Production of non-natural 5-methylorsellinate-derived meroterpenoids in .

Fungal meroterpenoids are diverse structurally intriguing molecules with various biological properties. One large group within this compound class is derived from the aromatic precursor 3,5-dimethylorsellinic acid (DMOA). In this study, we constructed engineered metabolic pathways in the fungus to expand the molecular diversity of meroterpenoids. We employed the 5-methylorsellinic acid (5-MOA) synthase FncE and three additional biosynthetic enzymes for the formation of (6,10')-epoxyfarnesyl-5-MOA methyl ester, which served as a non-native substrate for four terpene cyclases from DMOA-derived meroterpenoid pathways. As a result, we successfully generated six unnatural 5-MOA-derived meroterpenoid species, demonstrating the effectiveness of our approach in the generation of structural analogues of meroterpenoids.