Fungal Polyketide-Nonribosomal Peptide Synthetases and Their Associated Natural Products

Fungal hybrid polyketide synthase-nonribosomal peptide synthetases (PKS-NRPSs) significantly expand the diversity and functionalities of polyketide metabolites by fusing diverse polyketide backbones with a range of amino acids of different chemical properties. This gives rise to a plethora of polyketide acyl-aminoacyl chains that are further diversified by the mechanism of release and post-PKS-NRPS processing. Using selected examples from biosynthetic studies, this article provides an overview of the fungal PKS-NRPS biosynthetic logic, with emphasis on the strategies that introduce structural diversity and complexity to PKS-NRPS products. We have divided the common strategies into: (1) variations in polyketide branching and functional group modifications, (2) selection and incorporation of amino acids, (3) release mechanisms, and (4) post-PKS-NRPS cyclization/rearrangement of the polyketide-amino acid backbone. The prospects and challenges of engineering fungal PKS-NRPS hybrids are also discussed.