Cooperationof Multi-Redox Enzymes To BiosynthesizeCyclobutane Sesquiterpenoid Harzianoic Acids from <i>α-trans</i> -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.