabolismHill, TDWhite, JGRao, GHProstaglandins 38:21-321.1.1.23215S-HETE is oxidised to 15-oxoETE by 15-HEDH15S-HETE is oxidised to 15-oxoETE by 15-HEDHA 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Converted from EntitySet in ReactomeReactome DB_ID: 4282181NAD(P)+ [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNADP+ [cytosol]NAD+ [cytosol]Reactome DB_ID: 21427071Reactome DB_ID: 2142747115-oxo-ETE [ChEBI:15559]15-oxo-ETEChEBI15559Reactome DB_ID: 701061Converted from EntitySet in ReactomeReactome DB_ID: 4282061NAD(P)H [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityNADH [cytosol]NADPH [cytosol]PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 216167415-HEDH [cytosol]15-HEDH15-hydroxy-eicosatetraenoic acid dehydrogenaseGO0047034GO molecular functionReactome Database ID Release 742161741Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161741Reactome Database ID Release 742161789Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161789ReactomeR-HSA-21617892Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161789.21.13.11.33Arachidonic acid is oxidised to 15R-HETE by Acetyl-PTGS2Arachidonic acid is oxidised to 15R-HETE by Acetyl-PTGS2Aspirin 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 297681Reactome DB_ID: 701061Reactome DB_ID: 293681Reactome DB_ID: 293641Reactome DB_ID: 2142738115(R)-HETE [ChEBI:63989]15(R)-HETEChEBI63989Reactome DB_ID: 293661Reactome DB_ID: 293561PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2314687Reactome Database ID Release 742161919Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161919Reactome Database ID Release 742161951Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161951ReactomeR-HSA-21619512Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161951.27568157Pubmed1995Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactionsClària, JSerhan, Charles NProc Natl Acad Sci U S A 92:9475-9Reactome Database ID Release 742142770Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142770ReactomeR-HSA-21427701Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142770.1Synthesis of 12-eicosatetraenoic acid derivativesSynthesis of 12-eicosatetraenoic acid derivativesThe 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-241.13.11.31Arachidonic acid is oxidised to 12R-HpETE by ALOX12BArachidonic acid is oxidised to 12R-HpETE by ALOX12BThe arachidonate 12-lipoxygenase, 12R-type (ALOX12B) oxidises arachidonic acid to 12R-hydroperoxy-eicosatetraenoic acid (12R-HpETE) (Boeglin et al. 1998).Authored: Williams, MG, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 297681Reactome DB_ID: 293681Reactome DB_ID: 2142790112(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 acidChEBI34145PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142822ALOX12B:Fe2+ [cytosol]ALOX12B:Fe2+Reactome DB_ID: 21428321UniProt:O75342 ALOX12BALOX12BALOX12BFUNCTION 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.UniProtO753421EQUAL701EQUALReactome DB_ID: 710671Reactome Database ID Release 742142822Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142822ReactomeR-HSA-21428221Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142822.1GO0004052GO molecular functionReactome Database ID Release 742161752Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161752Reactome Database ID Release 742161950Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161950ReactomeR-HSA-21619502Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161950.29618483Pubmed1998A 12R-lipoxygenase in human skin: mechanistic evidence, molecular cloning, and expressionBoeglin, WEKim, RBBrash, ARProc Natl Acad Sci U S A 95:6744-91.11.1.912R-HpETE is reduced to 12R-HETE by GPX1/2/412R-HpETE is reduced to 12R-HETE by GPX1/2/4Glutathione 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 21427901Reactome DB_ID: 294502Reactome DB_ID: 293561Reactome DB_ID: 1117451Reactome DB_ID: 2142716112(R)-HETE [ChEBI:34144]12(R)-HETE12R-HETE12(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 acid12(R)-hydroxy-5(Z),8(Z),10(E),14(Z)-eicosatetraenoic acid(5Z,8Z,10E,12R,14Z)-12-hydroxy-5,8,10,14-eicosatetraenoic acid12(R)-hydroxy-5,8,14-cis-10-trans-eicosatetraenoic acidChEBI34144PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161954Reactome Database ID Release 742161959Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161959ReactomeR-HSA-21619592Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161959.2ALOXE3 isomerises 12R-HpETE to HXA3ALOXE3 isomerises 12R-HpETE to HXA3Hydroperoxide 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, 2016-10-11Reviewed: D'Eustachio, Peter, 2017-01-06Edited: Jassal, Bijay, 2016-10-11Reactome DB_ID: 21427901Reactome DB_ID: 89422091hepoxilin A3 [ChEBI:36190]hepoxilin A3ChEBI36190PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 8942204UniProt:Q9BYJ1 ALOXE3ALOXE3ALOXE3FUNCTION 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.UniProtQ9BYJ11EQUAL711EQUALGO0051120GO molecular functionReactome Database ID Release 748942207Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8942207Reactome Database ID Release 748942208Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8942208ReactomeR-HSA-89422081Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8942208.126370990Pubmed2015Homozygous 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 DysfunctionWang, TaoXu, ChenchenZhou, XipingLi, ChunjiaZhang, HongbingLian, Bill QLee, Jonathan JShen, JunLiu, YuehuaLian, Christine GuoInt J Mol Sci 16:21791-80121558561Pubmed2011Lipoxygenases mediate the effect of essential fatty acid in skin barrier formation: a proposed role in releasing omega-hydroxyceramide for construction of the corneocyte lipid envelopeZheng, YuxiangYin, HuiyongBoeglin, William EElias, Peter MCrumrine, DebraBeier, David RBrash, Alan RJ. Biol. Chem. 286:24046-5612881489Pubmed2003The lipoxygenase gene ALOXE3 implicated in skin differentiation encodes a hydroperoxide isomeraseYu, ZheyongSchneider, ClausBoeglin, William EMarnett, Lawrence JBrash, Alan RProc. Natl. Acad. Sci. U.S.A. 100:9162-715629692Pubmed2005Mutations associated with a congenital form of ichthyosis (NCIE) inactivate the epidermal lipoxygenases 12R-LOX and eLOX3Yu, ZheyongSchneider, ClausBoeglin, William EBrash, Alan RBiochim. Biophys. Acta 1686:238-471.13.11.31Arachidonic acid is oxidised to 12S-HpETE by ALOX12/15Arachidonic acid is oxidised to 12S-HpETE by ALOX12/15Arachidonate 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 297681Reactome DB_ID: 293681Reactome DB_ID: 2142811112(S)-HPETE [ChEBI:15626]12(S)-HPETEChEBI15626PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161958ALOX12/15 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome Database ID Release 742162014Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162014Reactome Database ID Release 742161964Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161964ReactomeR-HSA-21619642Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161964.22318885Pubmed1990Expression of cloned human reticulocyte 15-lipoxygenase and immunological evidence that 15-lipoxygenases of different cell types are relatedSigal, EGrunberger, DHighland, EGross, CDixon, RACraik, CSJ Biol Chem 265:5113-202377602Pubmed1990Molecular cloning, primary structure, and expression of the human platelet/erythroleukemia cell 12-lipoxygenaseFunk, CDFurci, LFitzGerald, GAProc Natl Acad Sci U S A 87:5638-422217179Pubmed1990Cloning of the cDNA for human 12-lipoxygenaseIzumi, THoshiko, SRådmark, OSamuelsson, BProc Natl Acad Sci U S A 87:7477-811.11.1.912S-HpETE is reduced to 12S-HETE by GPX1/2/412S-HpETE is reduced to 12S-HETE by GPX1/2/4Glutathione 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 21428111Reactome DB_ID: 294502Reactome DB_ID: 2142678112(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 acid12(S)-hydroxy-5,8,14(Z),10(E)-eicosatetraenoic acid12(S)-hydroxyeicosatetraenoic acid12S-HETE12(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 acidChEBI34146Reactome DB_ID: 293561Reactome DB_ID: 1117451PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161954Reactome Database ID Release 742161999Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161999ReactomeR-HSA-21619992Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161999.21.13.11.31Arachidonic acid is converted to 12-oxoETE by ALOX12Arachidonic acid is converted to 12-oxoETE by ALOX12Arachidonate 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 297681Reactome DB_ID: 2142745112-oxo-ETE [ChEBI:34151]12-oxo-ETE(5Z,8Z,10E,14Z)-12-Oxoicosa-5,8,10,14-tetraenoic acid12-ketoeicosatetraenoic acid12-OxoETE(5Z,8Z,10E,14Z)-12-Oxoeicosa-5,8,10,14-tetraenoic acid12-keto-ETE12-KETE12-oxo, 5c,8c,10t,14c-20:4(5Z,8Z,10E,14Z)-12-oxoeicosa-5,8,10,14-tetraenoic acidChEBI34151PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142793ALOX12:Fe2+ [cytosol]ALOX12:Fe2+Reactome DB_ID: 710671Reactome DB_ID: 21427681UniProt:P18054 ALOX12ALOX1212LOLOG12ALOX12FUNCTION 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:17493578, PubMed:1851637, PubMed:8319693, PubMed:8500694, PubMed:18311922). Mainly converts arachidonic acid to (12S)-hydroperoxyeicosatetraenoic acid/(12S)-HPETE but can also metabolize linoleic acid (PubMed:8250832, PubMed:17493578, PubMed:22984144, PubMed:24282679, PubMed:8319693, PubMed:8500694). In contrast does not react towards methyl esters of linoleic and arachidonic acids (By similarity). Also catalyzes the epoxidation of double bonds of polyunsaturated fatty acids such as 14S-hydroperoxy-docosahexaenoate (DHA) resulting in the formation of (13S,14S)-epoxy-DHA (PubMed:23504711). Has a dual activity since it also converts leukotriene A4/LTA4 into both the bioactive lipoxin A4/LXA4 and lipoxin B4/LXB4 (PubMed:8250832). Through the production of specific bioactive lipids like (12S)-HPETE it regulates different biological processes including platelet activation (PubMed:8319693, PubMed:8500694). It also probably positively regulates angiogenesis through regulation of the expression of the vascular endothelial growth factor (PubMed:9751607, PubMed:16638750). Plays a role in apoptotic process, promoting the survival of vascular smooth muscle cells for instance (PubMed:23578768). May also play a role in the control of cell migration and proliferation (PubMed:22237009).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.UniProtP180542EQUAL663EQUALReactome Database ID Release 742142793Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142793ReactomeR-HSA-21427931Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142793.1Reactome Database ID Release 742161926Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161926Reactome Database ID Release 742161948Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161948ReactomeR-HSA-21619482Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161948.210692117Pubmed2000Stereoselective biosynthesis of hepoxilin B3 in human epidermisAntón, RVila, LJ Invest Dermatol 114:554-9Reactome Database ID Release 742142712Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142712ReactomeR-HSA-21427122Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142712.2Synthesis 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Arachidonic acid is converted to HXA3/B3 by ALOX12Arachidonic acid is converted to HXA3/B3 by ALOX12Arachidonate 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 297681Reactome DB_ID: 293681Converted from EntitySet in ReactomeReactome DB_ID: 21620311HXA3/B3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityHXB3 [cytosol]HXA3 [cytosol]ChEBI34784PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142793Reactome Database ID Release 742161887Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161887Reactome Database ID Release 742161794Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161794ReactomeR-HSA-21617942Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161794.215123652Pubmed2004The rat leukocyte-type 12-lipoxygenase exhibits an intrinsic hepoxilin A3 synthase activityNigam, SPatabhiraman, SCiccoli, RIshdorj, GSchwarz, KPetrucev, BKühn, HHaeggström, Jesper ZJ Biol Chem 279:29023-303.3.2.7HXA3/B3 is hydrolysed to TrXA3/B3 by HXEHHXA3/B3 is hydrolysed to TrXA3/B3 by HXEHThe 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 293561Converted from EntitySet in ReactomeReactome DB_ID: 21620311Converted from EntitySet in ReactomeReactome DB_ID: 21619851TrXA3/B3 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTrXB3 [cytosol]TrXA3 [cytosol]ChEBI35032ChEBI15630PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2161957HXEH [cytosol]HXEHhepoxilin specific epoxide hydrolaseGO0047977GO molecular functionReactome Database ID Release 742161802Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161802Reactome Database ID Release 742161949Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161949ReactomeR-HSA-21619492Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161949.29540966Pubmed1998Occurrence of hepoxilins and trioxilins in psoriatic lesionsAntón, RPuig, LEsgleyes, Tde Moragas, JMVila, LJ Invest Dermatol 110:303-108829479Pubmed1995Characterization of arachidonic acid metabolites through the 12-lipoxygenase pathway in human epidermis by high-performance liquid chromatography and gas chromatography/mass spectrometryAntón, RAbián, JVila, LRapid Commun Mass SpectromS169-822722835Pubmed1989Purification of hepoxilin epoxide hydrolase from rat liverPace-Asciak, CRLee, WSJ Biol Chem 264:9310-36406490Pubmed1983Arachidonic acid epoxides. Isolation and structure of two hydroxy epoxide intermediates in the formation of 8,11,12- and 10,11,12-trihydroxyeicosatrienoic acidsPace-Asciak, CRGranström, ESamuelsson, BJ Biol Chem 258:6835-40Reactome Database ID Release 742142696Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142696ReactomeR-HSA-21426961Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142696.1GO0051121GO biological processSynthesis 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Arachidonic 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 1403561Reactome DB_ID: 1565401Reactome DB_ID: 1136011Reactome DB_ID: 1135341Reactome DB_ID: 1135641Reactome DB_ID: 1135191Converted from EntitySet in ReactomeReactome DB_ID: 2161639116/17/18-HETE [endoplasmic reticulum lumen]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity18-HETE [endoplasmic reticulum lumen]17-HETE [endoplasmic reticulum lumen]16-HETE [endoplasmic reticulum lumen]ChEBI63579ChEBI63995ChEBI63994PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2162028CYP(1) [endoplasmic reticulum membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityCYP1B1 [endoplasmic reticulum membrane]CYP1A2 [endoplasmic reticulum membrane]CYP1A1 [endoplasmic reticulum membrane]UniProtQ16678UniProtP05177UniProtP04798GO0004497GO molecular functionReactome Database ID Release 742161998Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161998Reactome Database ID Release 742161795Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161795ReactomeR-HSA-21617952Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161795.215258110Pubmed2004Metabolism of retinoids and arachidonic acid by human and mouse cytochrome P450 1b1Choudhary, DJansson, IStoilov, ISarfarazi, MSchenkman, JBDrug Metab Dispos 32:840-7Arachidonic 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 1403561Reactome DB_ID: 1565401Reactome DB_ID: 1136011Reactome DB_ID: 1135341Reactome DB_ID: 1135641Reactome DB_ID: 2142836119-HETE [ChEBI:63998]19-HETEChEBI63998Reactome DB_ID: 1135191PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161767CYP(2) [endoplasmic reticulum membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityCYP2U1 [endoplasmic reticulum membrane]CYP2C9 [endoplasmic reticulum membrane]CYP1B1 [endoplasmic reticulum membrane]CYP2C8 [endoplasmic reticulum membrane]CYP1A2 [endoplasmic reticulum membrane]CYP1A1 [endoplasmic reticulum membrane]CYP2C19 [endoplasmic reticulum membrane]CYP4A11 [endoplasmic reticulum membrane]UniProtQ7Z449UniProtP11712UniProtP10632UniProtP33261UniProtQ02928Reactome Database ID Release 742162026Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2162026Reactome Database ID Release 742161814Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161814ReactomeR-HSA-21618142Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161814.215611369Pubmed2005Functional variant of CYP4A11 20-hydroxyeicosatetraenoic acid synthase is associated with essential hypertensionGainer, JVBellamine, ADawson, EPWomble, KEGrant, SWWang, YCupples, LAGuo, CYDemissie, SO'Donnell, CJBrown, NJWaterman, MRCapdevila, JHCirculation 111:63-914660610Pubmed2004CYP2U1, a novel human thymus- and brain-specific cytochrome P450, catalyzes omega- and (omega-1)-hydroxylation of fatty acidsChuang, SSHelvig, CTaimi, MRamshaw, HACollop, AHAmad, MWhite, JAPetkovich, MJones, GKorczak, BJ Biol Chem 279:6305-149435160Pubmed1998Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomesBylund, JKunz, TValmsen, KOliw, EHJ Pharmacol Exp Ther 284:51-60Arachidonic 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 1403561Reactome DB_ID: 1565401Reactome DB_ID: 1136011Reactome DB_ID: 1135341Reactome DB_ID: 1135641Reactome DB_ID: 1135191Reactome DB_ID: 2142780120-HETE [ChEBI:34306]20-HETE20-Hydroxyicosatetraenoic acid20-Hydroxyeicosatetraenoic acid(5Z,8Z,11Z,14Z)-20-Hydroxyicosa-5,8,11,14-tetraenoic acid20-Hydroxy arachidonic acidChEBI34306PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161816CYP(3) [endoplasmic reticulum membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityCYP2U1 [endoplasmic reticulum membrane]CYP1B1 [endoplasmic reticulum membrane]CYP4F2 [endoplasmic reticulum membrane]CYP1A2 [endoplasmic reticulum membrane]CYP1A1 [endoplasmic reticulum membrane]CYP4A11 [endoplasmic reticulum membrane]Reactome Database ID Release 742161836Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161836Reactome Database ID Release 742161940Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161940ReactomeR-HSA-21619402Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161940.29618440Pubmed1998Metabolism of arachidonic acid to 20-hydroxy-5,8,11, 14-eicosatetraenoic acid by P450 enzymes in human liver: involvement of CYP4F2 and CYP4A11Powell, PKWolf, IJin, RLasker, JMJ Pharmacol Exp Ther 285:1327-3612432928Pubmed2002Prostaglandin and leukotriene omega-hydroxylasesKikuta, YKusunose, EKusunose, MProstaglandins Other Lipid Mediat 68:345-62Reactome Database ID Release 742142816Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142816ReactomeR-HSA-21428161Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142816.110681399Pubmed2000Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenaseCapdevila, JHFalck, JRHarris, RCJ Lipid Res 41:163-81GO0097267GO biological processSynthesis 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Arachidonic 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 297681Reactome DB_ID: 701061Reactome DB_ID: 293681Reactome DB_ID: 293641Reactome DB_ID: 293661Reactome DB_ID: 214273915,6-EET [ChEBI:34450]5,6-EETChEBI34450Reactome DB_ID: 293561PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161805CYP(4) [endoplasmic reticulum membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityCYP1B1 [endoplasmic reticulum membrane]CYP1A2 [endoplasmic reticulum membrane]CYP2J2 [endoplasmic reticulum membrane]CYP1A1 [endoplasmic reticulum membrane]UniProtP51589Reactome Database ID Release 742161927Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161927Reactome Database ID Release 742161890Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161890ReactomeR-HSA-21618902Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161890.28631948Pubmed1996Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heartWu, SMoomaw, CRTomer, KBFalck, JRZeldin, DCJ Biol Chem 271:3460-8Arachidonic 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 297681Reactome DB_ID: 701061Reactome DB_ID: 293681Reactome DB_ID: 293641Reactome DB_ID: 293661Reactome DB_ID: 293561Converted from EntitySet in ReactomeReactome DB_ID: 216175318,9/11,12/14,15-EET [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity11,12-EET [cytosol]8,9-EET [cytosol]14,15-EET [cytosol]ChEBI34130ChEBI34490ChEBI34157PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 2161990CYP(5) [endoplasmic reticulum membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityCYP2C9 [endoplasmic reticulum membrane]CYP1B1 [endoplasmic reticulum membrane]CYP2C8 [endoplasmic reticulum membrane]CYP1A2 [endoplasmic reticulum membrane]CYP2J2 [endoplasmic reticulum membrane]CYP1A1 [endoplasmic reticulum membrane]CYP2C19 [endoplasmic reticulum membrane]Reactome Database ID Release 742161882Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161882Reactome Database ID Release 742161899Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161899ReactomeR-HSA-21618992Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161899.27625847Pubmed1995Arachidonic 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 microsomesRifkind, ABLee, CChang, TKWaxman, DJArch Biochem Biophys 320:380-99866708Pubmed1998Analysis of cytochrome P450 metabolites of arachidonic and linoleic acids by liquid chromatography-mass spectrometry with ion trap MSBylund, JEricsson, JOliw, EHAnal Biochem 265:55-683.3.2.10EET(1) is hydrolysed to DHET(1) by EPHX2EET(1) is hydrolysed to DHET(1) by EPHX2Epoxide 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, 2012-02-24Reviewed: Rush, MG, 2012-11-10Edited: Williams, MG, 2012-02-24Reactome DB_ID: 293561Converted from EntitySet in ReactomeReactome DB_ID: 21618181EET(1) [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity5,6-EET [cytosol]11,12-EET [cytosol]8,9-EET [cytosol]14,15-EET [cytosol]Converted from EntitySet in ReactomeReactome DB_ID: 21618831DHET(1) [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity(5Z,8Z,14Z)-11,12-dihydroxyicosatrienoic acid [cytosol](5Z,11Z,14Z)-8,9-dihydroxyicosatrienoic acid [cytosol](5Z,8Z,11Z)-14,15-dihydroxyicosatrienoic acid [cytosol]5,6-DHET [cytosol]ChEBI63969ChEBI63970ChEBI63966ChEBI63974PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 2142777EPHX2 dimer [cytosol]EPHX2 dimerReactome DB_ID: 21428192UniProt:P34913 EPHX2EPHX2EPHX2FUNCTION 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.UniProtP349131EQUAL555EQUALReactome DB_ID: 299262magnesium(2+) [ChEBI:18420]magnesium(2+)ChEBI18420Reactome Database ID Release 742142777Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142777ReactomeR-HSA-21427771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142777.1GO0004301GO molecular functionReactome Database ID Release 742161846Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161846Reactome Database ID Release 742161961Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161961ReactomeR-HSA-21619612Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161961.212468260Pubmed2002Characterization and identification of cytochrome P450 metabolites of arachidonic acid released by human peritoneal macrophages obtained from the pouch of DouglasWerner, KSchaefer, WRSchweer, HDeppert, WRKarck, UZahradnik, HPProstaglandins Leukot Essent Fatty Acids 67:397-40415096040Pubmed2004Structure of human epoxide hydrolase reveals mechanistic inferences on bifunctional catalysis in epoxide and phosphate ester hydrolysisGomez, GAMorisseau, CHammock, BDChristianson, DWBiochemistry 43:4716-23Reactome Database ID Release 742142670Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142670ReactomeR-HSA-21426701Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142670.1GO0019373GO biological processReactome Database ID Release 742142753Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142753ReactomeR-HSA-21427535Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142753.5GO0019369GO biological process