Cytochrome P450 Mediated Cyclization in Eunicellane Derived Diterpenoid Biosynthesis

Angew Chem Int Ed Engl. 2023 Sep 21:e202312490. doi: 10.1002/anie.202312490. Online ahead of print.ABSTRACTTerpene cyclization, one of the most complex chemical reactions in nature, is generally catalyzed by two classes of terpene cyclases (TCs). Cytochrome P450s that act as unexpected TC-like enzymes are known but are very rare. Here, we genome-mined a cryptic bacterial terpenoid gene cluster, named ari, from the thermophilic actinomycete strain Amycolatopsis arida. By employing a heterologous production system, we isolated and characterized three highly oxidized eunicellane derived diterpenoids, aridacins A-C (1-3), that possess a 6/7/5-fused tricyclic scaffold. In vivo and in vitro experiments systematically established a non-canonical two-step biosynthetic pathway for diterpene skeleton formation. First, a class I TC (AriE) cyclizes geranylgeranyl diphosphate (GGPP) into a 6/10-fused bicyclic cis-eunicellane skeleton. Next, a cytochrome P450 (AriF) catalyzes cyclization of the eunicellane skeleton into the 6/7/5-fused tricyclic scaffold via C2-C6 bond formation. Based on the results of quantum chemical computations, hydrogen abstraction followed by electron transfer coupled to barrierless carbocation ring-closure is shown to be a viable mechanism for AriF-mediated cyclization. The biosynthetic logic of skeleton construction in the aridacins is unprecedented, expanding the catalytic capacity and diversity of P450s and setting the stage to investigate the inherent principle...

Source: Angewandte Chemie - September 22, 2023 Category: Chemistry Authors: Zengyuan Wang Qian Yang Jingyi He Haixin Li Xingming Pan Zining Li Hui-Min Xu Jeffrey Rudolf Dean Tantillo Liao-Bin Dong Source Type: research