Mycotoxins polyketides

A considerable number of mycotoxins that show high toxicity to vertebrates and/ or invertebrates are produced by organisms associated with crop plants (Flannigan 1991). There are many known cases of human poisoning caused by such compounds. There are three broad categories of mycotoxins represented here, based on the structures of the intermediates from which these secondary metabolites are derived. They are (1) compounds derived from polyketides, (2) terpenes derived from mevalonic acid, and (3) cyclic peptides and derivatives thereof. 

The main metabohtes produced by Monascus are polyketides formed by the condensation of one acetylcoA with one or more malonylcoAs with a simultaneous decarboxylation as in the case of lipidic synthesis. They consist of the pigments, monacohns, and under certain conditions a mycotoxin. 

C domains can display functions that deviate from typical amide bond formation. Several C domains are postulated to act as ester synthases, catalyzing ester formation instead of amide formation. NRPS modules containing C domains that display this activity are present in the biosynthetic pathways for the kutznerides, cryptophycins, " cereulide, valinomycin, hectochlorin, and beauvericin. Each of these C domains likely utilizes a PCP-bound a-hydroxyl acceptor in the condensation reaction. Another NRPS C domain that catalyzes ester bond formation is involved in the biosynthesis of the polyketide-derived mycotoxins known as the fiimonisins. Du and coworkers have shown that a recombinant PCP-C didomain of an NRPS involved in the biosynthetic pathway of the fnmonisins can catalyze ester bond formation between hydroxyfumonisins and the A-acetylcysteamine thioester of tricarballylic acid, even though PCP-bound tricarballylic acid is not... 

Mycotoxins are, in general, low molecular weight, non-antigenic fungal secondary metabolites formed by way of several metabolic pathways, e.g. the polyketide route (aflatoxins), the terpene route (trichothecenes), the amino acid... 

Phan, C.T. Phenolics and polyketides in carrots. In Mycotoxins and Phytoalexins. Sharma R.P., Salunkhe D.K., eds., CRC Press, Boca Raton, USA 1991. 

Simpson, T. J. 1986. Studies of polyketide chain-assembly processes, mycotoxins and phycotoxins. In "Mycotoxins and Phycotoxins" (P. S. Steyn and R. Vleggaar, eds.), pp. 85-96. Elsevier, Amsterdam, the Netherlands. 

Fusarin C 4 is a mycotoxin produced by a number of Fusarium species. These organisms are often significant pests of cereals. Isotopic labelling studies indicated that it is biosynthesised from a polyketide chain fused to a C4N unit most probably derived from an amino acid. Once again the polyketide moiety is methylated with carbon atoms from SAM (22). 

Natural products represent a diversity of chemical compounds with varied biological activities. Natural products are an important source of novel pharmaceuticals as well as agricultural pesticides (1,2). Natural products are derived from a number of pathways that create basic scaffolds that are further modified by various tailoring enzymes to create the wide diversity of structures that exist in nature. Polyketide synthases are responsible for the synthesis of an array of natural products including antibiotics such as erythromycin in bacteria (3) and mycotoxins such as aflatoxin in fungi (4). Furthermore, in plants they are part of the biosynthetic machinery of flavonoids, phytoalexins, and phenolic lipi (5,6). 

Cyclization of the polycarbonyl chain to form aromatic compounds is a very common biosynthetic process. These aromatic compounds can then undergo various further biosynthetic transformations, including ring cleavage reactions. Some polyketides are pigments of fungi and others are serious mycotoxins and these are described in Chapters 7 and 9, respectively. 

Proctor, R. H., Desjardins, A. E., Planner, R. D., and Hohn, T. M. (1999). A polyketide synthase gene required for biosynthesis of fumonisin mycotoxins in Gibberella fujikuroi mating population A. Fungal Genet. Biol. 27, 100-112. 

Patulin (Figure 42) is a small polyketide-derived mycotoxin, originally isolated as an antibiotic in the 1940 s. It was isolated from fungal strains of Byssochlamys nivea [149] as a FPTase inhibitor. 

KELLER, N.P., BROWN, D., BUTCHKO, R.A.E., FERNANDES, M., KELKAR, H., NESBITT, C., SEGNER, S., BHATNAGAR, D., CLEVELAND, T.E., ADAMS, T.H., A conserved polyketide mycotoxin gene cluster in Aspergillus nidulans, in Molecular Approaches to Food Safety Issues Involving Toxic Microorganisms (J.L. Richard, ed.), Alaken, Fort Collins, Colorado. 1995, pp. 263-277. 

C30H22O12, Mr 574.50, mp. 278 °C, [a]u -830° yellow, hepatotoxic mycotoxin from Penicillium islan-dicum. L. belongs to the bianthraquinones such as, e. g., rugulosin and skyrin. The biosynthesis proceeds on the polyketide pathway. On being fed daily with I mg toxin per 20 g animal, mice develop liver tumors within 6 months. The toxin accumulates in hepatic mitochondria. In the presence of Mg ions L. binds to double- and single-stranded DNA and inhibits the DNA-de-pendent RNA polymerases. L. has antimicrobial and cytotoxic properties and is active against protozoa. Chromosome breaks are induced in cell cultures. 

Mycotoxin from cultures of different Fusarium species, e.g., F. sambucimm and F. oxysporum C28H39NO4, Mr 453.62, prisms, mp. 197 C, [a] -200 (CH3OH). S. inhibits electron transport (complex III) in isolated mitochondria and is structurally related to funiculosin. It shows antifungal activity. S. is of mixed biosynthetic origin (polyketide chain and aromatic amino acid), see tenellin. 

C30H22O12, Mr 574.50, yellow-red crystals, decomp, at 264 °C. A hydroxynaphthoquinone produced by various species of fungi (e. g., Trichophyton, Penicillium, Aspergillus). X. is formed biosynthetically on the polyketide pathway and often occurs together with its precursors (e. g., semi-vioxanthin, vioxanthin, viomel-lein). X. is a mycotoxin, it has antibacterial and insecticidal activities and influences oxidative phosphorylation in rat liver mitochondria. 

Sterigmatocystin (15) is both a carcinogenic hepatotoxin and a biosynthetic precursor to the important mycotoxin, aflatoxin, and, as such, its biosynthesis pathway has been studied quite extensively (607-608). This is purported to begin with a single C20 polyketide unit, which is folded in only one mode to form averufin (103) and then sterigmatocystin (15) (609). The authors provided evidence to support the identity of this compound through the synthesis of a common product from both it and from a... 

Polyketide Compounds from Unusual Starter Units Methylenebisphloroglucinols and Related Compounds Polyketides from Lichens Mycotoxins... 

Animals that consume moldy feeds excrete the estrogenic polyketide mycotoxins zearalenone (51) and zearalenol (52) in milk and milk products (Fig. 5,24). The same compound sometimes is found in beer. Zearalenol and zearalenone are synthesized by Fusarium species these compounds produce sterility and other reproductive problems in livestock (Beier and Nigg, 1992). 

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