Production of dihydroisocoumarins in Fusarium verticillioides by swapping ketosynthase domain of the fungal iterative polyketide synthase Fum1p with that of lovastatin diketide synthase

Filamentous fungi are rich in polyketide synthase (PKS) genes. However, the polyketide products synthesized by the PKS remain largely unexplored. Even less is known about the mechanism by which the fungal PKS controls the structure of the products. Using a genetic system that allows specific and functional changes of the catalytic domains of FUM1, which is a PKS gene responsible for the biosynthesis of the highly reduced, linear 18-carbon polyketide chain of mycotoxin fumonisins in Fusarium verticillioides, we obtained fungal mutants containing a chimeric FUM1, in which the ketosynthase domain had been replaced by that of lovastatin diketide synthase gene. The mutants produced dihydroisocoumarins, which are known to have antimalarial, antifungal, and antituberculosis activities and had never been isolated from a Fusarium species. This work represents the first successful genetic manipulation of an iterative polyketide synthase gene to produce new, biologically active metabolites in a filamentous fungus. T...