Investigation of Fungal Iterative Polyketide Synthase Functions Using Partially Assembled Intermediates
Filamentous fungi produce a wide variety of bioactive secondary metabolites, including polyketides and polyketide-nonribosomal peptide hybrids. These compounds are synthesized by the highly-programmed and iterative multifunctional megasynthases: polyketide synthases (PKSs) and polyketide-nonribosomal peptide synthases (PKS-NRPSs). Compared to their well-studied bacterial counterparts, the biosynthetic programming rules utilized by the fungal PKSs remain mostly unknown. To obtain a better understanding of the biosynthetic logic of PKSs and to decipher the relationship between protein sequences and the chemical structures of fungal secondary metabolites, this dissertation will aim at studying one fungal biosynthetic system involving PKSs and probe the enzymatic programming rules in highly reducing PKSs (HR-PKS). Specifically, the biochemistry of the HR-PKS Hpm8 from a tandem fungal iterative PKS (IPKS) system for the formation of the resorcylic acid lactone hypothemycin will be extensively investigated with the help of a series of synthetically-prepared labeled intermediates.