Activation of a Silent Polyketide Synthase SlPKS4 Encoding the C-Methylated Isocoumarin in a Marine-Derived Fungus HDN13-430

Coumarins, isocoumarins and their derivatives are polyketides abundant in fungal metabolites. Although they were first discovered over 50 years ago, the biosynthetic process is still not entirely understood. Herein, we report the activation of a silent nonreducing polyketide synthase that encodes a C-methylated isocoumarin, similanpyrone B (), in a marine-derived fungus HDN13-430 by heterologous expression. Feeding studies revealed the host enzymes can change into its hydroxylated derivatives pestapyrone A (). Compounds and showed moderate radical scavenging activities with ED values of 67.4 µM and 104.2 µM. Our discovery fills the gap in the enzymatic elucidation of naturally occurring C-methylated isocoumarin derivatives.