BioPAX pathway converted from "Aflatoxin activation and detoxification" in the Reactome database. Aflatoxin activation and detoxification Aflatoxins are among the principal mycotoxins produced as secondary metabolites by the molds Aspergillus flavus and Aspergillus parasiticus that contaminate economically important food and feed crops (Wild & Turner 2002). Aflatoxin B1 (AFB1) is the most potent naturally occurring carcinogen known and is also an immunosuppressant. It is a potent hepatocarcinogenic agent in many species, and has been implicated in the etiology of human hepatocellular carcinoma. Poultry, especially turkeys, are extremely sensitive to the toxic and carcinogenic action of AFB1 present in animal feed, resulting in multi-million dollar losses to the industry. Discerning the biochemical and molecular mechanisms of this extreme sensitivity of poultry to AFB1 will help with the development of new strategies to increase aflatoxin resistance (Rawal et al. 2010, Diaz & Murcia 2011).<br><br><br>AFB1 has one major genotoxic metabolic fate, conversion to AFXBO, and several others that are less mutagenic but that can still be quite toxic. AFB1 can be oxidised to the toxic AFB1 exo 8,9 epoxide (AFXBO) product by several cytochrome P450 enzymes, especially P450 3A4 in the liver. This 8,9 epoxide can react with the N7 atom of a guanyl base of DNA to produce adducts by intercalating between DNA base pairs. The exo epoxide is unstable in solution, however, and can react spontaneously to form a diol that is no longer reactive with DNA. The diol product in turn undergoes base-catalysed rearrangement to a dialdehyde that can react with protein lysine residues. AFB1 can also be metabolised to products (AFQ1, AFM1, AFM1E) which have far less genotoxic consequences than AFB1. The main route of detoxification of AFB1 is conjugation of its reactive 8,9-epoxide form with glutathione (GSH). This reaction is carried out by trimeric glutathione transferases (GSTs), providing a chemoprotective mechanism against toxicity. Glutathione conjugates are usually excreted as mercapturic acids in urine (Guengerich et al. 1998, Hamid et al. 2013). The main metabolic routes of aflatoxin in humans are described here. Authored: Jassal, Bijay, 2014-05-09 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-09 LEFT-TO-RIGHT CYP3A4,5 hydroxylates AFB1 to AFQ1 Metabolites that are formed from aflatoxin B1 (AFB1) include AFQ1, AFM1 and AFP1 (Gallagher et al. 1996). These metabolites and other naturally occurring aflatoxins (G1, B2 and G2) are poorer substrates for epoxidation and, consequently, are less mutagenic, carcinogenic and toxic than AFB1. AFB1 metabolites can be useful biomarkers of human exposure to aflatoxins and AFM1, AFQ1 and AFP1 have all been detected in human urine samples (Groopman et al. 1985). Cytochrome P450 3A4 and 3A5 are the predominant enzymes involved in AFQ1 (3-hydroxy aflatoxin) production (Raney et al. 1992). Authored: Jassal, Bijay, 2014-05-09 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-09 AFB1 aflatoxin B1 Reactome DB_ID: 5423605 cytosol GENE ONTOLOGY GO:0005829 aflatoxin B1 [ChEBI:2504] aflatoxin B1 ChEBI CHEBI:2504 Reactome Database ID Release 78 5423605 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=5423605 Reactome R-ALL-5423605 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-5423605.3 Reactome http://www.reactome.org COMPOUND C06800 additional information MI MI:0361 H+ proton hydron Reactome DB_ID: 70106 hydron [ChEBI:15378] hydron ChEBI CHEBI:15378 Reactome Database ID Release 78 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 O2 Oxygen dioxygen Reactome DB_ID: 29368 dioxygen [ChEBI:15379] dioxygen ChEBI CHEBI:15379 Reactome Database ID Release 78 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 78 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 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 78 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 H2O water Reactome DB_ID: 29356 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 78 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 AFQ1 aflatoxin Q1 Reactome DB_ID: 5423660 aflatoxin Q1 [ChEBI:78582] aflatoxin Q1 ChEBI CHEBI:78582 Reactome Database ID Release 78 5423660 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=5423660 Reactome R-ALL-5423660 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-5423660.3 COMPOUND C06800 ACTIVATION Converted from EntitySet in Reactome CYP3A4,5 Reactome DB_ID: 5423680 NF-25 CYP3A4 Cytochrome P450 3A4 Quinine 3-monooxygenase CYPIIIA4 Nifedipine oxidase P450-PCN1 Reactome DB_ID: 52639 endoplasmic reticulum membrane GENE ONTOLOGY GO:0005789 UniProt:P08684 CYP3A4 CYP3A4 CYP3A3 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:20702771, PubMed:19965576, PubMed:21490593, 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). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:2732228, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:21576599, PubMed:21490593). 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 C-16 position (PubMed:11555828, PubMed:14559847, PubMed:12865317). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:2732228, PubMed:15373842, PubMed:15764715, PubMed:22773874). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:2732228, PubMed:15373842, PubMed:15764715). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981).ACTIVITY REGULATION Activated by cytochrome b5.PATHWAY Steroid hormone biosynthesis.PATHWAY Cofactor metabolism; retinol metabolism.PATHWAY Steroid metabolism; cholesterol metabolism.PATHWAY Lipid metabolism; fatty acid metabolism.SUBUNIT Interacts with PGRMC1; the interaction requires PGRMC1 homodimerization.TISSUE SPECIFICITY Expressed in prostate and liver. According to some authors, it is not expressed in brain (PubMed:19094056). According to others, weak levels of expression are measured in some brain locations (PubMed:19359404 and PubMed:18545703). Also expressed in epithelium of the small intestine and large intestine, bile duct, nasal mucosa, kidney, adrenal cortex, epithelium of the gastric mucosa with intestinal metaplasia, gallbladder, intercalated ducts of the pancreas, chief cells of the parathyroid and the corpus luteum of the ovary (at protein level).INDUCTION By drugs, such as rifampicin.PTM Polyubiquitinated in the presence of AMFR and UBE2G1 and also STUB1/CHIP and UBE2D1 (in vitro).MISCELLANEOUS Chimeric transcripts, characterized by CYP3A43 exon 1 joined at canonical splice sites to distinct sets of CYP3A4 exons, have been detected. All are possibly produced by trans-splicing. The chimeric transcripts exist in 3 different combinations: CYP3A43 exon 1 joined in frame to CYP3A4 exons 2-13, CYP3A43 exon 1 joined in frame to CYP3A4 exons 4-13 and CYP3A43 exon 1 joined in frame to CYP3A4 exon 7-13. The longest chimeric isoform (CYP3A43 exon 1 joined to CYP3A4 exons 2-13) exhibits 6-beta-hydroxylase activity, while a shorter isoform (CYP3A43 exon 1 joined to CYP3A4 exons 4-13) does not. All chimeric transcripts are expressed at very low levels in the liver (PubMed:11726664).SIMILARITY Belongs to the cytochrome P450 family. Homo sapiens NCBI Taxonomy 9606 UniProt P08684 2 EQUAL 503 EQUAL Reactome Database ID Release 78 52639 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=52639 Reactome R-HSA-52639 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-52639.1 CYP3A5 Cytochrome P450 3A5 CP35_HUMAN Reactome DB_ID: 211020 UniProt:P20815 CYP3A5 CYP3A5 FUNCTION A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:2732228, PubMed:10681376, PubMed:11093772, PubMed:12865317). 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). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:2732228, PubMed:10681376, PubMed:11093772). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228).PATHWAY Steroid hormone biosynthesis.PATHWAY Cofactor metabolism; retinol metabolism.INDUCTION By glucocorticoids, such as dexamethesone.MISCELLANEOUS Chimeric transcripts, characterized by CYP3A43 exon 1 joined at canonical splice sites to distinct sets of CYP3A5 exons, have been detected. All are possibly produced by trans-splicing. The chimeric transcripts exist in 2 different combinations: CYP3A43 exon 1 joined in frame to CYP3A5 exon 11-13 and CYP3A43 exon 1 joined in frame to CYP3A5 exon 12-13. All chimeric transcripts are expressed at very low levels in the liver (PubMed:11726664).SIMILARITY Belongs to the cytochrome P450 family. UniProt P20815 1 EQUAL 502 EQUAL Reactome Database ID Release 78 211020 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=211020 Reactome R-HSA-211020 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-211020.1 Reactome Database ID Release 78 5423680 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=5423680 Reactome R-HSA-5423680 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-5423680.1 GENE ONTOLOGY GO:0004497 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 78 5423671 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=5423671 Reactome Database ID Release 78 5423664 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=5423664 Reactome R-HSA-5423664 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-5423664.1 3931076 Pubmed 1985 Aflatoxin metabolism in humans: detection of metabolites and nucleic acid adducts in urine by affinity chromatography Groopman, J D Donahue, P R Zhu, J Q Chen, J S Wogan, G N Proc. Natl. Acad. Sci. U.S.A. 82:6492-6 1643250 Pubmed 1992 Oxidation of aflatoxins and sterigmatocystin by human liver microsomes: significance of aflatoxin Q1 as a detoxication product of aflatoxin B1 Raney, K D Shimada, T Kim, D H Groopman, J D Harris, T M Guengerich, F P Chem. Res. Toxicol. 5:202-10 8975785 Pubmed 1996 The kinetics of aflatoxin B1 oxidation by human cDNA-expressed and human liver microsomal cytochromes P450 1A2 and 3A4 Gallagher, E P Kunze, K L Stapleton, P L Eaton, D L Toxicol. Appl. Pharmacol. 141:595-606 LEFT-TO-RIGHT CYP1A2 hydroxylates AFB1 to AFM1 Aflatoxin B1 (AFB1) undergoes extensive oxidation, which is catalysed by cytochrome P450s. In addition to formation of the 8,9-oxide, oxidation by CYP1A2 yields a stable metabolite, aflatoxin M1 (AFM1), that is excreted in milk and urine (Ueng et al. 1995). AFM1 is less carcinogenic or mutagenic than AFB1, but is equally toxic. Authored: Jassal, Bijay, 2014-05-09 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-09 AFM1 aflatoxin M1 Reactome DB_ID: 5423629 aflatoxin M1 [ChEBI:78576] aflatoxin M1 ChEBI CHEBI:78576 Reactome Database ID Release 78 5423629 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=5423629 Reactome R-ALL-5423629 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-5423629.3 COMPOUND C06800 ACTIVATION 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 78 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 Reactome Database ID Release 78 5423677 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=5423677 Reactome Database ID Release 78 5423678 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=5423678 Reactome R-HSA-5423678 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-5423678.1 7766804 Pubmed 1995 Oxidation of aflatoxin B1 by bacterial recombinant human cytochrome P450 enzymes Ueng, Y F Shimada, T Yamazaki, H Guengerich, F P Chem. Res. Toxicol. 8:218-25 LEFT-TO-RIGHT CYP2A13 oxidises AFM1 to AFM1E Cytochrome P450 2A13 is able to oxidise aflatoxin M1 (AFM1) to the reactive aflatoxin M1 epoxide (AFM1E) (He et al. 2006). AFM1E is less carcinogenic or mutagenic than aflatoxin B1-exo-8,9-epoxide (AFBO), but is equally toxic. AFM1E would usually be detoxified by conjugation with glutathione, eventually excreted in urine as a mercapturic acid (not shown here). Authored: Jassal, Bijay, 2014-05-09 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-09 AFM1E Aflatoxin M1 epoxide aflatoxin M1 8,9-epoxide Reactome DB_ID: 5423657 aflatoxin M1 8,9-epoxide [ChEBI:78577] aflatoxin M1 8,9-epoxide ChEBI CHEBI:78577 Reactome Database ID Release 78 5423657 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=5423657 Reactome R-ALL-5423657 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-5423657.3 COMPOUND C06800 ACTIVATION CYP2A13 Cytochrome P450 2A13 CPAD_HUMAN Reactome DB_ID: 211034 UniProt:Q16696 CYP2A13 CYP2A13 FUNCTION Exhibits a coumarin 7-hydroxylase activity. Active in the metabolic activation of hexamethylphosphoramide, N,N-dimethylaniline, 2'-methoxyacetophenone, N-nitrosomethylphenylamine, and the tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Possesses phenacetin O-deethylation activity.TISSUE SPECIFICITY Expressed in liver and a number of extrahepatic tissues, including nasal mucosa, lung, trachea, brain, mammary gland, prostate, testis, and uterus, but not in heart, kidney, bone marrow, colon, small intestine, spleen, stomach, thymus, or skeletal muscle.POLYMORPHISM The frequencies of the Cys-257 allele in white, black, Hispanic, and Asian individuals are 1.9%, 14.4%, 5.8%, and 7.7%, respectively. The Cys-257 variant is 37 to 56% less active than the wild-type Arg-257 protein toward all substrates tested.SIMILARITY Belongs to the cytochrome P450 family. UniProt Q16696 1 EQUAL 494 EQUAL Reactome Database ID Release 78 211034 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=211034 Reactome R-HSA-211034 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-211034.1 Reactome Database ID Release 78 5423682 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=5423682 Reactome Database ID Release 78 5423647 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=5423647 Reactome R-HSA-5423647 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-5423647.1 16385575 Pubmed 2006 Efficient activation of aflatoxin B1 by cytochrome P450 2A13, an enzyme predominantly expressed in human respiratory tract He, Xiao-Yang Tang, Lili Wang, Shou-Lin Cai, Qing-Song Wang, Jia-Sheng Hong, Jun-Yan Int. J. Cancer 118:2665-71 LEFT-TO-RIGHT CYP1A2,3A4,3A5,2A13 oxidise AFB1 to AFXBO Aflatoxin B1 oxidized to Aflatoxin-8,9-oxide Aflatoxin B1 (AFB1) requires microsomal oxidation to produce epoxides which cause the toxic and carcinogenic effects. In humans, cytochrome P450 enzymes produce epoxide stereoisomers of AFB1, the most potent being aflatoxin exo-8,9-oxide (AFXBO). This conversion is carried out by at least four P450s; 1A2, 3A4, 3A5 and 2A13. CYP3A4 mainly produces the exo form whereas CYP1A2 produces a racemic mixture of exo and endo forms (Gallagher et al. 1996, He et al. 2006). Authored: Jassal, Bijay, 2014-05-09 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-09 AFXBO Aflatoxin exo-8,9-oxide aflatoxin B1 exo-8,9-epoxide Reactome DB_ID: 159211 aflatoxin B1 exo-8,9-epoxide [ChEBI:30725] aflatoxin B1 exo-8,9-epoxide ChEBI CHEBI:30725 Reactome Database ID Release 78 159211 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=159211 Reactome R-ALL-159211 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-159211.3 ACTIVATION Converted from EntitySet in Reactome CYP1A2,3A4,3A5,2A13 Reactome DB_ID: 5423602 Reactome Database ID Release 78 5423602 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=5423602 Reactome R-HSA-5423602 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-5423602.1 Reactome Database ID Release 78 5423603 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=5423603 Reactome Database ID Release 78 156526 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=156526 Reactome R-HSA-156526 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-156526.1 LEFT-TO-RIGHT CYP1A2, 3A4 oxidise AFB1 to AFNBO Aflatoxin B1 (AFB1) requires microsomal oxidation to produce epoxides which cause the toxic and carcinogenic effects. In humans, cytochrome P450 enzymes produce epoxide stereoisomers of AFB1, the most potent being aflatoxin exo-8,9-oxide (AFNBO). CYP3A4 and CYP1A2 can also produce aflatoxin B1-endo-8,9-epoxide (Raney et al. 1992, Ueng et al. 1995). Authored: Jassal, Bijay, 2014-05-09 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-09 AFNBO aflatoxin B1 endo-8,9-oxide Reactome DB_ID: 5423663 aflatoxin B1 endo-8,9-oxide [ChEBI:78586] aflatoxin B1 endo-8,9-oxide ChEBI CHEBI:78586 Reactome Database ID Release 78 5423663 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=5423663 Reactome R-ALL-5423663 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-5423663.3 ACTIVATION Converted from EntitySet in Reactome CYP1A2,3A4 Reactome DB_ID: 5423625 Reactome Database ID Release 78 5423625 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=5423625 Reactome R-HSA-5423625 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-5423625.1 Reactome Database ID Release 78 5423617 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=5423617 Reactome Database ID Release 78 5423672 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=5423672 Reactome R-HSA-5423672 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-5423672.1 1504254 Pubmed 1992 The endo-8,9-epoxide of aflatoxin B1: a new metabolite Raney, K D Coles, B Guengerich, F P Harris, T M Chem. Res. Toxicol. 5:333-5 LEFT-TO-RIGHT AFXBO translocates from cytosol to nucleoplasm For the reactive metabolite aflatoxin B1-exo-8,9-epoxide (AFBO) to react with DNA, it must translocate to the nucleus. This mechanism of translocation is thought to be simple diffusion (Guengerich et al. 1998). Authored: Jassal, Bijay, 2014-05-09 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-09 AFXBO Aflatoxin B1 exo-8,9-oxide aflatoxin B1 exo-8,9-epoxide Reactome DB_ID: 5423619 nucleoplasm GENE ONTOLOGY GO:0005654 Reactome Database ID Release 78 5423619 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=5423619 Reactome R-ALL-5423619 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-5423619.3 Reactome Database ID Release 78 5423728 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=5423728 Reactome R-HSA-5423728 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-5423728.1 9675258 Pubmed 1998 Activation and detoxication of aflatoxin B1 Guengerich, F P Johnson, W W Shimada, T Ueng, Y F Yamazaki, H Langouët, S Mutat. Res. 402:121-8 LEFT-TO-RIGHT AFXBO binds DNA Aflatoxin B1 (AFB1), a category I known human carcinogen and the most potent genotoxic agent, is mutagenic in many model systems. Aflatoxin B1 exo-8,9-epoxide (AFXBO) binds to DNA to form the predominant 8,9-dihydro-8-(N7 guanyl)-9-hydroxy-AFB1 (AFB1-N7-Gua) adduct. AFB1-N7-Gua confers the mutagenic properties of the compound (Raney et al. 1993, Bedard & Massey 2006). Authored: Jassal, Bijay, 2014-05-09 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-09 DNA Deoxyribonucleic Acid Reactome DB_ID: 29428 Reactome Database ID Release 78 29428 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=29428 Reactome R-ALL-29428 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-29428.1 ChEBI 4705 AFXBO:DNA Reactome DB_ID: 5423670 1 1 Reactome Database ID Release 78 5423670 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=5423670 Reactome R-ALL-5423670 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-5423670.1 Reactome Database ID Release 78 5423632 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=5423632 Reactome R-HSA-5423632 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-5423632.1 16458422 Pubmed 2006 Aflatoxin B1-induced DNA damage and its repair Bedard, Leanne L Massey, Thomas E Cancer Lett. 241:174-83 8448352 Pubmed 1993 DNA conformation mediates aflatoxin B1-DNA binding and the formation of guanine N7 adducts by aflatoxin B1 8,9-exo-epoxide Raney, V M Harris, T M Stone, M P Chem. Res. Toxicol. 6:64-8 LEFT-TO-RIGHT 2.5.1.18 MGST trimers transfer GS from GSH to AFXBO and AFNBO The microsomal glutathione S-transferases (MGSTs) catalyse the nucleophilic attack by reduced glutathione (GSH) on nonpolar compounds that contain an electrophilic C, N, or S atom. Three major families of proteins are widely distributed in nature. The cytosolic and mitochondrial GST families comprise soluble enzymes that are only distantly related whilst the third family comprises microsomal GST, referred to as membrane-associated proteins in eicosanoid and glutathione (MAPEG) metabolism. Three members of this family function as detoxification enzymes, MGST1-3 (DeJong et al. 1988, Kelner et al. 1996, Jakobsson et al. 1996, Jakobsson et al. 1997). Electron crystallography studies in rat Mgst1 indicate these enzymes function as homotrimers (Holm et al. 2002). Both aflatoxin B1 exo- and endo-epoxides (AFXBO and AFNBO) conjugate with glutathione. These conjugates are eventually excreted in urine as mercapturic acids. Authored: Jassal, Bijay, 2014-05-09 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-09 Converted from EntitySet in Reactome AFXBO,AFNBO Reactome DB_ID: 5423723 Reactome Database ID Release 78 5423723 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=5423723 Reactome R-ALL-5423723 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-5423723.1 GSH Reduced glutathione glutathione 5-L-Glutamyl-L-cysteinylglycine N-(N-gamma-L-Glutamyl-L-cysteinyl)glycine gamma-L-Glutamyl-L-cysteinyl-glycine glutathionate(1-) Reactome DB_ID: 29450 glutathionate(1-) [ChEBI:57925] glutathionate(1-) glutathionate ion glutathionate anion glutathionate glutathione ChEBI CHEBI:57925 Reactome Database ID Release 78 29450 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=29450 Reactome R-ALL-29450 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-29450.4 COMPOUND C00051 Converted from EntitySet in Reactome AFXBO-SG,AFNBO-SG Reactome DB_ID: 5423730 AFNBO-SG Aflatoxin B1 endo-SG conjugate Aflatoxin B1 endo glutathione conjugate Reactome DB_ID: 5423724 Aflatoxin B1 endo glutathione conjugate [ChEBI:78581] Aflatoxin B1 endo glutathione conjugate ChEBI CHEBI:78581 Reactome Database ID Release 78 5423724 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=5423724 Reactome R-ALL-5423724 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-5423724.3 AFXBO-SG Aflatoxin B1 exo-SG conjugate Aflatoxin B1 exo glutathione conjugate Reactome DB_ID: 5423692 Aflatoxin B1 exo glutathione conjugate [ChEBI:78587] Aflatoxin B1 exo glutathione conjugate ChEBI CHEBI:78587 Reactome Database ID Release 78 5423692 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=5423692 Reactome R-ALL-5423692 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-5423692.3 Reactome Database ID Release 78 5423730 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=5423730 Reactome R-ALL-5423730 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-5423730.1 ACTIVATION Converted from EntitySet in Reactome MGST trimers Reactome DB_ID: 176042 MGST1 trimer Reactome DB_ID: 158548 MGST1 Microsomal glutathione S-transferase 1 Reactome DB_ID: 158545 UniProt:P10620 MGST1 MGST1 GST12 MGST FUNCTION Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Has a wide substrate specificity.ACTIVITY REGULATION Can be activated by reagents that attack Cys-50 sulfhydryl, such as N-ethylmaleimide. Activation also occurs via nitration of Tyr-93 by peroxynitrite (By similarity).SUBUNIT Homotrimer; The trimer binds only one molecule of glutathione.TISSUE SPECIFICITY Highly expressed in liver.PTM Peroxynitrite induces nitration at Tyr-93 which activates the enzyme.SIMILARITY Belongs to the MAPEG family. UniProt P10620 2 EQUAL 155 EQUAL Reactome Database ID Release 78 158545 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=158545 Reactome R-HSA-158545 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-158545.1 3 Reactome Database ID Release 78 158548 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=158548 Reactome R-HSA-158548 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-158548.2 MGST2 trimer Reactome DB_ID: 176061 MGST2 Microsomal glutathione S-transferase 2 Reactome DB_ID: 176058 UniProt:Q99735 MGST2 MGST2 GST2 FUNCTION Catalyzes several different glutathione-dependent reactions (PubMed:8703034, PubMed:9278457, PubMed:23409838, PubMed:26656251, PubMed:26066610). Catalyzes the glutathione-dependent reduction of lipid hydroperoxides, such as 5-HPETE (PubMed:9278457, PubMed:23409838). Has glutathione transferase activity, toward xenobiotic electrophiles, such as 1-chloro-2, 4-dinitrobenzene (CDNB) (PubMed:23409838, PubMed:8703034). Catalyzes also the conjugation of leukotriene A4 with reduced glutathione to form leukotriene C4 (LTC4) (PubMed:23409838, PubMed:26656251). Involved in oxidative DNA damage induced by ER stress and anticancer agents by activating LTC4 biosynthetic machinery in nonimmune cells (PubMed:26656251).ACTIVITY REGULATION Each monomer can bind on GSH molecule but only one subunit is catalytically active.SUBUNIT Homotrimer.TISSUE SPECIFICITY Liver, spleen, skeletal muscle, heart, adrenals, pancreas, prostate, testis, fetal liver, and fetal spleen. Very low expression in lung, brain, placenta and bone marrow (PubMed:8703034). Abundantly expressed in human umbilical vein endothelial cells (at protein level) (PubMed:11322876).INDUCTION Upon ER stress with brefeldin A or with tunicamycin, MGST2 is down-regulated, in several non-haematopoietic cell types, during the early, protective phase of the unfolded protein response (UPR), and up-regulated at the late, death-promoting phase of the unfolded protein response (UPR).SIMILARITY Belongs to the MAPEG family. UniProt Q99735 1 EQUAL 147 EQUAL Reactome Database ID Release 78 176058 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=176058 Reactome R-HSA-176058 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-176058.1 3 Reactome Database ID Release 78 176061 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=176061 Reactome R-HSA-176061 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-176061.2 MGST3 trimer Reactome DB_ID: 176047 MGST3 Microsomal glutathione S-transferase 3 Reactome DB_ID: 176053 UniProt:O14880 MGST3 MGST3 FUNCTION Catalyzes oxydation of hydroxy-fatty acids (PubMed:9278457). Also catalyzes the conjugation of a reduced glutathione to leukotriene A4 in vitro (PubMed:9278457). May participate in the lipid metabolism (PubMed:9278457).ACTIVITY REGULATION Inhibited by MK-886 and leukotriene C4.TISSUE SPECIFICITY Predominantly expressed in heart, skeletal muscle, and adrenal cortex. Also found in brain, placenta, liver, kidney, pancreas, thyroid, testis and ovary. Almost absent in lung, thymus and peripheral blood leukocytes.SIMILARITY Belongs to the MAPEG family. UniProt O14880 1 EQUAL 152 EQUAL Reactome Database ID Release 78 176053 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=176053 Reactome R-HSA-176053 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-176053.1 3 Reactome Database ID Release 78 176047 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=176047 Reactome R-HSA-176047 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-176047.2 Reactome Database ID Release 78 176042 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=176042 Reactome R-HSA-176042 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-176042.1 GENE ONTOLOGY GO:0004364 Reactome Database ID Release 78 158544 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=158544 Reactome Database ID Release 78 5423653 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=5423653 Reactome R-HSA-5423653 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-5423653.1 3372534 Pubmed 1988 Gene expression of rat and human microsomal glutathione S-transferases DeJong, J L Morgenstern, R Jörnvall, Hans DePierre, J W Tu, C P J. Biol. Chem. 263:8430-6 8812420 Pubmed 1996 Structural organization of the human microsomal glutathione S-transferase gene (GST12) Kelner, M J Stokely, M N Stovall, N E Montoya, M A Genomics 36:100-3 11904223 Pubmed 2002 The 3-D structure of microsomal glutathione transferase 1 at 6 A resolution as determined by electron crystallography of p22(1)2(1) crystals Holm, Peter J Morgenstern, R Hebert, H Biochim. Biophys. Acta 1594:276-85 8703034 Pubmed 1996 Identification and characterization of a novel human microsomal glutathione S-transferase with leukotriene C4 synthase activity and significant sequence identity to 5-lipoxygenase-activating protein and leukotriene C4 synthase Jakobsson, P J Mancini, J A Ford-Hutchinson, A W J. Biol. Chem. 271:22203-10 9278457 Pubmed 1997 Identification and characterization of a novel microsomal enzyme with glutathione-dependent transferase and peroxidase activities Jakobsson, P J Mancini, J A Riendeau, D Ford-Hutchinson, A W J. Biol. Chem. 272:22934-9 LEFT-TO-RIGHT AFXBO-SG, AFNBO-SG translocate from cytosol to extracellular region As glutathione conjugates of aflatoxin exo-and endo-epoxides are secreted from the cell, they undergo several hydrolysis steps before they form the mercapturic acid form which is excreted in urine (Heisterkamp et al. 2008). The mechanism of translocation is unknown. Authored: Jassal, Bijay, 2014-05-19 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-19 Converted from EntitySet in Reactome AFXBO-SG,AFNBO-SG Reactome DB_ID: 5490253 AFNBO-SG Aflatoxin B1 endo-SG conjugate Aflatoxin B1 endo glutathione conjugate Reactome DB_ID: 5490243 extracellular region GENE ONTOLOGY GO:0005576 Reactome Database ID Release 78 5490243 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=5490243 Reactome R-ALL-5490243 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-5490243.3 AFXBO-SG Aflatoxin B1 exo-SG conjugate Aflatoxin B1 exo glutathione conjugate Reactome DB_ID: 5490264 Reactome Database ID Release 78 5490264 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=5490264 Reactome R-ALL-5490264 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-5490264.3 Reactome Database ID Release 78 5490253 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=5490253 Reactome R-ALL-5490253 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-5490253.1 Reactome Database ID Release 78 5490230 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=5490230 Reactome R-HSA-5490230 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-5490230.1 18357469 Pubmed 2008 The human gamma-glutamyltransferase gene family Heisterkamp, N Groffen, J Warburton, D Sneddon, TP Hum Genet 123:321-32 LEFT-TO-RIGHT 3.4.19.13 GGTs hydrolyse glutamate from AFXBO-SG, AFNBO-SG To be excreted in urine, glutathione conjugates undergo several hydrolysis steps to form mercapturic acids which are readily excreted. The first step is the hydrolysis of a gamma-glutamyl residue from the conjugate catalysed by gamma-glutamyltransferases (GGTs). These are membrane-bound, heterodimeric enzymes composed of light and heavy peptide chains. GGT1 and 2 are well characterised while GGT3P, 5, 6 and 7 are putative transferases. Extracellular glutathione or its conjugates can be hydrolysed to give cysteinylglycine (CG, or CG conjugates) and free glutamate (L-Glu) (Heisterkamp et al. 2008, Tate & Ross 1977, Pawlak et al. 1989). Authored: Jassal, Bijay, 2014-05-12 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-12 H2O water Reactome DB_ID: 109276 Reactome Database ID Release 78 109276 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=109276 Reactome R-ALL-109276 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-109276.4 COMPOUND C00001 L-Glu L-Glutamate L-glutamate(1-) L-glutamic acid L-Glutaminic acid Reactome DB_ID: 210382 L-glutamate(1-) [ChEBI:29985] L-glutamate(1-) L-glutamic acid, ion(1-) [NH3+][C@@H](CCC([O-])=O)C([O-])=O WHUUTDBJXJRKMK-VKHMYHEASA-M C5H8NO4 146.12136 (2S)-2-ammoniopentanedioate hydrogen L-glutamate L-glutamate L-glutamic acid monoanion InChI=1S/C5H9NO4/c6-3(5(9)10)1-2-4(7)8/h3H,1-2,6H2,(H,7,8)(H,9,10)/p-1/t3-/m0/s1 ChEBI CHEBI:29985 Reactome Database ID Release 78 210382 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=210382 Reactome R-ALL-210382 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-210382.4 COMPOUND C00025 Converted from EntitySet in Reactome AFXBO-CG,AFNBO-CG Reactome DB_ID: 5490235 AFNBO-CG Aflatoxin B1 endo-cysteinylglycine conjugate Reactome DB_ID: 5490245 Aflatoxin B1 endo-cysteinylglycine conjugate [ChEBI:78579] Aflatoxin B1 endo-cysteinylglycine conjugate ChEBI CHEBI:78579 Reactome Database ID Release 78 5490245 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=5490245 Reactome R-ALL-5490245 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-5490245.3 AFXBO-CG Aflatoxin B1 exo-cysteinylglycine conjugate Reactome DB_ID: 5490271 Aflatoxin B1 exo-cysteinylglycine conjugate [ChEBI:78584] Aflatoxin B1 exo-cysteinylglycine conjugate ChEBI CHEBI:78584 Reactome Database ID Release 78 5490271 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=5490271 Reactome R-ALL-5490271 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-5490271.3 Reactome Database ID Release 78 5490235 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=5490235 Reactome R-ALL-5490235 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-5490235.1 ACTIVATION Converted from EntitySet in Reactome GGT dimers gamma-glutamyltransferases Reactome DB_ID: 1247946 GGT1 dimer Gamma-glutamyltransferase 1 Reactome DB_ID: 1247898 plasma membrane GENE ONTOLOGY GO:0005886 GGT1 GGT1(381-569) GGT1 light chain GGT1lc Gamma-glutamyltranspeptidase 1 GGT1_HUMAN Reactome DB_ID: 8943263 UniProt:P19440 GGT1 GGT1 GGT FUNCTION Cleaves the gamma-glutamyl bond of extracellular glutathione (gamma-Glu-Cys-Gly), glutathione conjugates and other gamma-glutamyl compounds, such as leukotriene C4 (LTC4). The metabolism of glutathione by GGT1 releases free glutamate and the dipeptide cysteinyl-glycine, which is hydrolyzed to cysteine and glycine by dipeptidases. In the presence of high concentrations of dipeptides and some amino acids, can also catalyze a transpeptidation reaction, transferring the gamma-glutamyl moiety to an acceptor amino acid to form a new gamma-glutamyl compound (PubMed:17924658, PubMed:7673200, PubMed:7759490, PubMed:8095045, PubMed:8827453, PubMed:21447318). Contributes to cysteine homeostasis, glutathione homeostasis and in the conversion of the leukotriene LTC4 to LTD4.ACTIVITY REGULATION Activated by autocatalytic cleavage (PubMed:23682772). Inhibited by serine-borate (PubMed:21447318).PATHWAY Lipid metabolism; leukotriene D4 biosynthesis.PATHWAY Sulfur metabolism; glutathione metabolism.SUBUNIT Heterodimer composed of the light and heavy chains. The active site is located in the light chain.TISSUE SPECIFICITY Detected in fetal and adult kidney and liver, adult pancreas, stomach, intestine, placenta and lung. There are several other tissue-specific forms that arise from alternative promoter usage but that produce the same protein.PTM N-glycosylated on both chains. Contains hexoses, hexosamines and sialic acid residues. Glycosylation profiles tested in kidney and liver tissues reveal the presence of tissue-specific and site-specific glycan composition, despite the overlap in composition among the N-glycans. A total of 36 glycan compositions, with 40 unique structures are observed. Up to 15 different glycans are observed at a single site, with site-specific variation in glycan composition. The difference in glycosylation profiles in the 2 tissues do not affect the enzyme activity.PTM Cleaved by autocatalysis into a large and a small subunit and the autocatalytic cleavage is essential to the functional activation of the enzyme.MISCELLANEOUS Cys-454 was thought to bind the gamma-glutamyl moiety, but mutagenesis of this residue had no effect on activity.MISCELLANEOUS Chloride ions bound in the active site cavity may contribute to stabilize the protein fold.SIMILARITY Belongs to the gamma-glutamyltransferase family. UniProt P19440 381 EQUAL 569 EQUAL Reactome Database ID Release 78 8943263 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=8943263 Reactome R-HSA-8943263 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-8943263.1 1 GGT1 GGT1(1-380) GGT1 heavy chain GGT1hc Gamma-glutamyltranspeptidase 1 GGT1_HUMAN Reactome DB_ID: 1247889 1 EQUAL 380 EQUAL Reactome Database ID Release 78 1247889 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=1247889 Reactome R-HSA-1247889 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-1247889.1 1 Reactome Database ID Release 78 1247898 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=1247898 Reactome R-HSA-1247898 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-1247898.2 GGT5 dimer Gamma-glutamyltransferase 5 Reactome DB_ID: 265314 GGTLA1 GGT5(388-586) GGT5 light chain GGT5_HUMAN Reactome DB_ID: 265312 UniProt:P36269 GGT5 GGT5 GGTLA1 FUNCTION Cleaves the gamma-glutamyl peptide bond of glutathione and glutathione-S-conjugate such as leukotriene C4 (PubMed:21447318). Does not cleaves gamma-glutamyl compounds such as gamma-glutamyl leucine (PubMed:21447318). May also catalyze a transpeptidation reaction in addition to the hydrolysis reaction, transferring the gamma-glutamyl moiety to an acceptor amino acid to form a new gamma-glutamyl compound (PubMed:21447318). Acts as a negative regulator of geranylgeranyl glutathione bioactivity by cleaving off its gamma-glutamyl group, playing a role in adaptive immune responses (PubMed:30842656).ACTIVITY REGULATION Inhibited by serine-borate.PATHWAY Sulfur metabolism; glutathione metabolism.PATHWAY Lipid metabolism; leukotriene D4 biosynthesis.SUBUNIT Heterodimer composed of the light and heavy chains. The active site is located in the light chain.PTM Cleaved by autocatalysis into a large and a small subunit.PTM Glycosylated.MISCELLANEOUS A previous study reported that GSH and oxidized glutathione (GSSG) are not substrates for murine GGT5 (By similarity). However, this result contrasts with two studies reported that GSH is indeed a substrate for GGT5 (PubMed:21447318, PubMed:1676842).SIMILARITY Belongs to the gamma-glutamyltransferase family. UniProt P36269 388 EQUAL 586 EQUAL Reactome Database ID Release 78 265312 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=265312 Reactome R-HSA-265312 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-265312.1 1 GGT5 GGT5(1-387) GGT5 heavy chain GGT5_HUMAN GGTLA1 Reactome DB_ID: 265313 1 EQUAL 387 EQUAL Reactome Database ID Release 78 265313 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=265313 Reactome R-HSA-265313 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-265313.1 1 Reactome Database ID Release 78 265314 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=265314 Reactome R-HSA-265314 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-265314.2 GGT6 dimer Gamma-glutamyltransferase 6 Reactome DB_ID: 1247906 GGT6 GGT6(1-?) GGT6 heavy chain Gamma-glutamyltransferase 6 GGT6_HUMAN Reactome DB_ID: 1247944 UniProt:Q6P531 GGT6 GGT6 FUNCTION Cleaves glutathione conjugates.PATHWAY Sulfur metabolism; glutathione metabolism.SUBUNIT Heterodimer composed of the light and heavy chains. The active site is located in the light chain (By similarity).SIMILARITY Belongs to the gamma-glutamyltransferase family. UniProt Q6P531 Reactome Database ID Release 78 1247944 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=1247944 Reactome R-HSA-1247944 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-1247944.1 1 GGT6 GGT6(?-493) GGT6 light chain Gamma-glutamyltransferase 6 GGT6_HUMAN Reactome DB_ID: 1247936 1 EQUAL 493 EQUAL Reactome Database ID Release 78 1247936 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=1247936 Reactome R-HSA-1247936 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-1247936.1 1 Reactome Database ID Release 78 1247906 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=1247906 Reactome R-HSA-1247906 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-1247906.2 GGT7 dimer Gamma-glutamyltransferase 7 Reactome DB_ID: 1247950 GGT7 GGT7(1-472) GGT7 heavy chain Gamma-glutamyltransferase 7 GGT7_HUMAN Reactome DB_ID: 1247890 UniProt:Q9UJ14 GGT7 GGT7 GGTL3 GGTL5 FUNCTION Cleaves glutathione conjugates.PATHWAY Sulfur metabolism; glutathione metabolism.SUBUNIT Heterodimer composed of the light and heavy chains. The active site is located in the light chain (By similarity). Isoform 3 interacts with TLCD3A.TISSUE SPECIFICITY Widely expressed, but at low level, except in the airway epithelial cells. Detected in brain, heart, kidney, liver, lung, spleen, testis and trachea.SIMILARITY Belongs to the gamma-glutamyltransferase family. UniProt Q9UJ14 1 EQUAL 472 EQUAL Reactome Database ID Release 78 1247890 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=1247890 Reactome R-HSA-1247890 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-1247890.1 1 GGT7 GGT7(473-662) GGT7 light chain Gamma-glutamyltransferase 7 GGT7_HUMAN Reactome DB_ID: 1247919 473 EQUAL 662 EQUAL Reactome Database ID Release 78 1247919 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=1247919 Reactome R-HSA-1247919 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-1247919.1 1 Reactome Database ID Release 78 1247950 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=1247950 Reactome R-HSA-1247950 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-1247950.2 GGT3P dimer Reactome DB_ID: 5490244 GGT3_HUMAN GGT3P(381-568) Putative gamma-glutamyltranspeptidase 3 light chain Reactome DB_ID: 5490260 UniProt:A6NGU5 GGT3P GGT3P GGT3 FUNCTION Initiates extracellular glutathione (GSH) breakdown; catalyzes the transfer of the glutamyl moiety of glutathione to amino acids and dipeptide acceptors.PATHWAY Sulfur metabolism; glutathione metabolism.PTM Cleaved by autocatalysis into a large and a small subunit.MISCELLANEOUS In some epileptic patients treated with phenytoin, phenobarbital and carbamazepin, GGT3 is found, as an additional form of GGT. This group of patients has levels of ceruloplasmin and oxidase activity that were significantly higher than in the group of patients without GGT3. However, levels of ceruloplasmin and oxidase activity are significantly higher in this group of patients without GGT3 than those of the control group.SIMILARITY Belongs to the gamma-glutamyltransferase family.CAUTION Could be the product of a pseudogene. According to PubMed:18357469, it is not functional. UniProt A6NGU5 381 EQUAL 568 EQUAL Reactome Database ID Release 78 5490260 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=5490260 Reactome R-HSA-5490260 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-5490260.1 1 GGT3_HUMAN GGT3P(1-380) Putative gamma-glutamyltranspeptidase 3 heavy chain Reactome DB_ID: 5490267 1 EQUAL 380 EQUAL Reactome Database ID Release 78 5490267 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=5490267 Reactome R-HSA-5490267 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-5490267.1 1 Reactome Database ID Release 78 5490244 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=5490244 Reactome R-HSA-5490244 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-5490244.2 Reactome Database ID Release 78 1247946 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=1247946 Reactome R-HSA-1247946 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-1247946.2 GENE ONTOLOGY GO:0036374 Reactome Database ID Release 78 8943271 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=8943271 Reactome Database ID Release 78 5433072 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=5433072 Reactome R-HSA-5433072 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5433072.3 19463 Pubmed 1977 Human kidney gamma-glutamyl transpeptidase. Catalytic properties, subunit structure, and localization of the gamma-glutamyl binding site on the light subunit Tate, Suresh S Ross, M Elizabeth J Biol Chem 252:6042-5 2573352 Pubmed 1989 Different gamma-glutamyl transpeptidase mRNAs are expressed in human liver and kidney Pawlak, A Wu, SJ Bulle, F Suzuki, A Chikhi, N Ferry, N Baik, JH Siegrist, S Guellaën, G Biochem Biophys Res Commun 164:912-8 LEFT-TO-RIGHT 3.4.13.21 3.4.13.18 DPEPs hydrolyse glycine from AFXBO-CG, AFNBO-CG In the formation of mercapturic acid from glutathione conjugates, first a glutamate residue is hydrolysed from the conjugate then a glycine residue (Gly). The dipeptidases 1,2 and 3 (DPEP1,2,3) perform this second hydrolysis. They are membrane-bound, homodimeric enzymes which require zinc ions for activity. DPEP1 has been characterised (Satoh et al. 1993, 1994, Nitanai et al. 2002) whereas DPEP2 and 3 are thought to function as DPEP1 based on similarity. Authored: Jassal, Bijay, 2014-05-12 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-12 Gly Aminoacetic acid glycine zwitterion glycine Reactome DB_ID: 266029 glycine zwitterion [ChEBI:57305] glycine zwitterion glycine DHMQDGOQFOQNFH-UHFFFAOYSA-N 2-azaniumylacetate C2H5NO2 InChI=1S/C2H5NO2/c3-1-2(4)5/h1,3H2,(H,4,5) [NH3+]CC([O-])=O 75.06660 ChEBI CHEBI:57305 Reactome Database ID Release 78 266029 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=266029 Reactome R-ALL-266029 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-266029.4 COMPOUND C00037 Converted from EntitySet in Reactome AFXBO-C,AFNBO-C Reactome DB_ID: 5490250 AFNBO-C Aflatoxin B1 endo-cysteinyl-conjugate Reactome DB_ID: 5490257 Aflatoxin B1 endo-cysteinyl-conjugate [ChEBI:78578] Aflatoxin B1 endo-cysteinyl-conjugate ChEBI CHEBI:78578 Reactome Database ID Release 78 5490257 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=5490257 Reactome R-ALL-5490257 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-5490257.3 AFXBO-C Aflatoxin B1 exo-cysteinyl-conjugate Reactome DB_ID: 5490234 Aflatoxin B1 exo-cysteinyl-conjugate [ChEBI:78583] Aflatoxin B1 exo-cysteinyl-conjugate ChEBI CHEBI:78583 Reactome Database ID Release 78 5490234 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=5490234 Reactome R-ALL-5490234 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-5490234.3 Reactome Database ID Release 78 5490250 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=5490250 Reactome R-ALL-5490250 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-5490250.1 ACTIVATION Converted from EntitySet in Reactome DPEP1,2,3 dimers Reactome DB_ID: 2162149 DPEP1 dimer Reactome DB_ID: 2142831 DPEP1 Dipeptidase 1 DPEP1_HUMAN Reactome DB_ID: 2142820 UniProt:P16444 DPEP1 DPEP1 MDP RDP FUNCTION Hydrolyzes a wide range of dipeptides including the conversion of leukotriene D4 to leukotriene E4 (PubMed:2303490, PubMed:6334084, PubMed:31442408). Hydrolyzes cystinyl-bis-glycine (cys-bis-gly) formed during glutathione degradation (By similarity). Possesses also beta lactamase activity and hydrolytically inactivates beta-lactam antibiotics (PubMed:6334084).FUNCTION Independently of its dipeptidase activity acts as an adhesion receptor for neutrophils recruitement from bloodstream into inflammed lungs and liver.ACTIVITY REGULATION Inhibited by L-penicillamine (PubMed:31442408). Beta-lactamase activity is inhibited by cilastatin (PubMed:6334084, PubMed:31442408).SUBUNIT Homodimer; disulfide-linked.TISSUE SPECIFICITY Expressed in lung and kidneys.INDUCTION Up-regulated in n colorectal cancers.SIMILARITY Belongs to the metallo-dependent hydrolases superfamily. Peptidase M19 family. UniProt P16444 17 EQUAL 385 EQUAL Reactome Database ID Release 78 2142820 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=2142820 Reactome R-HSA-2142820 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-2142820.1 2 Zn2+ Zn++ zinc(2+) Zinc ion Zn(II) Reactome DB_ID: 29426 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI CHEBI:29105 Reactome Database ID Release 78 29426 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=29426 Reactome R-ALL-29426 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-29426.3 COMPOUND C00038 1 Reactome Database ID Release 78 2142831 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=2142831 Reactome R-HSA-2142831 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-2142831.1 DPEP2 dimer Dipeptidase homodimer (zinc cofactor) Reactome DB_ID: 266059 1 DPEP2 Dipeptidase 2-1 DPEP2_HUMAN Reactome DB_ID: 266067 UniProt:Q9H4A9 DPEP2 DPEP2 UNQ284/PRO323 FUNCTION Dipeptidase that hydrolyzes leukotriene D4 (LTD4) into leukotriene E4 (LTE4). Does not hydrolyze cystinyl-bis-glycine.FUNCTION Independently of its dipeptidase activity can also modulate macrophage inflammatory response by acting as a regulator of NF-kappaB inflammatory signaling pathway.ACTIVITY REGULATION Inhibited by L-penicillamine.SUBUNIT Homodimer; disulfide-linked.SIMILARITY Belongs to the metallo-dependent hydrolases superfamily. Peptidase M19 family. UniProt Q9H4A9 33 EQUAL 463 EQUAL Reactome Database ID Release 78 266067 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=266067 Reactome R-HSA-266067 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-266067.1 2 Reactome Database ID Release 78 266059 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=266059 Reactome R-HSA-266059 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-266059.1 DPEP3 dimer Reactome DB_ID: 5490228 1 DPEP3 Dipeptidase 3 ecNumber3.4.13.19/ecNumber DPEP3_HUMAN Reactome DB_ID: 5490265 UniProt:Q9H4B8 DPEP3 DPEP3 UNQ834/PRO1772 FUNCTION Dipeptidase that hydrolyzes cystinyl-bis-glycine. Does not hydrolyze leukotriene D4 (LTD4) into leukotriene E4 (LTE4).ACTIVITY REGULATION Inhibited by L-penicillamine.SUBUNIT Homodimer; disulfide-linked (By similarity). Interacts with TEX101; co-localized on the cell surface of spermatocytes, spermatids, and testicular spermatozoa, co-localized only in cytoplasmic droplets of caput and corpus epididymal sperm (By similarity).SIMILARITY Belongs to the metallo-dependent hydrolases superfamily. Peptidase M19 family. UniProt Q9H4B8 36 EQUAL 463 EQUAL Reactome Database ID Release 78 5490265 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=5490265 Reactome R-HSA-5490265 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-5490265.1 2 Reactome Database ID Release 78 5490228 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=5490228 Reactome R-HSA-5490228 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-5490228.1 Reactome Database ID Release 78 2162149 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=2162149 Reactome R-HSA-2162149 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-2162149.1 GENE ONTOLOGY GO:0016805 Reactome Database ID Release 78 266039 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=266039 Reactome Database ID Release 78 5433067 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=5433067 Reactome R-HSA-5433067 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-5433067.1 8439558 Pubmed 1993 Cloning and structural analysis of genomic DNA for human renal dipeptidase Satoh, S Kusunoki, C Konta, Y Niwa, M Kohsaka, M Biochim. Biophys. Acta 1172:181-3 7764673 Pubmed 1994 Gene structural analysis and expression of human renal dipeptidase Satoh, S Ohtsuka, K Keida, Y Kusunoki, C Konta, Y Niwa, M Kohsaka, M Biotechnol. Prog. 10:134-40 12144777 Pubmed 2002 Crystal structure of human renal dipeptidase involved in beta-lactam hydrolysis Nitanai, Yasushi Satow, Yoshinori Adachi, Hideki Tsujimoto, Masafumi J. Mol. Biol. 321:177-84 LEFT-TO-RIGHT AFXBO-C, AFNBO-C translocate from extracellular region to cytosol To be transformed into mercapturic acids, the endo and exo forms of aflatoxin B1 cysteine-S-conjugates (AFNBO-C, AFXBO-C) translocate into cells (Guengerich et al. 1998, Wu et al. 2009). The mechanism of translocation is unknown. Authored: Jassal, Bijay, 2014-05-19 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-19 Converted from EntitySet in Reactome AFXBO-C,AFNBO-C Reactome DB_ID: 5490231 AFNBO-C Aflatoxin B1 endo-cysteinyl-conjugate Reactome DB_ID: 5490254 Reactome Database ID Release 78 5490254 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=5490254 Reactome R-ALL-5490254 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-5490254.3 AFXBO-C Aflatoxin B1 exo-cysteinyl-conjugate Reactome DB_ID: 5490266 Reactome Database ID Release 78 5490266 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=5490266 Reactome R-ALL-5490266 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-5490266.3 Reactome Database ID Release 78 5490231 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=5490231 Reactome R-ALL-5490231 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-5490231.1 Reactome Database ID Release 78 5490269 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=5490269 Reactome R-HSA-5490269 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-5490269.1 19514968 Pubmed 2009 Biological degradation of aflatoxins Wu, Qinghua Jezkova, Alena Yuan, Zonghui Pavlikova, Lucie Dohnal, Vlastimil Kuca, Kamil Drug Metab. Rev. 41:1-7 LEFT-TO-RIGHT 2.3.1.80 Unknown NAT transfers COCH3 to AFXBO-C, AFNBO-C An unknown cysteine-S-conjugate N-acetyltransferase (NAT) catalyses the transfer of an acetyl group from acetyl CoA (Ac-CoA) to the exo and endo forms of aflatoxin B1-cysteinyl conjugates (AFXBO-C, AFNBO-C). The resultant N-acetylcysteine-S-conjugate is termed a mercapturic acid which is readily excreted in urine (Hinchman & Ballatori 1994). Authored: Jassal, Bijay, 2014-05-12 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-12 Ac-CoA Acetyl coenzyme A acetyl-CoA acetyl-CoA(4-) Reactome DB_ID: 76183 acetyl-CoA(4-) [ChEBI:57288] acetyl-CoA(4-) acetyl-CoA 3'-phosphonatoadenosine 5'-(3-{(3R)-4-[(3-{[2-(acetylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-3-hydroxy-2,2-dimethyl-4-oxobutyl} diphosphate) acetyl-coenzyme A(4-) acetyl-CoA tetraanion AcCoA(4-) ChEBI CHEBI:57288 Reactome Database ID Release 78 76183 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=76183 Reactome R-ALL-76183 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-76183.4 COMPOUND C00024 Converted from EntitySet in Reactome AFXBO-NAC,AFNBO-NAC Reactome DB_ID: 5490236 AFNBO-NAC Aflatoxin B1 endo-mercapturic acid Aflatoxin B1 endo-N-acetylcysteine conjugate Reactome DB_ID: 5490246 Aflatoxin B1 endo-N-acetylcysteine conjugate [ChEBI:78580] Aflatoxin B1 endo-N-acetylcysteine conjugate ChEBI CHEBI:78580 Reactome Database ID Release 78 5490246 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=5490246 Reactome R-ALL-5490246 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-5490246.3 AFXBO-NAC Aflatoxin B1 exo-mercapturic acid Aflatoxin B1 exo-N-acetylcysteine conjugate Reactome DB_ID: 5490238 Aflatoxin B1 exo-N-acetylcysteine conjugate [ChEBI:78585] Aflatoxin B1 exo-N-acetylcysteine conjugate ChEBI CHEBI:78585 Reactome Database ID Release 78 5490238 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=5490238 Reactome R-ALL-5490238 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-5490238.3 Reactome Database ID Release 78 5490236 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=5490236 Reactome R-ALL-5490236 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-5490236.1 CoA-SH coenzyme A coenzyme A(4-) Reactome DB_ID: 76194 coenzyme A(4-) [ChEBI:57287] coenzyme A(4-) 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-({3-oxo-3-[(2-sulfanylethyl)amino]propyl}amino)butyl] diphosphate} CoA ChEBI CHEBI:57287 Reactome Database ID Release 78 76194 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=76194 Reactome R-ALL-76194 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-76194.4 COMPOUND C00010 ACTIVATION unknown NAT unknown N-acetyltransferase Reactome DB_ID: 5490258 Reactome Database ID Release 78 5490258 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=5490258 Reactome R-HSA-5490258 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-5490258.2 ChEBI 36080 GENE ONTOLOGY GO:0047198 Reactome Database ID Release 78 5490256 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=5490256 Reactome Database ID Release 78 5433066 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=5433066 Reactome R-HSA-5433066 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-5433066.2 8145281 Pubmed 1994 Glutathione conjugation and conversion to mercapturic acids can occur as an intrahepatic process Hinchman, C A Ballatori, N J Toxicol Environ Health 41:387-409 LEFT-TO-RIGHT 3.5.1.14 ACY1:Zn2+ dimer hydrolyses mercapturic acids Cytosolic aminocyclases 1 and 3 (ACY1,3) can hydrolyse N-acylated amino acids and N-acylcysteine-S-conjugates (Lindner et al. 2003). They are functional as dimers and utilise zinc as a cofactor. Authored: Jassal, Bijay, 2014-05-12 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-12 CH3COO- Acetate acetic acid Ethanoic acid Reactome DB_ID: 2022890 Golgi lumen GENE ONTOLOGY GO:0005796 acetic acid [ChEBI:15366] acetic acid ChEBI CHEBI:15366 Reactome Database ID Release 78 2022890 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=2022890 Reactome R-ALL-2022890 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-2022890.3 COMPOUND C00033 ACTIVATION ACY1:Zn2+ dimer Reactome DB_ID: 5433068 ACY1 Aminoacylase-1 ACY1_HUMAN Reactome DB_ID: 5433075 UniProt:Q03154 ACY1 ACY1 FUNCTION Involved in the hydrolysis of N-acylated or N-acetylated amino acids (except L-aspartate).SUBUNIT Homodimer. Interacts with SPHK1 (By similarity).TISSUE SPECIFICITY Expression is highest in kidney, strong in brain and weaker in placenta and spleen.SIMILARITY Belongs to the peptidase M20A family. UniProt Q03154 2 EQUAL 408 EQUAL Reactome Database ID Release 78 5433075 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=5433075 Reactome R-HSA-5433075 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-5433075.1 2 2 Reactome Database ID Release 78 5433068 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=5433068 Reactome R-HSA-5433068 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-5433068.1 GENE ONTOLOGY GO:0004046 Reactome Database ID Release 78 5433071 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=5433071 Reactome Database ID Release 78 5433074 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=5433074 Reactome R-HSA-5433074 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-5433074.2 12933810 Pubmed 2003 Essential roles of zinc ligation and enzyme dimerization for catalysis in the aminoacylase-1/M20 family Lindner, Holger A Lunin, Vladimir V Alary, Alain Hecker, Regina Cygler, Miroslaw Ménard, Robert J. Biol. Chem. 278:44496-504 LEFT-TO-RIGHT 3.5.1.14 ACY3:Zn2+ dimer hydrolyses mercapturic acids Cytosolic aminocyclases 1 and 3 (ACY1,3) can hydrolyse N-acylated amino acids and N-acylcysteine-S-conjugates (Lindner et al. 2003). They are functional as dimers and utilise zinc as a cofactor. Authored: Jassal, Bijay, 2014-05-12 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-12 ACTIVATION ACY3:Zn2+ dimer Reactome DB_ID: 5433069 2 ACY3 Aspartoacylase-2 ecNumber3.5.1.-/ecNumber ACY3_HUMAN Reactome DB_ID: 5433065 UniProt:Q96HD9 ACY3 ACY3 ASPA2 FUNCTION Plays an important role in deacetylating mercapturic acids in kidney proximal tubules. Also acts on N-acetyl-aromatic amino acids (By similarity).SUBUNIT Exists as a mixture of homodimers and homotetramer, both catalytically active.SUBUNIT (Microbial infection) Interacts with hepatitis C virus/HCV core protein.SIMILARITY Belongs to the AspA/AstE family. Aspartoacylase subfamily. UniProt Q96HD9 1 EQUAL 319 EQUAL Reactome Database ID Release 78 5433065 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=5433065 Reactome R-HSA-5433065 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-5433065.1 2 Reactome Database ID Release 78 5433069 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=5433069 Reactome R-HSA-5433069 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-5433069.1 Reactome Database ID Release 78 9638047 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=9638047 Reactome Database ID Release 78 9638046 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=9638046 Reactome R-HSA-9638046 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-9638046.1 LEFT-TO-RIGHT AFXBO hydrolyses non-enzymatically to AFBDHD The exo- and endo-epoxides of aflatoxin B1 are unstable in water and can undergo rapid non-enzymatic hydrolysis to AFB1-8,9-dihydrodiol (AFBDHD) (Johnson et al. 1997, Guengerich et al. 1998). Authored: Jassal, Bijay, 2014-05-09 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-09 AFBDHD aflatoxin B1 8,9-dihydrodiol Reactome DB_ID: 5423726 aflatoxin B1 8,9-dihydrodiol [ChEBI:53106] aflatoxin B1 8,9-dihydrodiol ChEBI CHEBI:53106 Reactome Database ID Release 78 5423726 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=5423726 Reactome R-ALL-5423726 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-5423726.3 Reactome Database ID Release 78 5423656 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=5423656 Reactome R-HSA-5423656 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-5423656.1 9208174 Pubmed 1997 Aflatoxin B1 8,9-epoxide hydrolysis in the presence of rat and human epoxide hydrolase Johnson, W W Yamazaki, H Shimada, T Ueng, Y F Guengerich, F P Chem. Res. Toxicol. 10:672-6 LEFT-TO-RIGHT AFBDHD hydrolyses non-enzymatically to AFBDHO Aflatoxin B1-8,9-dihydrodiol (AFBDHD) undergoes base-catalysed rearrangement to aflatoxin B1 dialdehyde (AFBDHO) that can react with protein lysine residues (not shown here) (Guengerich et al. 1998). Authored: Jassal, Bijay, 2014-05-09 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-09 AFBDHO aflatoxin B1 dialdehyde Reactome DB_ID: 5423727 aflatoxin B1 dialdehyde [ChEBI:53107] aflatoxin B1 dialdehyde ChEBI CHEBI:53107 Reactome Database ID Release 78 5423727 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=5423727 Reactome R-ALL-5423727 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-5423727.3 Reactome Database ID Release 78 5423694 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=5423694 Reactome R-HSA-5423694 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-5423694.1 LEFT-TO-RIGHT 1.1.1 AKR dimers reduce AFBDHO to AFBDOH Aflatoxin B1 aldehyde reductases (AKR7A2, AKR7A3 and AKR7L) are dimeric, cytosolic, NADPH-dependent enzymes able to catalyse the reduction of aflatoxin B1 dialdehyde (AFBDHO) to aflatoxin B1-6,8-dialcohol (AFBDOH) (Ellis et al. 2003, Bodreddigari et al. 2008, Ireland et al. 1998, Guengerich et al. 2001). AKRs can turnover a vast range of substrates, including drugs, carcinogens, and reactive aldehydes. They play central roles in the metabolism of these agents, leading to either their bioactivation or detoxication (Jin & Penning 2007). The dialcohol is excreted in urine by conjugation with glucuronide (not shown here). Authored: Jassal, Bijay, 2014-05-09 Reviewed: D'Eustachio, Peter, 2014-05-22 Edited: Jassal, Bijay, 2014-05-09 AFBDOH Aflatoxin B1 dialcohol aflatoxin B1 triol Reactome DB_ID: 5423729 aflatoxin B1 triol [ChEBI:53108] aflatoxin B1 triol aflatoxin B1 dialcohol ChEBI CHEBI:53108 Reactome Database ID Release 78 5423729 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=5423729 Reactome R-ALL-5423729 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-5423729.3 ACTIVATION Converted from EntitySet in Reactome AKR dimers Reactome DB_ID: 5423668 AKR7A2 dimer Reactome DB_ID: 5423691 AKR7A2 Aflatoxin B1 aldehyde reductase member 2 ecNumber1.1.1.n11/ecNumber ARK72_HUMAN Reactome DB_ID: 5423681 UniProt:O43488 AKR7A2 AKR7A2 AFAR AFAR1 AKR7 FUNCTION Catalyzes the NADPH-dependent reduction of succinic semialdehyde to gamma-hydroxybutyrate. May have an important role in producing the neuromodulator gamma-hydroxybutyrate (GHB). Has broad substrate specificity. Has NADPH-dependent aldehyde reductase activity towards 2-carboxybenzaldehyde, 2-nitrobenzaldehyde and pyridine-2-aldehyde (in vitro). Can reduce 1,2-naphthoquinone and 9,10-phenanthrenequinone (in vitro). Can reduce the dialdehyde protein-binding form of aflatoxin B1 (AFB1) to the non-binding AFB1 dialcohol. May be involved in protection of liver against the toxic and carcinogenic effects of AFB1, a potent hepatocarcinogen.SUBUNIT Homodimer.TISSUE SPECIFICITY Detected in brain, liver, small intestine and testis, and at lower levels in heart, prostate, skeletal muscle and spleen. Detected in kidney proximal and distal tubules, endothelial cells lining the Bowman's capsules and some cysts. Detected at low levels in lung and pancreas (at protein level). Widely expressed.SIMILARITY Belongs to the aldo/keto reductase family. Aldo/keto reductase 2 subfamily.CAUTION It is uncertain whether Met-1 or Met-30 is the initiator. UniProt O43488 1 EQUAL 359 EQUAL Reactome Database ID Release 78 5423681 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=5423681 Reactome R-HSA-5423681 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-5423681.1 2 Reactome Database ID Release 78 5423691 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=5423691 Reactome R-HSA-5423691 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-5423691.1 AKR7A3 dimer Reactome DB_ID: 5423618 AKR7A3 Aflatoxin B1 aldehyde reductase member 3 ecNumber1.-.-.-/ecNumber ARK73_HUMAN Reactome DB_ID: 5423652 UniProt:O95154 AKR7A3 AKR7A3 AFAR2 FUNCTION Can reduce the dialdehyde protein-binding form of aflatoxin B1 (AFB1) to the non-binding AFB1 dialcohol. May be involved in protection of liver against the toxic and carcinogenic effects of AFB1, a potent hepatocarcinogen.SUBUNIT Homodimer.TISSUE SPECIFICITY Expressed in colon, kidney, liver, pancreas, adenocarcinoma and endometrium.SIMILARITY Belongs to the aldo/keto reductase family. Aldo/keto reductase 2 subfamily. UniProt O95154 1 EQUAL 331 EQUAL Reactome Database ID Release 78 5423652 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=5423652 Reactome R-HSA-5423652 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-5423652.1 2 Reactome Database ID Release 78 5423618 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=5423618 Reactome R-HSA-5423618 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-5423618.1 AKR7L dimer Reactome DB_ID: 5423636 AKR7L Aflatoxin B1 aldehyde reductase member 4 ecNumber1.-.-.-/ecNumber ARK74_HUMAN Reactome DB_ID: 5423689 UniProt:Q8NHP1 AKR7L AKR7L AFAR3 AKR7A4 FUNCTION Can reduce the dialdehyde protein-binding form of aflatoxin B1 (AFB1) to the non-binding AFB1 dialcohol. May be involved in protection of liver against the toxic and carcinogenic effects of AFB1, a potent hepatocarcinogen (By similarity).TISSUE SPECIFICITY Mainly expressed in uterus.SIMILARITY Belongs to the aldo/keto reductase family. Aldo/keto reductase 2 subfamily.CAUTION AKR7L is both a gene and a pseudogene in the human population, the reference genome corresponding currently to the non-functional allele with a stop codon at position 106 (GRCh38/hg38). The sequence shown here with a Arg at position 106 is the one of the functional protein. The functional allele is rare.CAUTION It has been speculated that AKR7L encodes a selenoprotein, which includes a selenocysteine (Sec) residue in lieu of a UGA translational termination codon at position 106 (PubMed:12879023). However, there is no evidence that such a protein is produced in vivo. UniProt Q8NHP1 1 EQUAL 331 EQUAL Reactome Database ID Release 78 5423689 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=5423689 Reactome R-HSA-5423689 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-5423689.1 2 Reactome Database ID Release 78 5423636 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=5423636 Reactome R-HSA-5423636 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-5423636.1 Reactome Database ID Release 78 5423668 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=5423668 Reactome R-HSA-5423668 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-5423668.1 GENE ONTOLOGY GO:0004033 Reactome Database ID Release 78 5423725 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=5423725 Reactome Database ID Release 78 5423637 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=5423637 Reactome R-HSA-5423637 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-5423637.1 9576847 Pubmed 1998 Molecular cloning, expression and catalytic activity of a human AKR7 member of the aldo-keto reductase superfamily: evidence that the major 2-carboxybenzaldehyde reductase from human liver is a homologue of rat aflatoxin B1-aldehyde reductase Ireland, L S Harrison, D J Neal, G E Hayes, J D Biochem. J. 332:21-34 12727802 Pubmed 2003 Characterization of the rat aflatoxin B1 aldehyde reductase gene, AKR7A1. Structure and chromosomal localization of AKR7A1 as well as identification of antioxidant response elements in the gene promoter Ellis, Elizabeth M Slattery, Cara M Hayes, John D Carcinogenesis 24:727-37 16970545 Pubmed 2007 Aldo-keto reductases and bioactivation/detoxication Jin, Yi Penning, Trevor M Annu. Rev. Pharmacol. Toxicol. 47:263-92 18416522 Pubmed 2008 Protection against aflatoxin B1-induced cytotoxicity by expression of the cloned aflatoxin B1-aldehyde reductases rat AKR7A1 and human AKR7A3 Bodreddigari, Sridevi Jones, Laundette Knight Egner, Patricia A Groopman, John D Sutter, Carrie Hayes Roebuck, Bill D Guengerich, FP Kensler, Thomas W Sutter, Thomas R Chem. Res. Toxicol. 21:1134-42 11409944 Pubmed 2001 Reduction of aflatoxin B1 dialdehyde by rat and human aldo-keto reductases Guengerich, F P Cai, H McMahon, M Hayes, J D Sutter, T R Groopman, J D Deng, Z Harris, T M Chem. Res. Toxicol. 14:727-37 Reactome Database ID Release 78 5423646 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=5423646 Reactome R-HSA-5423646 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5423646.4 23599745 Pubmed 2013 Aflatoxin B1-induced hepatocellular carcinoma in developing countries: Geographical distribution, mechanism of action and prevention Hamid, Abdu Selim Tesfamariam, Isaias Goitom Zhang, Yucheng Zhang, Zhen Gui Oncol Lett 5:1087-1092 978-953-307-395-8 ISBN 2011 Biotransformation of Aflatoxin B1 and Its Relationship with the Differential Toxicological Response to Aflatoxin in Commercial Poultry Species, Diaz, Gonzalo Murcia, Hansen Aflatoxins - Biochemistry and Molecular Biology (Book) 12435844 Pubmed 2002 The toxicology of aflatoxins as a basis for public health decisions Wild, C P Turner, P C Mutagenesis 17:471-81 GENE ONTOLOGY GO:0046222 gene ontology term for cellular process MI MI:0359