Publication

Fungal polyketides are diverse natural products synthesized by iterative polyketide synthases (i-PKSs) and modified by enzymes such as trans-acting enoylreductases (trans-ERs). In this study, we investigated PhiaB and PhomB, trans-ERs involved in the biosynthesis of polyhydroxy polyketides, phialotides, and phomenoic acids. In vitro assays using substrate analogs revealed distinct chain-length preferences. X-ray structural analysis of PhiaB revealed distinct N-terminal, central, and C-terminal regions. The importance of the central region, which possesses a canonical Rossmann fold for cofactor recognition, was further supported by biosynthetic refactoring using a chimeric enzyme. Docking studies revealed key amino acid residues that may be involved in substrate/cofactor recognition. These findings advance our understanding of trans-ER function, providing opportunities for the synthesis of structurally different polyhydroxy polyketides by genetic engineering of polyhydroxy polyketide biosynthesis.