Aflatoxin activation and detoxification (Homo sapiens)

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2, 8, 25, 285, 6, 10, 30, 323, 13, 14, 20, 21123259, 2617, 2511, 18, 2218, 278, 254, 7, 2312, 29253192716, 19, 24endoplasmic reticulum lumennucleoplasmcytosolendoplasmic reticulum lumenAFB1CYP3A5 GGT1(1-380) CYP3A4 H2OCYP3A5 AFB1AFNBO GGT1(381-569) AFNBO-C NADPHH+MGST1 AKR7L AFNBOZn2+ NADPHNADP+MGST3 AFM1ENADP+Ac-CoAGGT7(1-472) AFXBO-C AFBDOHCYP1A2AFXBO-C,AFNBO-CNADP+DPEP1,2,3 dimersH2OH+GSHGGT7(473-662) CYP1A2,3A4CH3COO-DPEP2 GGT5(1-387) AFXBODNA CYP3A4,5AFNBO-CG GGT dimersCYP1A2,3A4,3A5,2A13MGST2 H2OH+H2OAFXBO-C,AFNBO-CAFXBO H2OAFXBO-SG,AFNBO-SGAFM1GGT6(?-493) DNAAFXBO,AFNBOACY1:Zn2+,ACY3:Zn2+dimersAFXBO-SG,AFNBO-SGH2OGGT6(1-?) CYP1A2 O2AFBDHOH2OO2AFXBO-CG,AFNBO-CGCYP3A4 AFQ1CYP2A13O2AFXBO-NAC AFNBO-NAC AFXBO-SG AFXBO-C AFXBO-NAC,AFNBO-NACAKR dimersAFXBO:DNAAFXBO-CG AFXBO MGST trimersCYP1A2 ACY1 H+AFXBONADP+NADPHGGT3P(381-568) AFNBO-C AKR7A2 ACY3 CYP2A13 L-GluAFNBO-SG NADP+H2ODPEP3 unknown NATGGT3P(1-380) NADPHAFBDHDAFNBO-SG AKR7A3 CoA-SHZn2+ GlyCYP3A4 AFXBO-SG GGT5(388-586) DPEP1 15, 23


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).

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. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 5423646
Reactome version: 61
Reactome Author 
Reactome Author: Jassal, Bijay

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  1. Hinchman CA, Ballatori N.; ''Glutathione conjugation and conversion to mercapturic acids can occur as an intrahepatic process.''; PubMed
  2. Hamid AS, Tesfamariam IG, Zhang Y, Zhang ZG.; ''Aflatoxin B1-induced hepatocellular carcinoma in developing countries: Geographical distribution, mechanism of action and prevention.''; PubMed
  3. Ireland LS, Harrison DJ, Neal GE, Hayes JD.; ''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.''; PubMed
  4. Pawlak A, Wu SJ, Bulle F, Suzuki A, Chikhi N, Ferry N, Baik JH, Siegrist S, Guellaën G.; ''Different gamma-glutamyl transpeptidase mRNAs are expressed in human liver and kidney.''; PubMed
  5. Holm PJ, Morgenstern R, Hebert H.; ''The 3-D structure of microsomal glutathione transferase 1 at 6 A resolution as determined by electron crystallography of p22(1)2(1) crystals.''; PubMed
  6. Jakobsson PJ, Mancini JA, Riendeau D, Ford-Hutchinson AW.; ''Identification and characterization of a novel microsomal enzyme with glutathione-dependent transferase and peroxidase activities.''; PubMed
  7. Tate SS, Ross ME.; ''Human kidney gamma-glutamyl transpeptidase. Catalytic properties, subunit structure, and localization of the gamma-glutamyl binding site on the light subunit.''; PubMed
  8. Wu Q, Jezkova A, Yuan Z, Pavlikova L, Dohnal V, Kuca K.; ''Biological degradation of aflatoxins.''; PubMed
  9. Ueng YF, Shimada T, Yamazaki H, Guengerich FP.; ''Oxidation of aflatoxin B1 by bacterial recombinant human cytochrome P450 enzymes.''; PubMed
  10. Kelner MJ, Stokely MN, Stovall NE, Montoya MA.; ''Structural organization of the human microsomal glutathione S-transferase gene (GST12).''; PubMed
  11. Groopman JD, Donahue PR, Zhu JQ, Chen JS, Wogan GN.; ''Aflatoxin metabolism in humans: detection of metabolites and nucleic acid adducts in urine by affinity chromatography.''; PubMed
  12. Raney VM, Harris TM, Stone MP.; ''DNA conformation mediates aflatoxin B1-DNA binding and the formation of guanine N7 adducts by aflatoxin B1 8,9-exo-epoxide.''; PubMed
  13. Bodreddigari S, Jones LK, Egner PA, Groopman JD, Sutter CH, Roebuck BD, Guengerich FP, Kensler TW, Sutter TR.; ''Protection against aflatoxin B1-induced cytotoxicity by expression of the cloned aflatoxin B1-aldehyde reductases rat AKR7A1 and human AKR7A3.''; PubMed
  14. Ellis EM, Slattery CM, Hayes JD.; ''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.''; PubMed
  15. West MB, Wickham S, Parks EE, Sherry DM, Hanigan MH.; ''Human GGT2 does not autocleave into a functional enzyme: A cautionary tale for interpretation of microarray data on redox signaling.''; PubMed
  16. Nitanai Y, Satow Y, Adachi H, Tsujimoto M.; ''Crystal structure of human renal dipeptidase involved in beta-lactam hydrolysis.''; PubMed
  17. Johnson WW, Yamazaki H, Shimada T, Ueng YF, Guengerich FP.; ''Aflatoxin B1 8,9-epoxide hydrolysis in the presence of rat and human epoxide hydrolase.''; PubMed
  18. Gallagher EP, Kunze KL, Stapleton PL, Eaton DL.; ''The kinetics of aflatoxin B1 oxidation by human cDNA-expressed and human liver microsomal cytochromes P450 1A2 and 3A4.''; PubMed
  19. Satoh S, Ohtsuka K, Keida Y, Kusunoki C, Konta Y, Niwa M, Kohsaka M.; ''Gene structural analysis and expression of human renal dipeptidase.''; PubMed
  20. Jin Y, Penning TM.; ''Aldo-keto reductases and bioactivation/detoxication.''; PubMed
  21. Guengerich FP, Cai H, McMahon M, Hayes JD, Sutter TR, Groopman JD, Deng Z, Harris TM.; ''Reduction of aflatoxin B1 dialdehyde by rat and human aldo-keto reductases.''; PubMed
  22. Raney KD, Shimada T, Kim DH, Groopman JD, Harris TM, Guengerich FP.; ''Oxidation of aflatoxins and sterigmatocystin by human liver microsomes: significance of aflatoxin Q1 as a detoxication product of aflatoxin B1.''; PubMed
  23. Heisterkamp N, Groffen J, Warburton D, Sneddon TP.; ''The human gamma-glutamyltransferase gene family.''; PubMed
  24. Satoh S, Kusunoki C, Konta Y, Niwa M, Kohsaka M.; ''Cloning and structural analysis of genomic DNA for human renal dipeptidase.''; PubMed
  25. Guengerich FP, Johnson WW, Shimada T, Ueng YF, Yamazaki H, Langouët S.; ''Activation and detoxication of aflatoxin B1.''; PubMed
  26. Raney KD, Coles B, Guengerich FP, Harris TM.; ''The endo-8,9-epoxide of aflatoxin B1: a new metabolite.''; PubMed
  27. He XY, Tang L, Wang SL, Cai QS, Wang JS, Hong JY.; ''Efficient activation of aflatoxin B1 by cytochrome P450 2A13, an enzyme predominantly expressed in human respiratory tract.''; PubMed
  28. Wild CP, Turner PC.; ''The toxicology of aflatoxins as a basis for public health decisions.''; PubMed
  29. Bedard LL, Massey TE.; ''Aflatoxin B1-induced DNA damage and its repair.''; PubMed
  30. Jakobsson PJ, Mancini JA, Ford-Hutchinson AW.; ''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.''; PubMed
  31. Lindner HA, Lunin VV, Alary A, Hecker R, Cygler M, Ménard R.; ''Essential roles of zinc ligation and enzyme dimerization for catalysis in the aminoacylase-1/M20 family.''; PubMed
  32. DeJong JL, Morgenstern R, Jörnvall H, DePierre JW, Tu CP.; ''Gene expression of rat and human microsomal glutathione S-transferases.''; PubMed


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93959view13:47, 16 August 2017ReactomeTeamreactome version 61
93555view11:27, 9 August 2017ReactomeTeamreactome version 61
87079view14:22, 18 July 2016MkutmonOntology Term : 'aflatoxin metabolic pathway' added !
86657view09:23, 11 July 2016ReactomeTeamreactome version 56
83239view10:28, 18 November 2015ReactomeTeamVersion54
81346view12:52, 21 August 2015ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
ACY1 ProteinQ03154 (Uniprot-TrEMBL)
ACY1:Zn2+,ACY3:Zn2+ dimersComplexR-HSA-5433070 (Reactome)
ACY3 ProteinQ96HD9 (Uniprot-TrEMBL)
AFB1MetaboliteCHEBI:2504 (ChEBI)
AFBDHDMetaboliteCHEBI:53106 (ChEBI)
AFBDHOMetaboliteCHEBI:53107 (ChEBI)
AFBDOHMetaboliteCHEBI:53108 (ChEBI)
AFM1MetaboliteCHEBI:78576 (ChEBI)
AFM1EMetaboliteCHEBI:78577 (ChEBI)
AFNBO MetaboliteCHEBI:78586 (ChEBI)
AFNBO-C MetaboliteCHEBI:78578 (ChEBI)
AFNBO-CG MetaboliteCHEBI:78579 (ChEBI)
AFNBO-NAC MetaboliteCHEBI:78580 (ChEBI)
AFNBO-SG MetaboliteCHEBI:78581 (ChEBI)
AFNBOMetaboliteCHEBI:78586 (ChEBI)
AFQ1MetaboliteCHEBI:78582 (ChEBI)
AFXBO MetaboliteCHEBI:30725 (ChEBI)
AFXBO,AFNBOComplexR-ALL-5423723 (Reactome)
AFXBO-C MetaboliteCHEBI:78583 (ChEBI)
AFXBO-C,AFNBO-CComplexR-ALL-5490231 (Reactome)
AFXBO-C,AFNBO-CComplexR-ALL-5490250 (Reactome)
AFXBO-CG MetaboliteCHEBI:78584 (ChEBI)
AFXBO-CG,AFNBO-CGComplexR-ALL-5490235 (Reactome)
AFXBO-NAC MetaboliteCHEBI:78585 (ChEBI)
AFXBO-NAC,AFNBO-NACComplexR-ALL-5490236 (Reactome)
AFXBO-SG MetaboliteCHEBI:78587 (ChEBI)
AFXBO-SG,AFNBO-SGComplexR-ALL-5423730 (Reactome)
AFXBO-SG,AFNBO-SGComplexR-ALL-5490253 (Reactome)
AFXBO:DNAComplexR-ALL-5423670 (Reactome)
AFXBOMetaboliteCHEBI:30725 (ChEBI)
AKR dimersComplexR-HSA-5423668 (Reactome)
AKR7A2 ProteinO43488 (Uniprot-TrEMBL)
AKR7A3 ProteinO95154 (Uniprot-TrEMBL)
AKR7L ProteinQ8NHP1 (Uniprot-TrEMBL)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
CH3COO-MetaboliteCHEBI:15366 (ChEBI)
CYP1A2 ProteinP05177 (Uniprot-TrEMBL)
CYP1A2,3A4,3A5,2A13ComplexR-HSA-5423602 (Reactome)
CYP1A2,3A4ComplexR-HSA-5423625 (Reactome)
CYP1A2ProteinP05177 (Uniprot-TrEMBL)
CYP2A13 ProteinQ16696 (Uniprot-TrEMBL)
CYP2A13ProteinQ16696 (Uniprot-TrEMBL)
CYP3A4 ProteinP08684 (Uniprot-TrEMBL)
CYP3A4,5ComplexR-HSA-5423680 (Reactome)
CYP3A5 ProteinP20815 (Uniprot-TrEMBL)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DNA R-NUL-29428 (Reactome)
DNAR-NUL-29428 (Reactome)
DPEP1 ProteinP16444 (Uniprot-TrEMBL)
DPEP1,2,3 dimersComplexR-HSA-2162149 (Reactome)
DPEP2 ProteinQ9H4A9 (Uniprot-TrEMBL)
DPEP3 ProteinQ9H4B8 (Uniprot-TrEMBL)
GGT dimersComplexR-HSA-1247946 (Reactome)
GGT1(1-380) ProteinP19440 (Uniprot-TrEMBL)
GGT1(381-569) ProteinP19440 (Uniprot-TrEMBL)
GGT3P(1-380) ProteinA6NGU5 (Uniprot-TrEMBL)
GGT3P(381-568) ProteinA6NGU5 (Uniprot-TrEMBL)
GGT5(1-387) ProteinP36269 (Uniprot-TrEMBL)
GGT5(388-586) ProteinP36269 (Uniprot-TrEMBL)
GGT6(1-?) ProteinQ6P531 (Uniprot-TrEMBL)
GGT6(?-493) ProteinQ6P531 (Uniprot-TrEMBL)
GGT7(1-472) ProteinQ9UJ14 (Uniprot-TrEMBL)
GGT7(473-662) ProteinQ9UJ14 (Uniprot-TrEMBL)
GSHMetaboliteCHEBI:16856 (ChEBI)
GlyMetaboliteCHEBI:57305 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
L-GluMetaboliteCHEBI:29985 (ChEBI)
MGST trimersComplexR-HSA-176042 (Reactome)
MGST1 ProteinP10620 (Uniprot-TrEMBL)
MGST2 ProteinQ99735 (Uniprot-TrEMBL)
MGST3 ProteinO14880 (Uniprot-TrEMBL)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
unknown NATR-HSA-5490258 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ACY1:Zn2+,ACY3:Zn2+ dimersmim-catalysisR-HSA-5433074 (Reactome)
AFB1R-HSA-156526 (Reactome)
AFB1R-HSA-5423664 (Reactome)
AFB1R-HSA-5423672 (Reactome)
AFB1R-HSA-5423678 (Reactome)
AFBDHDArrowR-HSA-5423656 (Reactome)
AFBDHDR-HSA-5423694 (Reactome)
AFBDHOArrowR-HSA-5423694 (Reactome)
AFBDHOR-HSA-5423637 (Reactome)
AFBDOHArrowR-HSA-5423637 (Reactome)
AFM1ArrowR-HSA-5423678 (Reactome)
AFM1EArrowR-HSA-5423647 (Reactome)
AFM1R-HSA-5423647 (Reactome)
AFNBOArrowR-HSA-5423672 (Reactome)
AFQ1ArrowR-HSA-5423664 (Reactome)
AFXBO,AFNBOR-HSA-5423653 (Reactome)
AFXBO-C,AFNBO-CArrowR-HSA-5433067 (Reactome)
AFXBO-C,AFNBO-CArrowR-HSA-5433074 (Reactome)
AFXBO-C,AFNBO-CArrowR-HSA-5490269 (Reactome)
AFXBO-C,AFNBO-CR-HSA-5433066 (Reactome)
AFXBO-C,AFNBO-CR-HSA-5490269 (Reactome)
AFXBO-CG,AFNBO-CGArrowR-HSA-5433072 (Reactome)
AFXBO-CG,AFNBO-CGR-HSA-5433067 (Reactome)
AFXBO-NAC,AFNBO-NACArrowR-HSA-5433066 (Reactome)
AFXBO-NAC,AFNBO-NACR-HSA-5433074 (Reactome)
AFXBO-SG,AFNBO-SGArrowR-HSA-5423653 (Reactome)
AFXBO-SG,AFNBO-SGArrowR-HSA-5490230 (Reactome)
AFXBO-SG,AFNBO-SGR-HSA-5433072 (Reactome)
AFXBO-SG,AFNBO-SGR-HSA-5490230 (Reactome)
AFXBO:DNAArrowR-HSA-5423632 (Reactome)
AFXBOArrowR-HSA-156526 (Reactome)
AFXBOArrowR-HSA-5423728 (Reactome)
AFXBOR-HSA-5423632 (Reactome)
AFXBOR-HSA-5423656 (Reactome)
AFXBOR-HSA-5423728 (Reactome)
AKR dimersmim-catalysisR-HSA-5423637 (Reactome)
Ac-CoAR-HSA-5433066 (Reactome)
CH3COO-ArrowR-HSA-5433074 (Reactome)
CYP1A2,3A4,3A5,2A13mim-catalysisR-HSA-156526 (Reactome)
CYP1A2,3A4mim-catalysisR-HSA-5423672 (Reactome)
CYP1A2mim-catalysisR-HSA-5423678 (Reactome)
CYP2A13mim-catalysisR-HSA-5423647 (Reactome)
CYP3A4,5mim-catalysisR-HSA-5423664 (Reactome)
CoA-SHArrowR-HSA-5433066 (Reactome)
DNAR-HSA-5423632 (Reactome)
DPEP1,2,3 dimersmim-catalysisR-HSA-5433067 (Reactome)
GGT dimersmim-catalysisR-HSA-5433072 (Reactome)
GSHR-HSA-5423653 (Reactome)
GlyArrowR-HSA-5433067 (Reactome)
H+R-HSA-156526 (Reactome)
H+R-HSA-5423637 (Reactome)
H+R-HSA-5423647 (Reactome)
H+R-HSA-5423664 (Reactome)
H+R-HSA-5423672 (Reactome)
H+R-HSA-5423678 (Reactome)
H2OArrowR-HSA-156526 (Reactome)
H2OArrowR-HSA-5423647 (Reactome)
H2OArrowR-HSA-5423664 (Reactome)
H2OArrowR-HSA-5423672 (Reactome)
H2OArrowR-HSA-5423678 (Reactome)
H2OR-HSA-5423656 (Reactome)
H2OR-HSA-5423694 (Reactome)
H2OR-HSA-5433072 (Reactome)
H2OR-HSA-5433074 (Reactome)
L-GluArrowR-HSA-5433072 (Reactome)
MGST trimersmim-catalysisR-HSA-5423653 (Reactome)
NADP+ArrowR-HSA-156526 (Reactome)
NADP+ArrowR-HSA-5423637 (Reactome)
NADP+ArrowR-HSA-5423647 (Reactome)
NADP+ArrowR-HSA-5423664 (Reactome)
NADP+ArrowR-HSA-5423672 (Reactome)
NADP+ArrowR-HSA-5423678 (Reactome)
NADPHR-HSA-156526 (Reactome)
NADPHR-HSA-5423637 (Reactome)
NADPHR-HSA-5423647 (Reactome)
NADPHR-HSA-5423664 (Reactome)
NADPHR-HSA-5423672 (Reactome)
NADPHR-HSA-5423678 (Reactome)
O2R-HSA-156526 (Reactome)
O2R-HSA-5423647 (Reactome)
O2R-HSA-5423664 (Reactome)
O2R-HSA-5423672 (Reactome)
O2R-HSA-5423678 (Reactome)
R-HSA-156526 (Reactome) 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).
R-HSA-5423632 (Reactome) 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).
R-HSA-5423637 (Reactome) 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).
R-HSA-5423647 (Reactome) 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).
R-HSA-5423653 (Reactome) 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.
R-HSA-5423656 (Reactome) 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).
R-HSA-5423664 (Reactome) 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).
R-HSA-5423672 (Reactome) 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).
R-HSA-5423678 (Reactome) 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.
R-HSA-5423694 (Reactome) 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).
R-HSA-5423728 (Reactome) 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).
R-HSA-5433066 (Reactome) 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).
R-HSA-5433067 (Reactome) 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.
R-HSA-5433072 (Reactome) 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).
R-HSA-5433074 (Reactome) 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.
R-HSA-5490230 (Reactome) 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.
R-HSA-5490269 (Reactome) 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.
unknown NATmim-catalysisR-HSA-5433066 (Reactome)
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