BioPAX pathway converted from "Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET)" in the Reactome database. Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET) The epoxidation of arachidonic acid by cytochrome P450s (CYPs) results in the formation of unique bioactive lipid mediators termed epoxyeicosatrienoic acids (EETs). Each double bond has been shown to be susceptible to oxidation, resulting in 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. The majority of the EET biological activities are diminished by the hydrolysis to the corresponding dihydroxyeicosatrienoic acids (DHET) (Capdevila et al. 2000, Buczynski et al. 2009, Vance & Vance 2008). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Arachidonic acid is epoxidated to 5,6-EET by CYP(4) Arachidonic acid is epoxidated to 5,6-EET by CYP(4) Several cytochrome P450s (CYPs) convert arachidonic acid to 5,6-epoxyeicosatrienoic acid (5,6-EET). The CYPs and their references are as follows: CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004); CYP2J2 (Wu et al. 1996). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29364 1 cytosol GO 0005829 NADPH(4-) [ChEBI:57783] NADPH(4-) NADPH 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH tetraanion Reactome http://www.reactome.org ChEBI 57783 Reactome DB_ID: 29368 1 dioxygen [ChEBI:15379] dioxygen ChEBI 15379 Reactome DB_ID: 29768 1 arachidonate [ChEBI:32395] arachidonate (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (20:4n6) (5Z,8Z,11Z,14Z)-eicosatetraenoate ChEBI 32395 Reactome DB_ID: 70106 1 hydron [ChEBI:15378] hydron ChEBI 15378 Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 2142739 1 5,6-EET [ChEBI:34450] 5,6-EET ChEBI 34450 Reactome DB_ID: 29366 1 NADP(3-) [ChEBI:58349] NADP(3-) NADP(+) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADP trianion ChEBI 58349 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161805 endoplasmic reticulum membrane GO 0005789 CYP(4) [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP1A2 [endoplasmic reticulum membrane] CYP2J2 [endoplasmic reticulum membrane] CYP1A1 [endoplasmic reticulum membrane] CYP1B1 [endoplasmic reticulum membrane] Homo sapiens NCBI Taxonomy 9606 UniProt P05177 UniProt P51589 UniProt P04798 UniProt Q16678 GO 0004497 GO molecular function Reactome Database ID Release 82 2161927 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161927 Reactome Database ID Release 82 2161890 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161890 Reactome R-HSA-2161890 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161890.2 8631948 Pubmed 1996 Molecular cloning and expression of CYP2J2, a human cytochrome P450 arachidonic acid epoxygenase highly expressed in heart Wu, S Moomaw, CR Tomer, KB Falck, JR Zeldin, DC J Biol Chem 271:3460-8 15258110 Pubmed 2004 Metabolism of retinoids and arachidonic acid by human and mouse cytochrome P450 1b1 Choudhary, D Jansson, I Stoilov, I Sarfarazi, M Schenkman, JB Drug Metab Dispos 32:840-7 Arachidonic acid is epoxidated to 8,9/11,12/14,15-EET by CYP(5) Arachidonic acid is epoxidated to 8,9/11,12/14,15-EET by CYP(5) Several cytochrome P450s (CYPs) convert arachidonic acid to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (8,9-, 11,12-, 14,15-EETs). The CYPs and their references are as follows: CYP1A1, CYP1A2, CYP1B1 (Choudhary et al. 2004); CYP2C8, CYP2C9 (Rifkind et al. 1995); CYP2C19 (Bylund et al. 1998, Rifkind et al. 1995); CYP2J2 (Wu et al. 1996). Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29364 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 29768 1 Reactome DB_ID: 70106 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161753 1 8,9/11,12/14,15-EET [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 8,9-EET [cytosol] 11,12-EET [cytosol] 14,15-EET [cytosol] ChEBI 34490 ChEBI 34130 ChEBI 34157 Reactome DB_ID: 29356 1 Reactome DB_ID: 29366 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2161990 CYP(5) [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP1A2 [endoplasmic reticulum membrane] CYP2C8 [endoplasmic reticulum membrane] CYP2C9 [endoplasmic reticulum membrane] CYP2C19 [endoplasmic reticulum membrane] CYP2J2 [endoplasmic reticulum membrane] CYP1A1 [endoplasmic reticulum membrane] CYP1B1 [endoplasmic reticulum membrane] UniProt P10632 UniProt P11712 UniProt P33261 Reactome Database ID Release 82 2161882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161882 Reactome Database ID Release 82 2161899 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161899 Reactome R-HSA-2161899 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161899.2 9866708 Pubmed 1998 Analysis of cytochrome P450 metabolites of arachidonic and linoleic acids by liquid chromatography-mass spectrometry with ion trap MS Bylund, J Ericsson, J Oliw, EH Anal Biochem 265:55-68 7625847 Pubmed 1995 Arachidonic acid metabolism by human cytochrome P450s 2C8, 2C9, 2E1, and 1A2: regioselective oxygenation and evidence for a role for CYP2C enzymes in arachidonic acid epoxygenation in human liver microsomes Rifkind, AB Lee, C Chang, TK Waxman, DJ Arch Biochem Biophys 320:380-9 3.3.2.10 EET(1) is hydrolysed to DHET(1) by EPHX2 EET(1) is hydrolysed to DHET(1) by EPHX2 Epoxide hydrolase 2 (EPHX2) hydrolyses 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids ("EET(1)") to their corresponding dihydroxyeicosatrienoic acids ("DHET(1)") (Werner et al. 2002; Gomez et al. 2004). The majority of the EET biological activities are diminished by this hydrolysis. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Reactome DB_ID: 29356 1 Converted from EntitySet in Reactome Reactome DB_ID: 2161818 1 EET(1) [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 5,6-EET [cytosol] 8,9-EET [cytosol] 11,12-EET [cytosol] 14,15-EET [cytosol] Converted from EntitySet in Reactome Reactome DB_ID: 2161883 1 DHET(1) [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 5,6-DHET [cytosol] (5Z,11Z,14Z)-8,9-dihydroxyicosatrienoic acid [cytosol] (5Z,8Z,14Z)-11,12-dihydroxyicosatrienoic acid [cytosol] (5Z,8Z,11Z)-14,15-dihydroxyicosatrienoic acid [cytosol] ChEBI 63974 ChEBI 63970 ChEBI 63969 ChEBI 63966 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2142777 EPHX2 dimer [cytosol] EPHX2 dimer Reactome DB_ID: 2142819 2 UniProt:P34913 EPHX2 EPHX2 EPHX2 FUNCTION Bifunctional enzyme (PubMed:12574510). The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides (PubMed:12869654, PubMed:12574510, PubMed:22798687). Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides (By similarity). Also determines steady-state levels of physiological mediators (PubMed:12869654, PubMed:12574510, PubMed:22798687, PubMed:21217101).FUNCTION Bifunctional enzyme (PubMed:12574510). The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid and 12-phosphonooxy-octadec-9E-enoic acid (PubMed:12574510). Has phosphatase activity toward lyso-glycerophospholipids with also some lower activity toward lysolipids of sphingolipid and isoprenoid phosphates (PubMed:22217705, PubMed:22387545).ACTIVITY REGULATION Inhibited by 1-(1-acetylpiperidin-4-yl)-3-(4-(trifl uoromethoxy)phenyl)urea (TPAU), 1-cyclohexyl-3-dodecylurea (CDU), 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), 1-((3S, 5S, 7S)-adamantan-1-yl)-3-(5-(2-(2-ethoxyethoxy) ethoxy)pentyl)urea (AEPU), N-adamantyl-N[']-cyclohexyl urea (ACU), 4-(((1S, 4S)-4-(3-((3S, 5S, 7S)-adamantan-1-yl) ureido)cyclohexyl)oxy)benzoic acid (c-AUCB), 4-(((1R, 4R)-4-(3-((3S, 5S, 7S)-adamantan-1-yl)ureido)cyclohexyl)oxy)benzoic acid (t-AUCB), 4-(((1R, 4R)-4-(3-(4(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid (t-TAUCB) and to a lesser extent by 8-(3-((3S, 5S, 7S)-adamantan-1-yl)ureido) octanoic acid (AUOA). Phosphatase activity is inhibited by dodecyl-phosphate, phospholipids such as phospho-lysophosphatidic acids and fatty acids such as palmitic acid and lauric acid (PubMed:22217705, PubMed:22387545).SUBUNIT Homodimer.INDUCTION By compounds that cause peroxisome proliferation such as clofibrate, tiadenol and fenofibrate.DOMAIN The N-terminal domain has phosphatase activity. The C-terminal domain has epoxide hydrolase activity.PTM The N-terminus is blocked.PTM The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation (Probable).SIMILARITY Belongs to the AB hydrolase superfamily. Epoxide hydrolase family. UniProt P34913 Chain Coordinates 1 EQUAL 555 EQUAL Reactome DB_ID: 29926 2 magnesium(2+) [ChEBI:18420] magnesium(2+) ChEBI 18420 Reactome Database ID Release 82 2142777 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142777 Reactome R-HSA-2142777 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142777.1 GO 0004301 GO molecular function Reactome Database ID Release 82 2161846 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161846 Reactome Database ID Release 82 2161961 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161961 Reactome R-HSA-2161961 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2161961.2 15096040 Pubmed 2004 Structure of human epoxide hydrolase reveals mechanistic inferences on bifunctional catalysis in epoxide and phosphate ester hydrolysis Gomez, GA Morisseau, C Hammock, BD Christianson, DW Biochemistry 43:4716-23 12468260 Pubmed 2002 Characterization and identification of cytochrome P450 metabolites of arachidonic acid released by human peritoneal macrophages obtained from the pouch of Douglas Werner, K Schaefer, WR Schweer, H Deppert, WR Karck, U Zahradnik, HP Prostaglandins Leukot Essent Fatty Acids 67:397-404 Reactome Database ID Release 82 2142670 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142670 Reactome R-HSA-2142670 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142670.1 19244215 Pubmed 2009 Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology Buczynski, MW Dumlao, DS Dennis, EA J Lipid Res 50:1015-38 978-0-444-53219-0 ISBN 2008 The eicosanoids: cyclooxygenase, lipoxygenase, and epoxygenase pathways Smith, William L Murphy, RC Biochemistry of Lipids, Lipoproteins and Membranes, 5th Edition (Book): 331-362 10681399 Pubmed 2000 Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase Capdevila, JH Falck, JR Harris, RC J Lipid Res 41:163-81 GO 0019373 GO biological process