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discounted EARLY registration ends Dec 31, 2014
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discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
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for maintenance.
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
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discounted EARLY registration ends Dec 31, 2014
BioCyc websites down
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MetaCyc Pathway: superpathway of aflatoxin biosynthesis

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: Biosynthesis Secondary Metabolites Biosynthesis
Superpathways

Some taxa known to possess this pathway include ? : Aspergillus flavus , Aspergillus parasiticus

Expected Taxonomic Range: Fungi

Summary:
The mycotoxins sterigmatocystin and dihydrosterigmatocystin are intermediates in the biosynthesis of the B-group and G-group aflatoxins, which constitute the major groups of naturally occurring aflatoxins. The production of aflatoxins by some strains of several Aspergillus species has been extensively studied. However many species, including the model organism Emericella nidulans (previously known as Aspergullus nidulans), produce only sterigmatocystin as a final product (in [Cai08]). Aspergillus parasiticus produces both B- and G-group aflatoxins from sterigmatocystin and dihydrosterigmatocystin, while Aspergillus flavus produces only B-group aflatoxins. The biological role of these mycotoxins in fungi remains unclear (in [Carbone07, Holmes08] and reviewed in [Yabe04]).

Aflatoxins are highly toxic and carcinogenic crop contaminants that create major economic and public health problems worldwide. Much research has been focused on identifying compounds that inhibit aflatoxin biosynthesis. aflatoxin B1 is metabolized by mammalian liver cytochrome P450 enzymes to a mutagenic epoxide that covalently binds to DNA. Its genotoxic mechanism of action has been studied in yeast [Sengstag96, Kaplanski98]. Other species, such as Aspergillus oryzae and Aspergillus sojae, are unable to produce aflatoxins and are used in food fermentation [Chang07].

Most of the aflatoxin biosynthetic genes are clustered in Aspergilli and are positively regulated by gene aflR (in [Carbone07, Price06, Ehrlich05, Yu04, Trail95, Flaherty97] and reviewed in [Yabe04] and [Yu04a]). The enzyme reactions and biosynthetic intermediates in the aflatoxin biosynthetic pathway have been reviewed [Yabe04].

For detailed pathway comments, click on the subpathways listed below. Overall, the aflatoxin biosynthesis pathway contains several cytochrome P450 monooxygenase-catalyzed steps that mediate the major skeletal rearrangements (in [Udwary02]). Monooxygenases are involved in both the biosynthesis and degradation of toxic compounds (in [Keller00]). The pathway is costly in its consumption of NADPH and appears to be dependent on the energy status of the organism. A key desaturation step of the bisfuran ring occurs during the conversion of versicolorin B to versicolorin A. This desaturation is a branch point that separates the biosynthesis of aflatoxins B1 and G1 from aflatoxins B2 and G2. The production of aflatoxin B1 from 8-O-methylsterigmatocystin and aflatoxin B2 from 8-O-methyldihydrosterigmatocystin remarkably appears to involve multiple transformations catalyzed by a single cytochrome P-450 enzyme [Udwary02] and reviewed in [Yabe04]. Aflatoxins are excreted from mycelia and their biosynthetic intermediates accumulate in cells. No aflatoxin export system has yet been identified. The biochemistry of the pathway has been reviewed in detail in [Yabe04]. Strains of Aspergillus flavus are thought to produce only aflatoxins B1 and B2, while strains of Aspergillus parasiticus produce all four major aflatoxins (B1, B2, G1 and G2).

Subpathways: (1'S,5'S)-averufin biosynthesis , versicolorin B biosynthesis , sterigmatocystin biosynthesis , aflatoxins B1 and G1 biosynthesis , aflatoxins B2 and G2 biosynthesis

Credits:
Created 18-Jun-2008 by Fulcher CA , SRI International


References

Cai08: Cai J, Zeng H, Shima Y, Hatabayashi H, Nakagawa H, Ito Y, Adachi Y, Nakajima H, Yabe K (2008). "Involvement of the nadA gene in formation of G-group aflatoxins in Aspergillus parasiticus." Fungal Genet Biol 45(7);1081-93. PMID: 18486503

Carbone07: Carbone I, Ramirez-Prado JH, Jakobek JL, Horn BW (2007). "Gene duplication, modularity and adaptation in the evolution of the aflatoxin gene cluster." BMC Evol Biol 7;111. PMID: 17620135

Chang07: Chang PK, Matsushima K, Takahashi T, Yu J, Abe K, Bhatnagar D, Yuan GF, Koyama Y, Cleveland TE (2007). "Understanding nonaflatoxigenicity of Aspergillus sojae: a windfall of aflatoxin biosynthesis research." Appl Microbiol Biotechnol 76(5);977-84. PMID: 17665189

Ehrlich05: Ehrlich KC, Yu J, Cotty PJ (2005). "Aflatoxin biosynthesis gene clusters and flanking regions." J Appl Microbiol 99(3);518-27. PMID: 16108793

Flaherty97: Flaherty JE, Payne GA (1997). "Overexpression of aflR Leads to Upregulation of Pathway Gene Transcription and Increased Aflatoxin Production in Aspergillus flavus." Appl Environ Microbiol 63(10);3995-4000. PMID: 16535712

Holmes08: Holmes RA, Boston RS, Payne GA (2008). "Diverse inhibitors of aflatoxin biosynthesis." Appl Microbiol Biotechnol 78(4);559-72. PMID: 18246345

Kaplanski98: Kaplanski C, Wild CP, Sengstag C (1998). "Rearrangements in minisatellite sequences induced by aflatoxin B1 in a metabolically competent strain of Saccharomyces cerevisiae." Carcinogenesis 19(9);1673-8. PMID: 9771940

Keller00: Keller NP, Watanabe CM, Kelkar HS, Adams TH, Townsend CA (2000). "Requirement of monooxygenase-mediated steps for sterigmatocystin biosynthesis by Aspergillus nidulans." Appl Environ Microbiol 66(1);359-62. PMID: 10618248

Price06: Price MS, Yu J, Nierman WC, Kim HS, Pritchard B, Jacobus CA, Bhatnagar D, Cleveland TE, Payne GA (2006). "The aflatoxin pathway regulator AflR induces gene transcription inside and outside of the aflatoxin biosynthetic cluster." FEMS Microbiol Lett 255(2);275-9. PMID: 16448506

Sengstag96: Sengstag C, Weibel B, Fasullo M (1996). "Genotoxicity of aflatoxin B1: evidence for a recombination-mediated mechanism in Saccharomyces cerevisiae." Cancer Res 56(23);5457-65. PMID: 8968101

Trail95: Trail F, Mahanti N, Rarick M, Mehigh R, Liang SH, Zhou R, Linz JE (1995). "Physical and transcriptional map of an aflatoxin gene cluster in Aspergillus parasiticus and functional disruption of a gene involved early in the aflatoxin pathway." Appl Environ Microbiol 61(7);2665-73. PMID: 7618880

Udwary02: Udwary DW, Casillas LK, Townsend CA (2002). "Synthesis of 11-hydroxyl O-methylsterigmatocystin and the role of a cytochrome P-450 in the final step of aflatoxin biosynthesis." J Am Chem Soc 124(19);5294-303. PMID: 11996570

Yabe04: Yabe K, Nakajima H (2004). "Enzyme reactions and genes in aflatoxin biosynthesis." Appl Microbiol Biotechnol 64(6);745-55. PMID: 15022028

Yu04: Yu J, Bhatnagar D, Cleveland TE (2004). "Completed sequence of aflatoxin pathway gene cluster in Aspergillus parasiticus." FEBS Lett 564(1-2);126-30. PMID: 15094053

Yu04a: Yu J, Chang PK, Ehrlich KC, Cary JW, Bhatnagar D, Cleveland TE, Payne GA, Linz JE, Woloshuk CP, Bennett JW (2004). "Clustered pathway genes in aflatoxin biosynthesis." Appl Environ Microbiol 70(3);1253-62. PMID: 15006741

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Bhatnagar91: Bhatnagar D, Cleveland TE, Kingston DG (1991). "Enzymological evidence for separate pathways for aflatoxin B1 and B2 biosynthesis." Biochemistry 30(17);4343-50. PMID: 1902378

Byers07: Byers DM, Gong H (2007). "Acyl carrier protein: structure-function relationships in a conserved multifunctional protein family." Biochem Cell Biol 85(6);649-62. PMID: 18059524

Cary06: Cary JW, Ehrlich KC, Bland JM, Montalbano BG (2006). "The aflatoxin biosynthesis cluster gene, aflX, encodes an oxidoreductase involved in conversion of versicolorin A to demethylsterigmatocystin." Appl Environ Microbiol 72(2);1096-101. PMID: 16461654

Chang00: Chang PK, Yu J, Ehrlich KC, Boue SM, Montalbano BG, Bhatnagar D, Cleveland TE (2000). "adhA in Aspergillus parasiticus is involved in conversion of 5'-hydroxyaverantin to averufin." Appl Environ Microbiol 66(11);4715-9. PMID: 11055914

Chang04: Chang PK, Yabe K, Yu J (2004). "The Aspergillus parasiticus estA-encoded esterase converts versiconal hemiacetal acetate to versiconal and versiconol acetate to versiconol in aflatoxin biosynthesis." Appl Environ Microbiol 70(6);3593-9. PMID: 15184162

Chang95: Chang PK, Cary JW, Yu J, Bhatnagar D, Cleveland TE (1995). "The Aspergillus parasiticus polyketide synthase gene pksA, a homolog of Aspergillus nidulans wA, is required for aflatoxin B1 biosynthesis." Mol Gen Genet 248(3);270-7. PMID: 7565588

Crawford06: Crawford JM, Dancy BC, Hill EA, Udwary DW, Townsend CA (2006). "Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase." Proc Natl Acad Sci U S A 103(45);16728-33. PMID: 17071746

Crawford08: Crawford JM, Thomas PM, Scheerer JR, Vagstad AL, Kelleher NL, Townsend CA (2008). "Deconstruction of iterative multidomain polyketide synthase function." Science 320(5873);243-6. PMID: 18403714

Crawford09: Crawford JM, Korman TP, Labonte JW, Vagstad AL, Hill EA, Kamari-Bidkorpeh O, Tsai SC, Townsend CA (2009). "Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization." Nature 461(7267);1139-43. PMID: 19847268

Crawford10: Crawford JM, Townsend CA (2010). "New insights into the formation of fungal aromatic polyketides." Nat Rev Microbiol 8(12);879-89. PMID: 21079635

Ehrlich04: Ehrlich KC, Chang PK, Yu J, Cotty PJ (2004). "Aflatoxin biosynthesis cluster gene cypA is required for G aflatoxin formation." Appl Environ Microbiol 70(11);6518-24. PMID: 15528514

Ehrlich05a: Ehrlich KC, Montalbano B, Boue SM, Bhatnagar D (2005). "An aflatoxin biosynthesis cluster gene encodes a novel oxidase required for conversion of versicolorin a to sterigmatocystin." Appl Environ Microbiol 71(12);8963-5. PMID: 16332900

Ehrlich10: Ehrlich KC, Li P, Scharfenstein L, Chang PK (2010). "HypC, the anthrone oxidase involved in aflatoxin biosynthesis." Appl Environ Microbiol 76(10);3374-7. PMID: 20348292

Feng95: Feng GH, Leonard TJ (1995). "Characterization of the polyketide synthase gene (pksL1) required for aflatoxin biosynthesis in Aspergillus parasiticus." J Bacteriol 177(21);6246-54. PMID: 7592391

Gullestad92: Gullestad L, Forfang K, Simonsen S (1992). "Differential effect of selective beta 1 and nonselective beta-adrenoceptor blockade on epinephrine and atropine response in normal humans." J Cardiovasc Pharmacol 20(6);976-81. PMID: 1282602

Henry05: Henry KM, Townsend CA (2005). "Ordering the reductive and cytochrome P450 oxidative steps in demethylsterigmatocystin formation yields general insights into the biosynthesis of aflatoxin and related fungal metabolites." J Am Chem Soc 127(11);3724-33. PMID: 15771506

Hitchman01: Hitchman TS, Schmidt EW, Trail F, Rarick MD, Linz JE, Townsend CA (2001). "Hexanoate synthase, a specialized type I fatty acid synthase in aflatoxin B1 biosynthesis." Bioorg Chem 29(5);293-307. PMID: 16256699

Kawai84: Kawai K, Nozawa Y, Maebayashi Y, Yamazaki M, Hamasaki T (1984). "Averufin, an anthraquinone mycotoxin possessing a potent uncoupling effect on mitochondrial respiration." Appl Environ Microbiol 47(3);481-3. PMID: 6712217

Keller93: Keller NP, Dischinger HC, Bhatnagar D, Cleveland TE, Ullah AH (1993). "Purification of a 40-kilodalton methyltransferase active in the aflatoxin biosynthetic pathway." Appl Environ Microbiol 59(2);479-84. PMID: 8434913

Korman10: Korman TP, Crawford JM, Labonte JW, Newman AG, Wong J, Townsend CA, Tsai SC (2010). "Structure and function of an iterative polyketide synthase thioesterase domain catalyzing Claisen cyclization in aflatoxin biosynthesis." Proc Natl Acad Sci U S A 107(14);6246-51. PMID: 20332208

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Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Fri Dec 19, 2014, biocyc12.