Terpenoid balance in unveiled by heterologous squalene synthase expression.

Filamentous fungi produce numerous uncharacterized natural products (NPs) that are often challenging to characterize due to cryptic expression in laboratory conditions. Previously, we have successfully isolated novel NPs by expressing fungal artificial chromosomes (FACs) from a variety of fungal species into . Here, we demonstrate a new twist to FAC utility wherein heterologous expression of a FAC in altered endogenous terpene biosynthetic pathways. In contrast to wildtype, the FAC transformant produced increased levels of squalene and aspernidine type compounds, including three new nidulenes (-, ), and lost nearly all ability to synthesize the major characteristic terpene, austinol. Deletion of a squalene synthase gene in the FAC restored wildtype chemical profiles. The altered squalene to farnesyl pyrophosphate ratio leading to synthesis of nidulenes and aspernidines at the expense of farnesyl pyrophosphate derived austinols provides unexpected insight into routes of terpene synthesis in fungi.