Polyketides aflatoxins

Figure 2.1 Predicted pattern in the biosynthesis of polyketide aflatoxin B1.

Previous studies have determined that aflatoxins are biosynthesized by the polyketide metabolic pathway and are considered secondary metabolites b ause... 

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... 

Chang P-K, Cary JW, Yu J, Bhatnagar D, Cleveland TE The Aspergillus parasiticus polyketide synthase gene pksA, a homolog of Aspergillus nidulans wA, is required for aflatoxin Bj biosynthesis. Mol Gen Genetics 1995 248 270-277. 

Watanabe CMH, Townsend CA. Initial characterisation of a type 1 fatty acid synthase and polyketide synthase multienzyme complex NorS in the biosynthesis of aflatoxin Bi. Chem. Biol. 2002 9 981-988. 

Structurally complex fused ring flm polyketides studied in this manner include the potent carcinogen aflatoxin Bi (7/ and its precursors averufin (8) and sterigmatocystin (9) (Scheme 4). The resulting couplings were consistent with... 

The relationship of 13C acetate and averufin (i60)183 and very detailed 13C nuclear magnetic resonance enrichment studies of the abovementioned intermediates have recently led Steyn and co-workers184-187 to conclude187 that a biosynthetic pathway starting with polyketide (161), going through averufin (160), versicolorin A (162), and sterigmatocystin (30), eventually results in aflatoxin Bj (i). 

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). 

Unlike primary metabolites, the genes that regulate the formation of the enzymes of seeondary metaboUte biosynthesis are often clustered. In several eases the loei of these genes have been determined. This has considerable sig-nifieanee in the control of secondary metabolite biosynthesis. The genes that eode for several important polyketide pathways such as those leading to the aflatoxins and the statins have been identified. Similar work has also been reported for penicillin biosynthesis and some non-ribosomal peptides as well as terpenoid pathways such as that leading to the gibberellins. 

Other medically important polyketides include the antibiotics doxorubicin (14-hydroxydaunomycin Fig. 5-23), rifamycin (Box 28-and the antifimgal pimaricin, griseofulvin, and amphotericin (Fig. 21-10), the HMG-CoA reductase inhibitor lovastatin, the 2-butanyl-4-methylthreonine of cyclosporin A (Box 9-F), and other immunosuppressants such as rapamycin. Many characteristic plant products, including stilbenes and chalcones (Box 21-E), are polyketides. A variety of different polyketides serve as phytoalexins. Some such as aflatoxin are dangerous toxins. Ants and ladybird beetles make toxic polyamine alkaloids using a polyketide pathway. ... 

WATANABE, C.M.H., WILSON, D., LINZ, J.E., TOWNSEND, C.A., Demonstration of the catal)rtic roles and evidence for the physical association of t)T)eI fatty acid synthase and a polyketide synthase in the biosynthesis of aflatoxin Bl, Chem. Biol., 1996, 3,463-469. 

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