MetaCyc Pathway: versicolorin B biosynthesis

Pathway diagram: versicolorin B biosynthesis

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

Superclasses: Biosynthesis Secondary Metabolites Biosynthesis

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

Expected Taxonomic Range: Fungi

General Background

Versicolorin B is an intermediate in the biosynthesis of the mycotoxin sterigmatocystin. 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 in detail [Yabe04]. See MetaCyc pathways (1'S,5'S)-averufin biosynthesis, sterigmatocystin biosynthesis, aflatoxins B1 and G1 biosynthesis, aflatoxins B2 and G2 biosynthesis and superpathway of aflatoxin biosynthesis.

About This Pathway

The conversion of (1'S,5'S)-averufin to versicolorin B appears to involve a main pathway and a side pathway. These form a metabolic grid, or network thought to be regulated by NADPH levels in the cell [Yabe03, Yabe91] . In the main pathway, a stereospecific monooxygenase converts (1'S,5'S)-averufin to hydroxyversicolorone, followed by another monooxygenase that converts this compound to versiconal hemiacetal acetate. At least one cytosolic esterase converts versiconal hemiacetal acetate to versiconal. Under physiological conditions a cyclase stereospecific for the (2'S) configuration of versiconal converts it to the (1'R,2'S) configuration of versicolorin B. The substrates hydroxyversicolorone, versiconal hemiacetal acetate and versiconal are probably racemic. Under physiological conditions the (2'R) configuration of versiconal spontaneously forms the (2'S) configuration, resulting in production of optically pure (1'R,2'S) configuration of versicolorin B by the cyclase in the pathway. This compound determines the (1'R,2'S)-bisfuran configuration of versicolorin A, sterigmatocystin and the aflatoxins [Yabe93]. In the side pathway, a reductase/dehydrogenase can utilize hydroxyversicolorone, versiconal hemiacetal acetate and versiconal as substrates, the products of which are also substrates for the main pathway enzymes. Reviewed in detail in [Yabe04].

versicolorin B is a branch point in the pathway. In one branch it can be converted to versicolorin A and subsequently to sterigmatocystin, aflatoxin B1 and aflatoxin G1. In the other branch it can be converted directly to dihydrosterigmatocystin by a series of uncharacterized reactions and then to aflatoxin B2 and aflatoxin G2 (reviewed in detail in [Yabe04]). This is indicated by the pathway links.

Superpathways: superpathway of aflatoxin biosynthesis

Created 13-Jun-2008 by Fulcher CA , SRI International


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

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

Yabe03: Yabe K, Chihaya N, Hamamatsu S, Sakuno E, Hamasaki T, Nakajima H, Bennett JW (2003). "Enzymatic conversion of averufin to hydroxyversicolorone and elucidation of a novel metabolic grid involved in aflatoxin biosynthesis." Appl Environ Microbiol 69(1);66-73. PMID: 12513978

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

Yabe91: Yabe K, Ando Y, Hamasaki T (1991). "A metabolic grid among versiconal hemiacetal acetate, versiconol acetate, versiconol and versiconal during aflatoxin biosynthesis." J Gen Microbiol 137(10);2469-75. PMID: 1770361

Yabe93: Yabe K, Hamasaki T (1993). "Stereochemistry during aflatoxin biosynthesis: cyclase reaction in the conversion of versiconal to versicolorin B and racemization of versiconal hemiacetal acetate." Appl Environ Microbiol 59(8);2493-500. PMID: 8368837

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

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

Kusumoto96: Kusumoto K, Hsieh DP (1996). "Purification and characterization of the esterases involved in aflatoxin biosynthesis in Aspergillus parasiticus." Can J Microbiol 42(8);804-10. PMID: 8776851

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Lin92: Lin BK, Anderson JA (1992). "Purification and properties of versiconal cyclase from Aspergillus parasiticus." Arch Biochem Biophys 293(1);67-70. PMID: 1731640

Matsushima94: Matsushima KI, Ando Y, Hamasaki T, Yabe K (1994). "Purification and Characterization of Two Versiconal Hemiacetal Acetate Reductases Involved in Aflatoxin Biosynthesis." Appl Environ Microbiol 60(7);2561-2567. PMID: 16349333

McGuire96: McGuire SM, Silva JC, Casillas EG, Townsend CA (1996). "Purification and characterization of versicolorin B synthase from Aspergillus parasiticus. Catalysis of the stereodifferentiating cyclization in aflatoxin biosynthesis essential to DNA interaction." Biochemistry 35(35);11470-86. PMID: 8784203

Sakuno05: Sakuno E, Wen Y, Hatabayashi H, Arai H, Aoki C, Yabe K, Nakajima H (2005). "Aspergillus parasiticus cyclase catalyzes two dehydration steps in aflatoxin biosynthesis." Appl Environ Microbiol 71(6);2999-3006. PMID: 15932995

Shima09: Shima Y, Shiina M, Shinozawa T, Ito Y, Nakajima H, Adachi Y, Yabe K (2009). "Participation in aflatoxin biosynthesis by a reductase enzyme encoded by vrdA gene outside the aflatoxin gene cluster." Fungal Genet Biol 46(3);221-31. PMID: 19211038

Silva96: Silva JC, Minto RE, Barry CE, Holland KA, Townsend CA (1996). "Isolation and characterization of the versicolorin B synthase gene from Aspergillus parasiticus. Expansion of the aflatoxin b1 biosynthetic gene cluster." J Biol Chem 271(23);13600-8. PMID: 8662689

Silva97: Silva JC, Townsend CA (1997). "Heterologous expression, isolation, and characterization of versicolorin B synthase from Aspergillus parasiticus. A key enzyme in the aflatoxin B1 biosynthetic pathway." J Biol Chem 272(2);804-13. PMID: 8995367

Wen05: Wen Y, Hatabayashi H, Arai H, Kitamoto HK, Yabe K (2005). "Function of the cypX and moxY genes in aflatoxin biosynthesis in Aspergillus parasiticus." Appl Environ Microbiol 71(6);3192-8. PMID: 15933021

Yu00: Yu J, Chang PK, Bhatnagar D, Cleveland TE (2000). "Genes encoding cytochrome P450 and monooxygenase enzymes define one end of the aflatoxin pathway gene cluster in Aspergillus parasiticus." Appl Microbiol Biotechnol 53(5);583-90. PMID: 10855719

Yu02: Yu J, Chang PK, Bhatnagar D, Cleveland TE (2002). "Cloning and functional expression of an esterase gene in Aspergillus parasitcus." Mycopathologia 156(3);227-34. PMID: 12749588

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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