Recent advancements in the biosynthetic mechanisms for polyketide‐derived mycotoxins

Polyketides (PKs) are a large group of natural products produced by microorganisms and plants. They are biopolymers of acetate and other short carboxylates and are biosynthesized by multifunctional enzymes called polyketide synthases (PKSs). This review discusses the biosynthesis of four toxic PK, aflatoxins, fumonisins, ochratoxins (OTs), and zearalenone. These metabolites are structurally diverse and differ in their mechanisms of toxicity. However, they are all of concern in food safety and agriculture because of their toxic properties and their frequent accumulation in crops used for food and feed. The focus is on the recent advancements in the understanding of the molecular mechanisms for the biosynthesis of these mycotoxins. Several of the mycotoxin PKSs have been genetically and biochemically studied while other PKSs remain to be investigated. Multiple post‐PKS modifications are often required for the maturation of the mycotoxins. Many of these modification steps for aflatoxins and fumonisins are well established while the post‐PKS modifications for zearalenone and OTs remain to be biochemically characterized. More efforts are needed to completely illustrate the biosynthetic mechanisms for this important group of PKs. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 764–776, 2010.

[1]  J. Richard,et al.  Some major mycotoxins and their mycotoxicoses--an overview. , 2007, International journal of food microbiology.

[2]  K. Zaleta-Rivera,et al.  Biosynthesis of sphinganine-analog mycotoxins , 2008, Journal of Industrial Microbiology & Biotechnology.

[3]  M. Busman,et al.  The Fusarium verticillioides FUM Gene Cluster Encodes a Zn(II)2Cys6 Protein That Affects FUM Gene Expression and Fumonisin Production , 2007, Eukaryotic Cell.

[4]  K. Zaleta-Rivera,et al.  A bidomain nonribosomal peptide synthetase encoded by FUM14 catalyzes the formation of tricarballylic esters in the biosynthesis of fumonisins. , 2006, Biochemistry.

[5]  Xing-Cong Li,et al.  Production of dihydroisocoumarins in Fusarium verticillioides by swapping ketosynthase domain of the fungal iterative polyketide synthase Fum1p with that of lovastatin diketide synthase. , 2007, Journal of the American Chemical Society.

[6]  Kenji Watanabe,et al.  Biosynthesis of lovastatin analogs with a broadly specific acyltransferase. , 2006, Chemistry & biology.

[7]  Jeong-Ah Seo,et al.  Characterization of four clustered and coregulated genes associated with fumonisin biosynthesis in Fusarium verticillioides. , 2001, Fungal genetics and biology : FG & B.

[8]  A. Dobson,et al.  Molecular biology of mycotoxin biosynthesis. , 1999, FEMS microbiology letters.

[9]  L. Du,et al.  Fumonisin level in corn-based food and feed from Linxian County, a high-risk area for esophageal cancer in China , 2008 .

[10]  J. O'callaghan,et al.  A polyketide synthase gene required for ochratoxin A biosynthesis in Aspergillus ochraceus. , 2003, Microbiology.

[11]  L. Du,et al.  Fum3p, a 2-Ketoglutarate-Dependent Dioxygenase Required for C-5 Hydroxylation of Fumonisins in Fusarium verticillioides , 2004, Applied and Environmental Microbiology.

[12]  F. Chu,et al.  Simultaneous occurrence of fumonisin B1 and other mycotoxins in moldy corn collected from the People's Republic of China in regions with high incidences of esophageal cancer , 1994, Applied and environmental microbiology.

[13]  R. Proctor,et al.  Molecular biology of Fusarium mycotoxins. , 2007, International journal of food microbiology.

[14]  Daren W Brown,et al.  Functional Analysis of the Polyketide Synthase Genes in the Filamentous Fungus Gibberella zeae (Anamorph Fusarium graminearum) , 2005, Eukaryotic Cell.

[15]  John E. Linz,et al.  Function of Native OmtA In Vivo and Expression and Distribution of This Protein in Colonies of Aspergillus parasiticus , 2002, Applied and Environmental Microbiology.

[16]  P. Hamilton,et al.  Bioconversion of alpha-[14C]zearalenol and beta-[14C]zearalenol into [14C]zearalenone by Fusarium roseum 'Gibbosum' , 1984, Applied and environmental microbiology.

[17]  P. Khadikar,et al.  Biosynthesis of zearalenone: a simple and efficient method to incorporate [13C]acetate label by using solid cultures , 1989, Applied and environmental microbiology.

[18]  S. Missmer,et al.  Fumonisins disrupt sphingolipid metabolism, folate transport, and neural tube development in embryo culture and in vivo: a potential risk factor for human neural tube defects among populations consuming fumonisin-contaminated maize. , 2004, The Journal of nutrition.

[19]  L. Du,et al.  Developing a genetic system for functional manipulations of FUM1, a polyketide synthase gene for the biosynthesis of fumonisins in Fusarium verticillioides. , 2005, FEMS microbiology letters.

[20]  Marika Jestoi,et al.  Emerging Fusarium -Mycotoxins Fusaproliferin, Beauvericin, Enniatins, And Moniliformin—A Review , 2008, Critical reviews in food science and nutrition.

[21]  Daniel W. Udwary,et al.  Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase , 2006, Proceedings of the National Academy of Sciences.

[22]  R. Proctor,et al.  FUM13 encodes a short chain dehydrogenase/reductase required for C-3 carbonyl reduction during fumonisin biosynthesis in Gibberella moniliformis. , 2003, Journal of agricultural and food chemistry.

[23]  C. Woloshuk,et al.  Fck1, a C-type cyclin-dependent kinase, interacts with Fcc1 to regulate development and secondary metabolism in Fusarium verticillioides. , 2006, Fungal genetics and biology : FG & B.

[24]  H. Nakajima,et al.  Enzyme reactions and genes in aflatoxin biosynthesis , 2004, Applied Microbiology and Biotechnology.

[25]  T. Hamasaki,et al.  Purification and Characterization ofO-Methyltransferase I Involved in Conversion of Demethylsterigmatocystin to Sterigmatocystin and of Dihydrodemethylsterigmatocystin to Dihydrosterigmatocystin during Aflatoxin Biosynthesis , 1998, Applied and Environmental Microbiology.

[26]  L. Du,et al.  Functional complementation of fumonisin biosynthesis in FUM1-disrupted fusarium verticillioides by the AAL-toxin polyketide synthase gene ALT1 from Alternaria alternata f. sp. Lycopersici. , 2008, Journal of natural products.

[27]  J. Flaherty,et al.  PAC1, a pH-Regulatory Gene from Fusarium verticillioides , 2003, Applied and Environmental Microbiology.

[28]  J. Frisvad,et al.  Review of secondary metabolites and mycotoxins from the Aspergillus niger group , 2009, Analytical and bioanalytical chemistry.

[29]  R. A. Butchko,et al.  Deletion analysis of FUM genes involved in tricarballylic ester formation during fumonisin biosynthesis. , 2006, Journal of agricultural and food chemistry.

[30]  A. Atoui,et al.  Aspergillus westerdijkiae polyketide synthase gene "aoks1" is involved in the biosynthesis of ochratoxin A. , 2009, Fungal genetics and biology : FG & B.

[31]  James L. Baker,et al.  Ochratoxins: A global perspective , 2006, Mycopathologia.

[32]  C. Woloshuk,et al.  ord1, an oxidoreductase gene responsible for conversion of O-methylsterigmatocystin to aflatoxin in Aspergillus flavus , 1997, Applied and environmental microbiology.

[33]  W. Shim,et al.  Regulation of Fumonisin B1 Biosynthesis and Conidiation in Fusarium verticillioides by a Cyclin-Like (C-Type) Gene, FCC1 , 2001, Applied and Environmental Microbiology.

[34]  N. Kelleher,et al.  Deconstruction of Iterative Multidomain Polyketide Synthase Function , 2008, Science.

[35]  H. Nakagawa,et al.  Involvement of the nadA gene in formation of G-group aflatoxins in Aspergillus parasiticus. , 2008, Fungal genetics and biology : FG & B.

[36]  Ge Yang,et al.  A polyketide synthase is required for fungal virulence and production of the polyketide T-toxin. , 1996, The Plant cell.

[37]  Y. Ando,et al.  Biosynthetic relationship among aflatoxins B1, B2, G1, and G2 , 1988, Applied and environmental microbiology.

[38]  Daniel W. Udwary,et al.  A method for prediction of the locations of linker regions within large multifunctional proteins, and application to a type I polyketide synthase. , 2002, Journal of molecular biology.

[39]  D. Bhatnagar,et al.  Molecular genetic analysis and regulation of aflatoxin biosynthesis , 2003, Applied Microbiology and Biotechnology.

[40]  A. Dobson,et al.  Characterisation of a pks gene which is expressed during ochratoxin A production by Aspergillus carbonarius. , 2009, International journal of food microbiology.

[41]  T. Utterback,et al.  Comparative analysis of 87,000 expressed sequence tags from the fumonisin-producing fungus Fusarium verticillioides. , 2005, Fungal genetics and biology : FG & B.

[42]  K. Ehrlich,et al.  Are the Genes nadA and norB Involved in Formation of Aflatoxin G1? , 2008, International journal of molecular sciences.

[43]  J. Flaherty,et al.  Regulation of Fumonisin Biosynthesis in Fusarium verticillioides by a Zinc Binuclear Cluster-Type Gene, ZFR1 , 2004, Applied and Environmental Microbiology.

[44]  M. Stob,et al.  Isolation of an Anabolic, Uterotrophic Compound from Corn infected with Gibberella zeae , 1962, Nature.

[45]  T. Hamasaki,et al.  Enzymatic Formation of G-Group Aflatoxins and Biosynthetic Relationship between G- and B-Group Aflatoxins , 1999, Applied and Environmental Microbiology.

[46]  J. Frisvad,et al.  Isolation and NMR characterization of fumonisin B2 and a new fumonisin B6 from Aspergillus niger. , 2010, Journal of agricultural and food chemistry.

[47]  J. Vederas,et al.  Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. , 1999, Science.

[48]  R. Cox,et al.  Polyketides, proteins and genes in fungi: programmed nano-machines begin to reveal their secrets. , 2007, Organic & biomolecular chemistry.

[49]  R. Proctor,et al.  A polyketide synthase gene required for biosynthesis of fumonisin mycotoxins in Gibberella fujikuroi mating population A. , 1999, Fungal genetics and biology : FG & B.

[50]  W. Marasas,et al.  Discovery and occurrence of the fumonisins: a historical perspective. , 2001, Environmental health perspectives.

[51]  S. Baker,et al.  Two polyketide synthase-encoding genes are required for biosynthesis of the polyketide virulence factor, T-toxin, by Cochliobolus heterostrophus. , 2006, Molecular plant-microbe interactions : MPMI.

[52]  A. Logrieco,et al.  Fumonisin B2 production by Aspergillus niger from grapes and natural occurrence in must , 2009, Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment.

[53]  J. Ma,et al.  The fumonisin B1 content in corn from North China, a high-risk area of esophageal cancer. , 2000, Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer.

[54]  J. Tuite,et al.  Zearalenone production by Fusarium species. , 1970, Applied microbiology.

[55]  J. Staunton,et al.  Polyketide biosynthesis: a millennium review. , 2001, Natural product reports.

[56]  P. F. Ross,et al.  Fumonisin mycotoxins and equine leukoencephalomalacia. , 1991, Journal of the American Veterinary Medical Association.

[57]  N. Keller,et al.  Metabolic pathway gene clusters in filamentous fungi. , 1997, Fungal genetics and biology : FG & B.

[58]  K. Hendricks.  Fumonisins and neural tube defects in South Texas. , 1999, Epidemiology.

[59]  W. Marasas,et al.  Fumonisins: their implications for human and animal health. , 1995, Natural toxins.

[60]  D. Hopwood,et al.  Genetic Contributions to Understanding Polyketide Synthases. , 1997, Chemical reviews.

[61]  G. Payne,et al.  Genetic regulation of aflatoxin biosynthesis: from gene to genome. , 2009, Fungal genetics and biology : FG & B.

[62]  L. Du,et al.  A PLP-dependent polyketide chain releasing mechanism in the biosynthesis of mycotoxin fumonisins in Fusarium verticillioides. , 2009, Journal of the American Chemical Society.

[63]  T. Hamasaki,et al.  Stereochemistry during aflatoxin biosynthesis: cyclase reaction in the conversion of versiconal to versicolorin B and racemization of versiconal hemiacetal acetate , 1993, Applied and environmental microbiology.

[64]  C. Townsend,et al.  Enzymology and Molecular Biology of Aflatoxin Biosynthesis. , 1997, Chemical reviews.

[65]  G. Payne,et al.  Genetic and molecular analysis of aflatoxin biosynthesis. , 1999, Fungal genetics and biology : FG & B.

[66]  W. Haschek,et al.  Fumonisin toxicosis in swine: an overview of porcine pulmonary edema and current perspectives. , 2001, Environmental health perspectives.

[67]  N. Keller,et al.  Sequence‐specific binding by Aspergillus nidulans AflR, a C6 zinc cluster protein regulating mycotoxin biosynthesis , 1998, Molecular microbiology.

[68]  M. Busman,et al.  FvVE1 regulates biosynthesis of the mycotoxins fumonisins and fusarins in Fusarium verticillioides. , 2009, Journal of agricultural and food chemistry.

[69]  R. Plattner,et al.  Fumonisins, mycotoxins produced by fusarium species: biology, chemistry, and significance. , 1993, Annual review of phytopathology.

[70]  B. Hammock,et al.  Multiple Epoxide Hydrolases in Alternaria alternata f. sp. lycopersici and Their Relationship to Medium Composition and Host-Specific Toxin Production , 1999, Applied and Environmental Microbiology.

[71]  W. Marasas,et al.  The implications of naturally occurring levels of fumonisins in corn for human and animal health , 1992, Mycopathologia.

[72]  P. Mantle,et al.  Biosynthesis of ochratoxins by Aspergillus ochraceus. , 2001, Phytochemistry.

[73]  G. Payne,et al.  Cloning of the afl-2 gene involved in aflatoxin biosynthesis from Aspergillus flavus , 1993, Applied and environmental microbiology.

[74]  D. Ramljak,et al.  Fumonisin-induced hepatocarcinogenesis: mechanisms related to cancer initiation and promotion. , 2001, Environmental health perspectives.

[75]  L. Bullerman.  Occurrence of Fusarium and fumonisins on food grains and in foods. , 1996, Advances in experimental medicine and biology.

[76]  T. Shinozawa,et al.  Participation in aflatoxin biosynthesis by a reductase enzyme encoded by vrdA gene outside the aflatoxin gene cluster. , 2009, Fungal genetics and biology : FG & B.

[77]  John P. Rheeder,et al.  Production of Fumonisin Analogs by Fusarium Species , 2002, Applied and Environmental Microbiology.

[78]  B. Lin,et al.  Purification and properties of versiconal cyclase from Aspergillus parasiticus. , 1992, Archives of biochemistry and biophysics.

[79]  C. Townsend,et al.  Initial characterization of a type I fatty acid synthase and polyketide synthase multienzyme complex NorS in the biosynthesis of aflatoxin B(1). , 2002, Chemistry & biology.

[80]  J. Frisvad,et al.  Production of Fumonisin B2 and B4 by Aspergillus niger on grapes and raisins. , 2010, Journal of agricultural and food chemistry.

[81]  P. Scott,et al.  Risk assessment of the mycotoxin zearalenone. , 1987, Regulatory toxicology and pharmacology : RTP.

[82]  Jason W. Labonte,et al.  Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization , 2009, Nature.

[83]  M. Busman,et al.  Fumonisin production in the maize pathogen Fusarium verticillioides: genetic basis of naturally occurring chemical variation. , 2006, Journal of agricultural and food chemistry.

[84]  G. Payne,et al.  Genetics and physiology of aflatoxin biosynthesis. , 1998, Annual review of phytopathology.

[85]  Kap-Hoon Han,et al.  Two different polyketide synthase genes are required for synthesis of zearalenone in Gibberella zeae , 2005, Molecular microbiology.

[86]  L. Du,et al.  Determining the biosynthetic sequence in the early steps of the fumonisin pathway by use of three gene-disruption mutants of Fusarium verticillioides. , 2004, Journal of agricultural and food chemistry.

[87]  J. Frisvad,et al.  Fumonisin B2 production by Aspergillus niger. , 2007, Journal of agricultural and food chemistry.

[88]  L. Du,et al.  PKS and NRPS release mechanisms. , 2010, Natural product reports.

[89]  L. Du,et al.  Direct evidence for the function of FUM13 in 3-ketoreduction of mycotoxin fumonisins in Fusarium verticillioides. , 2005, Journal of agricultural and food chemistry.

[90]  R. Geisen,et al.  Cloning a part of the ochratoxin A biosynthetic gene cluster of Penicillium nordicum and characterization of the ochratoxin polyketide synthase gene. , 2005, Systematic and applied microbiology.

[91]  C. Townsend,et al.  Synthetic Strategy of Nonreducing Iterative Polyketide Synthases and the Origin of the Classical “Starter‐Unit Effect” , 2008, Chembiochem : a European journal of chemical biology.

[92]  K. R. Koch,et al.  Natural occurrence of some Fusarium mycotoxins in corn from low and high esophageal cancer prevalence areas of the Transkei, Southern Africa , 1990 .

[93]  Jiujiang Yu,et al.  Characterization of the Critical Amino Acids of anAspergillus parasiticus Cytochrome P-450 Monooxygenase Encoded by ordA That Is Involved in the Biosynthesis of Aflatoxins B1, G1, B2, and G2 , 1998, Applied and Environmental Microbiology.

[94]  Y. Ando,et al.  Desaturase Activity in the Branching Step between Aflatoxins B1 and G1 and Aflatoxins B2 and G2 , 1991 .

[95]  S. Bräse,et al.  Chemistry and biology of mycotoxins and related fungal metabolites. , 2009, Chemical reviews.

[96]  S. Marín,et al.  Ecophysiology of ochratoxigenic Aspergillus ochraceus and Penicillium verrucosum isolates. Predictive models for fungal spoilage prevention – a review , 2006, Food additives and contaminants.

[97]  R. W. Beaver,et al.  Fumonisin Toxicosis in Swine: Clinical and Pathologic Findings , 1993, Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc.

[98]  J. Richard,et al.  Worldwide occurrence of mycotoxins in commodities, feeds and feed ingredients , 2007 .

[99]  Yi Tang,et al.  A thioesterase from an iterative fungal polyketide synthase shows macrocyclization and cross coupling activity and may play a role in controlling iterative cycling through product offloading. , 2009, Biochemistry.

[100]  Kenji Watanabe,et al.  A polyketide macrolactone synthase from the filamentous fungus Gibberella zeae , 2008, Proceedings of the National Academy of Sciences.

[101]  A. Hocking,et al.  Fungi and mycotoxins in vineyards and grape products. , 2007, International journal of food microbiology.

[102]  John E. Linz,et al.  Clustered Pathway Genes in Aflatoxin Biosynthesis , 2004, Applied and Environmental Microbiology.

[103]  H. Giese,et al.  The PKS4 Gene of Fusarium graminearum Is Essential for Zearalenone Production , 2006, Applied and Environmental Microbiology.

[104]  F. Trail,et al.  Characterization of Two Polyketide Synthase Genes Involved in Zearalenone Biosynthesis in Gibberella zeae , 2006, Applied and Environmental Microbiology.

[105]  John E. Linz,et al.  Isolation and characterization of a gene from Aspergillus parasiticus associated with the conversion of versicolorin A to sterigmatocystin in aflatoxin biosynthesis , 1992, Applied and environmental microbiology.

[106]  Daren W Brown,et al.  Co-expression of 15 contiguous genes delineates a fumonisin biosynthetic gene cluster in Gibberella moniliformis. , 2003, Fungal genetics and biology : FG & B.

[107]  John E. Linz,et al.  Characterization of the function of the ver-1A and ver-1B genes, involved in aflatoxin biosynthesis in Aspergillus parasiticus , 1996, Applied and environmental microbiology.