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Biosynthetic mechanism for antimycotic macrolactam HSAF and mycotoxin fumonisins

Lili Lou, University of Nebraska - Lincoln


Polyketides (PKs) and nonribosomal peptides (NRPs) are secondary metabolites produced by many organisms. Bacteria and fungi can serve as PKs or NPRs production organisms, while plants normally serve as PKs production organisms. PKs and NRPs are two large groups of natural products with remarkable structural diversity and biological activities. The study of the biosynthesis of PKs and NRPs has been one of the most active areas of natural product research. HSAF (heat stable antifungal factor) is a tetramic acid containing antifungal metabolite produced by the biological control agent Lysobacter enzymogenes C3. It exhibits potent inhibitory activities against a wide range of fungal species and has a novel mode of action which involves disrupting the biosynthesis of fungal sphingolipids. Our data shows that there is only a single-module polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) present in the biosynthetic gene cluster although the structure of HSAF suggests multiple PKS modules would be needed in order to synthesize the two separate PK chains. The iterative use of a single-module PKS/NRPS is common in fungi but rare in bacteria. We have also expressed the NRPS module and demonstrated in vitro that it specifically activates L-ornithine and catalyzes the formation of a tetramate product. In addition, we found that the thioesterase (TE) domain, which is located at the end of the assembly line and responsible for the product release to terminate the biosynthesis, possesses unuaual peptide ligase/protease activities. Mycotoxins are toxic secondary metabolites that are produced by certain filamentous fungi. Mycotoxins frequently contaminate food and cause diseases in animals and humans. Fumonisins are polyketide-derived mycotoxins produced by several agriculturally important fungi, such as Fusarium verticillioides . In the biosynthesis of fumonisins, the most intriguing modification of the polyketide chain of fumonisns is tricarballylic esterification of the C-14 and C-15 hydroxyls. Tricarballylic esters of vicinal diol are rare structural features in natural products and important for the fumonisin toxicity. A study of the FUM genes involved in the tricarballylic ester formation will be discussed. An unprecedented polyketide chain release mechanism in the biosynthesis of fumonisins will also be described.

Subject Area


Recommended Citation

Lou, Lili, "Biosynthetic mechanism for antimycotic macrolactam HSAF and mycotoxin fumonisins" (2012). ETD collection for University of Nebraska - Lincoln. AAI3546806.