Genome Mining and Comparative Biosynthesis of Meroterpenoids from Two Phylogenetically Distinct Fungi

Abstract Two homologous meroterpenoid gene clusters consisting of contiguous genes encoding polyketide synthase (PKS), prenyltransferase (PT), terpenoid cyclase (TC) and other tailoring enzymes were identified from two phylogenetically distinct fungi through computational analysis. Media optimization guided by reverse‐transcription PCR (RT‐PCR) enabled two strains to produce eight new and two known meroterpenoids ( 1 – 10 ). Using gene inactivation, heterologous expression, and biochemical analyses, we revealed a new polyketide‐terpenoid assembly line that utilizes a pair of PKSs to synthesize 2,4‐dihydroxy‐6‐alkylbenzoic acid, followed by oxidative decarboxylation, farnesyl transfer, and terpene cyclization to construct the meroterpenoid scaffold. In addition, two of the isolated meroterpenoids ( 3 and 17 d ) showed immunosuppressive bioactivity. Our work reveals a new strategy for meroterpenoid natural products discovery, and reveals the biosynthetic pathway for compounds 1 – 10 .