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 of the most representative families is cosmosporasides, which feature hybrid degree of oxidized terpenoid units and saccharide moieties, however, the assembly line of these building blocks is elusive to date. 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. In addition, the absolute configurations of C-4, C-6 and C-7 of 1 are also established. Our work importantly 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.