Cooperation of Multi-Redox Enzymes To Biosynthesize Cyclobutane Sesquiterpenoid Harzianoic Acids from α-trans -Bergamotene

Abstract

Harzianoic acids (HAs) are polysubstituted cyclobutane sesquiterpenoids that display inhibitory effects against hepatitis C virus. Herein, we report the identification and characterization of the biosynthetic gene cluster of HA from Trichoderma asperellum. Genetic and biochemical analysis revealed an unexpected pathway to biosynthesize HA from farnesyl pyrophosphate via α-trans-bergamotene. This pathway involves three redox enzymes acting cooperatively to break down the six-membered ring of bergamotene to generate the skeleton of HA.