BioPAX pathway converted from "Synthesis of epoxy (EET) and dihydroxyeicosatrienoic acids (DHET)" in the Reactome database. 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 LEFT-TO-RIGHT 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 TPNH NADPH Reactome DB_ID: 29364 cytosol GENE ONTOLOGY GO:0005829 NADPH(4-) [ChEBI:57783] NADPH(4-) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH NADPH tetraanion ChEBI CHEBI:57783 Reactome Database ID Release 82 29364 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29364 Reactome R-ALL-29364 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29364.3 Reactome http://www.reactome.org COMPOUND C00005 additional information MI MI:0361 O2 Oxygen dioxygen Reactome DB_ID: 29368 dioxygen [ChEBI:15379] dioxygen ChEBI CHEBI:15379 Reactome Database ID Release 82 29368 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29368 Reactome R-ALL-29368 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29368.5 COMPOUND C00007 AA Arachidonate arachidonic acid cis-5,8,11,14-Eicosatetraenoic acid Reactome DB_ID: 29768 arachidonate [ChEBI:32395] arachidonate (20:4n6) (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate (5Z,8Z,11Z,14Z)-eicosatetraenoate ChEBI CHEBI:32395 Reactome Database ID Release 82 29768 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29768 Reactome R-ALL-29768 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29768.4 COMPOUND C00219 H+ proton hydron Reactome DB_ID: 70106 hydron [ChEBI:15378] hydron ChEBI CHEBI:15378 Reactome Database ID Release 82 70106 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70106 Reactome R-ALL-70106 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-70106.4 COMPOUND C00080 H2O water Reactome DB_ID: 29356 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 82 29356 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29356 Reactome R-ALL-29356 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29356.5 COMPOUND C00001 5,6-EET Reactome DB_ID: 2142739 5,6-EET [ChEBI:34450] 5,6-EET ChEBI CHEBI:34450 Reactome Database ID Release 82 2142739 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142739 Reactome R-ALL-2142739 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142739.2 TPN NADP+ NADP NADP(+) Nicotinamide adenine dinucleotide phosphate beta-Nicotinamide adenine dinucleotide phosphate Triphosphopyridine nucleotide NADP(3-) Reactome DB_ID: 29366 NADP(3-) [ChEBI:58349] NADP(3-) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADP(+) NADP trianion ChEBI CHEBI:58349 Reactome Database ID Release 82 29366 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29366 Reactome R-ALL-29366 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29366.4 COMPOUND C00006 ACTIVATION Converted from EntitySet in Reactome CYP(4) Reactome DB_ID: 2161805 CYP1A1 CYPIA1 Cytochrome P450 1A1 P450-P1 P450 form 6 P450-C Reactome DB_ID: 52623 endoplasmic reticulum membrane GENE ONTOLOGY GO:0005789 UniProt:P04798 CYP1A1 CYP1A1 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11555828, PubMed:14559847, PubMed:12865317, PubMed:15805301, PubMed:15041462, PubMed:18577768, PubMed:19965576, PubMed:20972997, PubMed:10681376). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11555828, PubMed:14559847, PubMed:12865317, PubMed:15805301, PubMed:15041462, PubMed:18577768, PubMed:19965576, PubMed:20972997, PubMed:10681376). Catalyzes the hydroxylation of carbon-hydrogen bonds. Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C15-alpha and C16-alpha positions (PubMed:11555828, PubMed:14559847, PubMed:12865317, PubMed:15805301). Displays different regioselectivities for polyunsaturated fatty acids (PUFA) hydroxylation (PubMed:15041462, PubMed:18577768). Catalyzes the epoxidation of double bonds of certain PUFA (PubMed:15041462, PubMed:19965576, PubMed:20972997). Converts arachidonic acid toward epoxyeicosatrienoic acid (EET) regioisomers, 8,9-, 11,12-, and 14,15-EET, that function as lipid mediators in the vascular system (PubMed:20972997). Displays an absolute stereoselectivity in the epoxidation of eicosapentaenoic acid (EPA) producing the 17(R),18(S) enantiomer (PubMed:15041462). May play an important role in all-trans retinoic acid biosynthesis in extrahepatic tissues. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195).PATHWAY Steroid hormone biosynthesis.PATHWAY Lipid metabolism; fatty acid metabolism.PATHWAY Cofactor metabolism; retinol metabolism.SUBUNIT Interacts with cytosolic chaperones HSP70 and HSP90; this interaction is required for initial targeting to mitochondria. Interacts (via mitochondrial targeting signal) with TOMM40 (via N-terminus); this interaction is required for translocation across the mitochondrial outer membrane.TISSUE SPECIFICITY Lung, lymphocytes and placenta.INDUCTION By 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).SIMILARITY Belongs to the cytochrome P450 family. Homo sapiens NCBI Taxonomy 9606 UniProt P04798 1 EQUAL 512 EQUAL Reactome Database ID Release 82 52623 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=52623 Reactome R-HSA-52623 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-52623.1 CYP1A2 CYPIA2 Cytochrome P450 1A2 P450-P3 P(3)450 P450 4 Reactome DB_ID: 52625 UniProt:P05177 CYP1A2 CYP1A2 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:9435160, PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:9435160, PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable).PATHWAY Cofactor metabolism; retinol metabolism.PATHWAY Steroid metabolism; cholesterol metabolism.PATHWAY Lipid metabolism; arachidonate metabolism.SUBUNIT Interacts with PGRMC1; the interaction requires PGRMC1 homodimerization.TISSUE SPECIFICITY Liver.INDUCTION By nicotine, omeprazole, phenobarbital, primidone and rifampicin.POLYMORPHISM The CYP1A2*1F allele which is quite common (40 to 50%) is due to a substitution of a base in the non-coding region of the CYP1A2 gene and has the effect of decreasing the enzyme inducibility. Individuals who are homozygous for the CYP1A2*1F allele are 'slow' caffeine metabolizers. Thus for these individual increased intake of caffeine seems to be associated with a concomitant increase in the risk of non-fatal myocardial infraction (MI).SIMILARITY Belongs to the cytochrome P450 family. UniProt P05177 2 EQUAL 515 EQUAL Reactome Database ID Release 82 52625 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=52625 Reactome R-HSA-52625 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-52625.1 CYP1B1 Cytochrome P450 1B1 CP1B_HUMAN Reactome DB_ID: 211021 UniProt:Q16678 CYP1B1 CYP1B1 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:20972997, PubMed:11555828, PubMed:12865317, PubMed:10681376, PubMed:15258110). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:20972997, PubMed:11555828, PubMed:12865317, PubMed:10681376, PubMed:15258110). Exhibits catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2- and 4-hydroxy E1 and E2. Displays a predominant hydroxylase activity toward E2 at the C-4 position (PubMed:11555828, PubMed:12865317). Metabolizes testosterone and progesterone to B or D ring hydroxylated metabolites (PubMed:10426814). May act as a major enzyme for all-trans retinoic acid biosynthesis in extrahepatic tissues. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376, PubMed:15258110). Catalyzes the epoxidation of double bonds of certain PUFA. Converts arachidonic acid toward epoxyeicosatrienoic acid (EpETrE) regioisomers, 8,9-, 11,12-, and 14,15- EpETrE, that function as lipid mediators in the vascular system (PubMed:20972997). Additionally, displays dehydratase activity toward oxygenated eicosanoids hydroperoxyeicosatetraenoates (HpETEs). This activity is independent of cytochrome P450 reductase, NADPH, and O2 (PubMed:21068195). Also involved in the oxidative metabolism of xenobiotics, particularly converting polycyclic aromatic hydrocarbons and heterocyclic aryl amines procarcinogens to DNA-damaging products (PubMed:10426814). Plays an important role in retinal vascular development. Under hyperoxic O2 conditions, promotes retinal angiogenesis and capillary morphogenesis, likely by metabolizing the oxygenated products generated during the oxidative stress. Also, contributes to oxidative homeostasis and ultrastructural organization and function of trabecular meshwork tissue through modulation of POSTN expression (By similarity).ACTIVITY REGULATION Enzyme activity is increased by liposomes containing anionic phospholipids, phosphatidic acid and cardiolipin. Inhibited by naringenin with an IC(50) of 5 uM (PubMed:22888116, PubMed:22935222). Enzyme activity is increased by cytochrome b5.PATHWAY Steroid hormone biosynthesis.PATHWAY Cofactor metabolism; retinol metabolism.PATHWAY Lipid metabolism; arachidonate metabolism.TISSUE SPECIFICITY Expressed in heart, brain, lung, skeletal muscle, kidney, spleen, thymus, prostate, testis, ovary, small intestine, colon, and peripheral blood leukocytes (PubMed:8175734). Expressed in retinal endothelial cells and umbilical vein endothelial cells (at protein level) (PubMed:19005183).INDUCTION By polycyclic aromatic hydrocarbons (PAH) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).POLYMORPHISM Various CYP1B1 alleles are known. The sequence shown is that of allele CYP1B1*1.SIMILARITY Belongs to the cytochrome P450 family. UniProt Q16678 1 EQUAL 543 EQUAL Reactome Database ID Release 82 211021 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211021 Reactome R-HSA-211021 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-211021.1 CYP2J2 Cytochrome P450 2J2 CPJ2_HUMAN Reactome DB_ID: 211022 UniProt:P51589 CYP2J2 CYP2J2 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) in the cardiovascular system (PubMed:8631948, PubMed:19965576). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:8631948, PubMed:19965576). Catalyzes the epoxidation of double bonds of PUFA (PubMed:8631948, PubMed:19965576). Converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EpETrE), likely playing a major role in the epoxidation of endogenous cardiac arachidonic acid pools (PubMed:8631948). In endothelial cells, participates in eicosanoids metabolism by converting hydroperoxide species into hydroxy epoxy metabolites. In combination with 15-lipoxygenase metabolizes arachidonic acid and converts hydroperoxyicosatetraenoates (HpETEs) into hydroxy epoxy eicosatrienoates (HEETs), which are precursors of vasodilatory trihydroxyicosatrienoic acids (THETAs). This hydroperoxide isomerase activity is NADPH- and O2-independent (PubMed:19737933). Catalyzes the monooxygenation of a various xenobiotics, such as danazol, amiodarone, terfenadine, astemizole, thioridazine, tamoxifen, cyclosporin A and nabumetone (PubMed:19923256). Catalyzes hydroxylation of the anthelmintics albendazole and fenbendazole (PubMed:23959307). Catalyzes the sulfoxidation of fenbedazole (PubMed:19923256).PATHWAY Lipid metabolism; arachidonate metabolism.TISSUE SPECIFICITY Highly expressed in heart, present at lower levels in liver, kidney and skeletal muscle (at protein level).SIMILARITY Belongs to the cytochrome P450 family. UniProt P51589 1 EQUAL 502 EQUAL Reactome Database ID Release 82 211022 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211022 Reactome R-HSA-211022 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-211022.1 Reactome Database ID Release 82 2161805 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161805 Reactome R-HSA-2161805 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-2161805.1 GENE ONTOLOGY GO:0004497 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity 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 LEFT-TO-RIGHT 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 Converted from EntitySet in Reactome 8,9/11,12/14,15-EET Reactome DB_ID: 2161753 8,9-EET Reactome DB_ID: 2142662 8,9-EET [ChEBI:34490] 8,9-EET ChEBI CHEBI:34490 Reactome Database ID Release 82 2142662 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142662 Reactome R-ALL-2142662 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142662.2 11,12-EET Reactome DB_ID: 2142835 11,12-EET [ChEBI:34130] 11,12-EET ChEBI CHEBI:34130 Reactome Database ID Release 82 2142835 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142835 Reactome R-ALL-2142835 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142835.2 14,15-EET Reactome DB_ID: 2142792 14,15-EET [ChEBI:34157] 14,15-EET 14(15)-EpETrE-EA 14,15-epoxy-5Z,8Z,11Z-icosatrienoic acid all-cis-14,15-epoxyeicosa-5,8,11-trienoic acid (5Z,8Z,11Z)-14,15-Epoxyicosa-5.8.11-trienoic acid (+/-)14,15-EpETrE (5Z,8Z,11Z)-14,15-Epoxyeicosa-5.8.11-trienoic acid 14,15-epoxy-5Z,8Z,11Z-eicosatrienoic acid ChEBI CHEBI:34157 Reactome Database ID Release 82 2142792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142792 Reactome R-ALL-2142792 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142792.2 Reactome Database ID Release 82 2161753 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161753 Reactome R-ALL-2161753 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2161753.1 ACTIVATION Converted from EntitySet in Reactome CYP(5) Reactome DB_ID: 2161990 CYP2C8 Cytochrome P450 2C8 CPC8_HUMAN Reactome DB_ID: 211009 UniProt:P10632 CYP2C8 CYP2C8 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:7574697, PubMed:15766564, PubMed:19965576). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316).PATHWAY Steroid metabolism.PATHWAY Lipid metabolism; arachidonate metabolism.PATHWAY Cofactor metabolism; retinol metabolism.INDUCTION By phenobarbital.POLYMORPHISM Several alleles are found in the human population, contributing to interindividual variations in the therapeutic efficacy and toxicity of a myriad of drugs such as paclitaxel or amodiaquine. The allele shown here is CYP2C8*1 (PubMed:26427316). CYP2C8 genetic variations are associated with altered drug metabolism and adverse drug effects including acute rhabdomyolysis after cerivastatin use [MIM:618018].SIMILARITY Belongs to the cytochrome P450 family.CAUTION Alternative splicing has been shown to occur but the shorter forms are believed to be non-functional. UniProt P10632 1 EQUAL 490 EQUAL Reactome Database ID Release 82 211009 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211009 Reactome R-HSA-211009 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-211009.1 CYP2C9 Cytochrome P450 2C9 CPC9_HUMAN Reactome DB_ID: 211017 UniProt:P11712 CYP2C9 CYP2C9 CYP2C10 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:7574697, PubMed:9866708, PubMed:9435160, PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:7574697, PubMed:9866708, PubMed:9435160, PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:7574697, PubMed:15766564, PubMed:19965576, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9866708, PubMed:9435160). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031).PATHWAY Lipid metabolism; arachidonate metabolism.PATHWAY Steroid metabolism; cholesterol metabolism.PATHWAY Terpene metabolism; (4R)-limonene degradation.INDUCTION By rifampicin.SIMILARITY Belongs to the cytochrome P450 family. UniProt P11712 1 EQUAL 490 EQUAL Reactome Database ID Release 82 211017 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211017 Reactome R-HSA-211017 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-211017.1 CYP2C19 Cytochrome P450 2C19 CPCJ_HUMAN Reactome DB_ID: 211055 UniProt:P33261 CYP2C19 CYP2C19 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:20972997, PubMed:19965576). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307).PATHWAY Lipid metabolism; fatty acid metabolism.PATHWAY Terpene metabolism; (4R)-limonene degradation.INDUCTION P450 can be induced to high levels in liver and other tissues by various foreign compounds, including drugs, pesticides, and carcinogens.POLYMORPHISM Genetic variation in CYP2C19 is responsible for poor drug metabolism [MIM:609535]. Individuals can be characterized as either extensive metabolizers (EM) or poor metabolizers (PM). The PM phenotype is inherited in an autosomal recessive manner, with the EM phenotype comprising both homozygous dominant and heterozygote genotypes. There are marked interracial differences in the frequency of this polymorphism. Poor metabolizers represent 2-5% of Caucasians, 13-23% of Asian populations, and as many as 38-79% of individuals of some of the islands of Polynesia and Micronesia. At least 38 different alleles are known including CYP2C19*1A, CYP2C19*1B, CYP2C19*1C, CYP2C19*2A (CYP2C19m1 or CYP2C19m1A), CYP2C19*2B (CYP2C19m1B), CYP2C19*2C (CYP2C19*21), CYP2C19*3A (CYP2C19m2), CYP2C19*3B (CYP2C19*20), CYP2C19*4 (CYP2C19m3), CYP2C19*5A (CYP2C19m4), CYP2C19*5B, CYP2C19*6, CYP2C19*7, CYP2C19*8, CYP2C19*9, CYP2C19*10, CYP2C19*11 CYP2C19*12, CYP2C19*13, CYP2C19*14 CYP2C19*15, CYP2C19*16, CYP2C19*18 and CYP2C19*19. Defective CYP2C19*2 and CYP2C19*3 alleles are characterized by a splice mutation and a stop codon, respectively, and account for most of the PM alleles. The sequence shown is that of allele CYP2C19*1A.SIMILARITY Belongs to the cytochrome P450 family.CAUTION P450-254C was originally listed as a separate gene (CYP2C17). Resequencing demonstrated that it is not a separate gene, but a chimera. The 5'-portion corresponds to a partial 2C18 clone, and the 3'-portion corresponds to a partial 2C19 clone. UniProt P33261 1 EQUAL 490 EQUAL Reactome Database ID Release 82 211055 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211055 Reactome R-HSA-211055 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-211055.1 Reactome Database ID Release 82 2161990 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161990 Reactome R-HSA-2161990 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-2161990.1 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 LEFT-TO-RIGHT 3.3.2.10 EET(1) is hydrolysed to DHET(1) by EPHX2 Epoxide hydrolase 2 (EPHX2) hydrolyses 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids ("EET(1)") to their corresponding dihydroxyeicosatrienoic acids ("DHET(1)") (Werner et al. 2002; Gomez et al. 2004). The majority of the EET biological activities are diminished by this hydrolysis. Authored: Williams, MG, 2012-02-24 Reviewed: Rush, MG, 2012-11-10 Edited: Williams, MG, 2012-02-24 Converted from EntitySet in Reactome EET(1) Reactome DB_ID: 2161818 Reactome Database ID Release 82 2161818 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161818 Reactome R-ALL-2161818 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2161818.1 Converted from EntitySet in Reactome DHET(1) Reactome DB_ID: 2161883 5,6-DHET Reactome DB_ID: 2142682 5,6-DHET [ChEBI:63974] 5,6-DHET ChEBI CHEBI:63974 Reactome Database ID Release 82 2142682 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142682 Reactome R-ALL-2142682 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142682.2 8,9-DHET (5Z,11Z,14Z)-8,9-dihydroxyicosatrienoic acid Reactome DB_ID: 2142765 (5Z,11Z,14Z)-8,9-dihydroxyicosatrienoic acid [ChEBI:63970] (5Z,11Z,14Z)-8,9-dihydroxyicosatrienoic acid ChEBI CHEBI:63970 Reactome Database ID Release 82 2142765 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142765 Reactome R-ALL-2142765 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142765.3 11,12-DHET (5Z,8Z,14Z)-11,12-dihydroxyicosatrienoic acid Reactome DB_ID: 2142779 (5Z,8Z,14Z)-11,12-dihydroxyicosatrienoic acid [ChEBI:63969] (5Z,8Z,14Z)-11,12-dihydroxyicosatrienoic acid ChEBI CHEBI:63969 Reactome Database ID Release 82 2142779 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142779 Reactome R-ALL-2142779 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142779.3 14,15-DHET (5Z,8Z,11Z)-14,15-dihydroxyicosatrienoic acid Reactome DB_ID: 2142783 (5Z,8Z,11Z)-14,15-dihydroxyicosatrienoic acid [ChEBI:63966] (5Z,8Z,11Z)-14,15-dihydroxyicosatrienoic acid ChEBI CHEBI:63966 Reactome Database ID Release 82 2142783 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142783 Reactome R-ALL-2142783 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2142783.3 Reactome Database ID Release 82 2161883 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2161883 Reactome R-ALL-2161883 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2161883.1 ACTIVATION EPHX2 dimer Reactome DB_ID: 2142777 EPHX2 Epoxide hydrolase 2 HYES_HUMAN Reactome DB_ID: 2142819 UniProt:P34913 EPHX2 EPHX2 FUNCTION Bifunctional enzyme (PubMed:12574510). The C-terminal domain has epoxide hydrolase activity and acts on epoxides (alkene oxides, oxiranes) and arene oxides (PubMed:12869654, PubMed:12574510, PubMed:22798687). Plays a role in xenobiotic metabolism by degrading potentially toxic epoxides (By similarity). Also determines steady-state levels of physiological mediators (PubMed:12869654, PubMed:12574510, PubMed:22798687, PubMed:21217101).FUNCTION Bifunctional enzyme (PubMed:12574510). The N-terminal domain has lipid phosphatase activity, with the highest activity towards threo-9,10-phosphonooxy-hydroxy-octadecanoic acid, followed by erythro-9,10-phosphonooxy-hydroxy-octadecanoic acid, 12-phosphonooxy-octadec-9Z-enoic acid and 12-phosphonooxy-octadec-9E-enoic acid (PubMed:12574510). Has phosphatase activity toward lyso-glycerophospholipids with also some lower activity toward lysolipids of sphingolipid and isoprenoid phosphates (PubMed:22217705, PubMed:22387545).ACTIVITY REGULATION Inhibited by 1-(1-acetylpiperidin-4-yl)-3-(4-(trifl uoromethoxy)phenyl)urea (TPAU), 1-cyclohexyl-3-dodecylurea (CDU), 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), 1-((3S, 5S, 7S)-adamantan-1-yl)-3-(5-(2-(2-ethoxyethoxy) ethoxy)pentyl)urea (AEPU), N-adamantyl-N[']-cyclohexyl urea (ACU), 4-(((1S, 4S)-4-(3-((3S, 5S, 7S)-adamantan-1-yl) ureido)cyclohexyl)oxy)benzoic acid (c-AUCB), 4-(((1R, 4R)-4-(3-((3S, 5S, 7S)-adamantan-1-yl)ureido)cyclohexyl)oxy)benzoic acid (t-AUCB), 4-(((1R, 4R)-4-(3-(4(trifluoromethoxy)phenyl)ureido)cyclohexyl)oxy)benzoic acid (t-TAUCB) and to a lesser extent by 8-(3-((3S, 5S, 7S)-adamantan-1-yl)ureido) octanoic acid (AUOA). Phosphatase activity is inhibited by dodecyl-phosphate, phospholipids such as phospho-lysophosphatidic acids and fatty acids such as palmitic acid and lauric acid (PubMed:22217705, PubMed:22387545).SUBUNIT Homodimer.INDUCTION By compounds that cause peroxisome proliferation such as clofibrate, tiadenol and fenofibrate.DOMAIN The N-terminal domain has phosphatase activity. The C-terminal domain has epoxide hydrolase activity.PTM The N-terminus is blocked.PTM The covalent modification of cysteine by 15-deoxy-Delta12,14-prostaglandin-J2 is autocatalytic and reversible. It may occur as an alternative to other cysteine modifications, such as S-nitrosylation and S-palmitoylation (Probable).SIMILARITY Belongs to the AB hydrolase superfamily. Epoxide hydrolase family. UniProt P34913 1 EQUAL 555 EQUAL Reactome Database ID Release 82 2142819 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142819 Reactome R-HSA-2142819 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-2142819.1 2 Mg2+ Magnesium magnesium(2+) Mg++ Reactome DB_ID: 29926 magnesium(2+) [ChEBI:18420] magnesium(2+) ChEBI CHEBI:18420 Reactome Database ID Release 82 29926 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29926 Reactome R-ALL-29926 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29926.5 COMPOUND C00305 2 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 GENE ONTOLOGY GO:0004301 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 GENE ONTOLOGY GO:0019373 gene ontology term for cellular process MI MI:0359