Biosynthesis of O-Prenylated Chaetophenols Triggers Nonenzymatic Pathways toward Structural Diversity.

Chaetophenols (CPs) are structurally diverse aromatic polyketides that have been isolated from Chaetomium fungi. They exhibit two distinct prenylation patterns that have key roles in generating chemical diversity and controlling the dimerization modes. We investigated the mechanism of CP biogenesis through heterologous expression and in vitro assays, revealing that CP structural diversification involves both enzymatic and nonenzymatic steps. In particular, C-prenylated CPs are generated nonenzymatically from enzymatically synthesized O-prenylated CPs. We also discovered a nonenzymatic conversion pathway that forms a chaetoline skeleton. These findings highlight a unique strategy for the structural diversification of fungal aromatic polyketides through enzymatic and nonenzymatic chemistries.