BioPAX pathway converted from "Arachidonic acid is epoxidated to 5,6-EET by CYP(4)" in the Reactome database. 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 H+ proton hydron Reactome DB_ID: 70106 cytosol GENE ONTOLOGY GO:0005829 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 Reactome http://www.reactome.org COMPOUND C00080 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 TPNH NADPH Reactome DB_ID: 29364 NADPH(4-) [ChEBI:57783] NADPH(4-) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH NADPH tetraanion ChEBI CHEBI:57783 Reactome Database ID Release 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 COMPOUND C00005 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 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