If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Biosynthesis → Secondary Metabolites Biosynthesis|
Expected Taxonomic Range: Fungi
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).
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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
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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
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
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
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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
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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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