Biosynthesis of Cosmosporasides Reveals the Assembly Line for Fungal Hybrid Terpenoid Saccharides.

Fungal hybrid terpenoid saccharides constitute a new and growing family of natural products with significant biomedical and agricultural activities. One representative family is the cosmosporasides, which feature oxidized terpenoid units and saccharide moieties; however, the assembly line of these building blocks has been elusive. Herein, a cos cluster from Fusarium orthoceras was discovered for the synthesis of cosmosporaside C (1) by genome mining. A UbiA family intramembrane prenyltransferase (UbiA-type PT), a multifunctional cytochrome P450, an α,β-hydrolase, an acetyltransferase, a dimethylallyl transferase (DMAT-type PT) and a glycosyltransferase function cooperatively in the assembly of the scaffold of 1 using primary central metabolites. The absolute configuration at C4, C6 and C7 of 1 was also established. Our work clarifies the unexpected functions of UbiA-type and DMAT-type PTs and provides an example for understanding the synthetic logic of hybrid terpenoid saccharides in fungi.