Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism

摘要: Artemisinin, a sesquiterpene lactone produced by Artemisia annua glandular secretory trichomes, is the active ingredient in most effective treatment for malaria currently available. We identified mutation that disrupts amorpha-4,11-diene C-12 oxidase (CYP71AV1) enzyme, responsible series of oxidation reactions artemisinin biosynthetic pathway. Detailed metabolic studies cyp71av1-1 revealed consequence blocking pathway redirection metabolism to epoxide, which we designate arteannuin X. This approaches half concentration observed wild-type plants, demonstrating high-flux plasticity A. trichomes and their potential as factories production novel alternate sesquiterpenes at commercially viable levels. metabolite profiling leaf maturation time-series precursor-feeding experiments nonenzymatic conversion steps are central both X biosynthesis. In particular, feeding using 13C-labeled dihydroartemisinic acid (DHAA) provided strong evidence final synthesis vivo. Our findings also suggest specialized subapical cavity functions location chemical storage phytotoxic compounds, including artemisinin. conclude engineering produce high yields secondary compounds such feasible complex trichomes. Such systems offer advantages over single-cell microbial hosts toxic natural products.