BioPAX pathway converted from "Aflatoxin activation and detoxification" in the Reactome database. Aflatoxin activation and detoxification 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 CYP3A4,5 hydroxylates AFB1 to AFQ1 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 Reactome DB_ID: 5423605 1 cytosol GO 0005829 aflatoxin B1 [ChEBI:2504] aflatoxin B1 Reactome http://www.reactome.org ChEBI 2504 Reactome DB_ID: 70106 1 hydron [ChEBI:15378] hydron ChEBI 15378 Reactome DB_ID: 29368 1 dioxygen [ChEBI:15379] dioxygen ChEBI 15379 Reactome DB_ID: 29364 1 NADPH(4-) [ChEBI:57783] NADPH(4-) NADPH 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoyl-1,4-dihydropyridin-1-yl)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADPH tetraanion ChEBI 57783 Reactome DB_ID: 29366 1 NADP(3-) [ChEBI:58349] NADP(3-) NADP(+) 2'-O-phosphonatoadenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NADP trianion ChEBI 58349 Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 5423660 1 aflatoxin Q1 [ChEBI:78582] aflatoxin Q1 ChEBI 78582 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5423680 endoplasmic reticulum membrane GO 0005789 CYP3A4,5 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP3A5 [endoplasmic reticulum membrane] CYP3A4 [endoplasmic reticulum membrane] Homo sapiens NCBI Taxonomy 9606 UniProt P20815 UniProt P08684 GO 0004497 GO molecular function 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 CYP1A2 hydroxylates AFB1 to AFM1 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 Reactome DB_ID: 5423605 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 29366 1 Reactome DB_ID: 5423629 1 aflatoxin M1 [ChEBI:78576] aflatoxin M1 ChEBI 78576 Reactome DB_ID: 29356 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 52625 UniProt:P05177 CYP1A2 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 Chain Coordinates 2 EQUAL 515 EQUAL 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 CYP2A13 oxidises AFM1 to AFM1E 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 Reactome DB_ID: 5423629 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 29366 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 5423657 1 aflatoxin M1 8,9-epoxide [ChEBI:78577] aflatoxin M1 8,9-epoxide ChEBI 78577 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 211034 UniProt:Q16696 CYP2A13 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 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 CYP1A2,3A4,3A5,2A13 oxidise AFB1 to AFXBO 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 Reactome DB_ID: 5423605 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 29366 1 Reactome DB_ID: 159211 1 aflatoxin B1 exo-8,9-epoxide [ChEBI:30725] aflatoxin B1 exo-8,9-epoxide ChEBI 30725 Reactome DB_ID: 29356 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5423602 CYP1A2,3A4,3A5,2A13 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP2A13 [endoplasmic reticulum membrane] CYP3A5 [endoplasmic reticulum membrane] CYP3A4 [endoplasmic reticulum membrane] CYP1A2 [endoplasmic reticulum membrane] 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 CYP1A2, 3A4 oxidise AFB1 to AFNBO 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 Reactome DB_ID: 5423605 1 Reactome DB_ID: 70106 1 Reactome DB_ID: 29368 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 29366 1 Reactome DB_ID: 5423663 1 aflatoxin B1 endo-8,9-oxide [ChEBI:78586] aflatoxin B1 endo-8,9-oxide ChEBI 78586 Reactome DB_ID: 29356 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5423625 CYP1A2,3A4 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CYP3A4 [endoplasmic reticulum membrane] CYP1A2 [endoplasmic reticulum membrane] 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 AFXBO translocates from cytosol to nucleoplasm 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 Reactome DB_ID: 159211 1 Reactome DB_ID: 5423619 1 nucleoplasm GO 0005654 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 AFXBO binds DNA 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 Reactome DB_ID: 5423619 1 Reactome DB_ID: 29428 1 DNA [nucleoplasm] DNA Deoxyribonucleic Acid Reactome DB_ID: 5423670 1 AFXBO:DNA [nucleoplasm] AFXBO:DNA Reactome DB_ID: 5423619 1 Reactome DB_ID: 29428 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 2.5.1.18 MGST trimers transfer GS from GSH to AFXBO and AFNBO 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 Reactome DB_ID: 5423723 1 AFXBO,AFNBO [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AFNBO [cytosol] AFXBO [cytosol] Reactome DB_ID: 29450 1 glutathionate(1-) [ChEBI:57925] glutathionate(1-) glutathionate anion glutathionate ion glutathione glutathionate ChEBI 57925 Converted from EntitySet in Reactome Reactome DB_ID: 5423730 1 AFXBO-SG,AFNBO-SG [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AFNBO-SG [cytosol] AFXBO-SG [cytosol] ChEBI 78581 ChEBI 78587 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 176042 MGST trimers [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0004364 GO molecular function 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 AFXBO-SG, AFNBO-SG translocate from cytosol to extracellular region 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 Reactome DB_ID: 5423730 1 Converted from EntitySet in Reactome Reactome DB_ID: 5490253 1 extracellular region GO 0005576 AFXBO-SG,AFNBO-SG [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AFNBO-SG [extracellular region] AFXBO-SG [extracellular region] 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 3.4.19.13 GGTs hydrolyse glutamate from AFXBO-SG, AFNBO-SG 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 Reactome DB_ID: 109276 1 Converted from EntitySet in Reactome Reactome DB_ID: 5490253 1 Reactome DB_ID: 210382 1 L-glutamate(1-) [ChEBI:29985] L-glutamate(1-) C5H8NO4 WHUUTDBJXJRKMK-VKHMYHEASA-M (2S)-2-ammoniopentanedioate 146.12136 L-glutamate hydrogen L-glutamate 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 L-glutamic acid, ion(1-) [NH3+][C@@H](CCC([O-])=O)C([O-])=O L-glutamic acid monoanion ChEBI 29985 Converted from EntitySet in Reactome Reactome DB_ID: 5490235 1 AFXBO-CG,AFNBO-CG [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AFNBO-CG [extracellular region] AFXBO-CG [extracellular region] ChEBI 78579 ChEBI 78584 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 1247946 plasma membrane GO 0005886 GGT dimers [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0036374 GO molecular function 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 3.4.13.21 3.4.13.18 DPEPs hydrolyse glycine from AFXBO-CG, AFNBO-CG 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 Converted from EntitySet in Reactome Reactome DB_ID: 5490235 1 Reactome DB_ID: 266029 1 glycine zwitterion [ChEBI:57305] glycine zwitterion glycine DHMQDGOQFOQNFH-UHFFFAOYSA-N C2H5NO2 2-azaniumylacetate [NH3+]CC([O-])=O InChI=1S/C2H5NO2/c3-1-2(4)5/h1,3H2,(H,4,5) 75.06660 ChEBI 57305 Converted from EntitySet in Reactome Reactome DB_ID: 5490250 1 AFXBO-C,AFNBO-C [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AFNBO-C [extracellular region] AFXBO-C [extracellular region] ChEBI 78578 ChEBI 78583 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 2162149 DPEP1,2,3 dimers [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0016805 GO molecular function 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 AFXBO-C, AFNBO-C translocate from extracellular region to cytosol 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 Reactome DB_ID: 5490250 1 Converted from EntitySet in Reactome Reactome DB_ID: 5490231 1 AFXBO-C,AFNBO-C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AFXBO-C [cytosol] AFNBO-C [cytosol] 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 2.3.1.80 Unknown NAT transfers COCH3 to AFXBO-C, AFNBO-C 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 Converted from EntitySet in Reactome Reactome DB_ID: 5490231 1 Reactome DB_ID: 76183 1 acetyl-CoA(4-) [ChEBI:57288] acetyl-CoA(4-) 3'-phosphonatoadenosine 5'-(3-{(3R)-4-[(3-{[2-(acetylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-3-hydroxy-2,2-dimethyl-4-oxobutyl} diphosphate) acetyl-CoA acetyl-CoA tetraanion acetyl-coenzyme A(4-) AcCoA(4-) ChEBI 57288 Converted from EntitySet in Reactome Reactome DB_ID: 5490236 1 AFXBO-NAC,AFNBO-NAC [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AFXBO-NAC [cytosol] AFNBO-NAC [cytosol] ChEBI 78585 ChEBI 78580 Reactome DB_ID: 76194 1 coenzyme A(4-) [ChEBI:57287] coenzyme A(4-) CoA 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-({3-oxo-3-[(2-sulfanylethyl)amino]propyl}amino)butyl] diphosphate} ChEBI 57287 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5490258 unknown NAT [cytosol] unknown NAT unknown N-acetyltransferase GO 0047198 GO molecular function 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 3.5.1.14 ACY1:Zn2+ dimer hydrolyses mercapturic acids 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 Converted from EntitySet in Reactome Reactome DB_ID: 5490236 1 Reactome DB_ID: 29356 1 Converted from EntitySet in Reactome Reactome DB_ID: 5490231 1 Reactome DB_ID: 2022890 1 Golgi lumen GO 0005796 acetic acid [ChEBI:15366] acetic acid ChEBI 15366 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5433068 ACY1:Zn2+ dimer [cytosol] ACY1:Zn2+ dimer Reactome DB_ID: 5433075 2 UniProt:Q03154 ACY1 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 DB_ID: 29426 2 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 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 GO 0004046 GO molecular function 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 3.5.1.14 ACY3:Zn2+ dimer hydrolyses mercapturic acids 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 Converted from EntitySet in Reactome Reactome DB_ID: 5490236 1 Reactome DB_ID: 29356 1 Converted from EntitySet in Reactome Reactome DB_ID: 5490231 1 Reactome DB_ID: 2022890 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5433069 ACY3:Zn2+ dimer [cytosol] ACY3:Zn2+ dimer Reactome DB_ID: 29426 2 Reactome DB_ID: 5433065 2 UniProt:Q96HD9 ACY3 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 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 AFXBO hydrolyses non-enzymatically to AFBDHD 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 Reactome DB_ID: 159211 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 5423726 1 aflatoxin B1 8,9-dihydrodiol [ChEBI:53106] aflatoxin B1 8,9-dihydrodiol ChEBI 53106 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 AFBDHD hydrolyses non-enzymatically to AFBDHO 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 Reactome DB_ID: 29356 1 Reactome DB_ID: 5423726 1 Reactome DB_ID: 5423727 1 aflatoxin B1 dialdehyde [ChEBI:53107] aflatoxin B1 dialdehyde ChEBI 53107 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 1.1.1 AKR dimers reduce AFBDHO to AFBDOH 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 Reactome DB_ID: 70106 1 Reactome DB_ID: 5423727 1 Reactome DB_ID: 29364 1 Reactome DB_ID: 29366 1 Reactome DB_ID: 5423729 1 aflatoxin B1 triol [ChEBI:53108] aflatoxin B1 triol aflatoxin B1 dialcohol ChEBI 53108 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 5423668 AKR dimers [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0004033 GO molecular function 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 GO 0046222 GO biological process