Biosynthesis of the Fully Saturated C ₁₆ Homosesquiterpene Descartane Through Deprotonation With Cyclopropanation

Abstract

ABSTRACT Non‐canonical terpene biosynthesis expands structural diversity beyond the classical C 5n logic. Here we report the discovery of descartane, a C 16 homosesquiterpene with an unprecedented scaffold produced by a bacterial type I terpene cyclase from Morganella morganii (MmTC). Unlike most terpene cyclase products, descartane is fully saturated and lacks both alkene and alcohol functions, while containing a cyclopropane ring formed in an unusual termination step. Functional characterisation demonstrated that MmTC converts α‐presodorifen pyrophosphate (α‐PSPP) into descartane. The cyclisation cascade was investigated by extensive isotopic labelling experiments and density functional theory (DFT) calculations, revealing a complex pathway involving fragmentation‐recombination, multiple hydride shifts, and cyclopropane formation. Site‐directed mutagenesis identified active site residues that control product formation and redirect the cascade towards related terpenes, including voltairene, malebranchene, de‐beauvoirol, and pythagorene. These findings establish the biosynthetic origin of descartane and show how subtle changes in the active site can reprogram complex terpene cyclisation cascades.