Terpenes constitute the largest class of natural products. Their skeletons are formed by terpene cyclases (TCs) from acyclic oligoprenyl diphosphates through sophisticated enzymatic conversions. These enzyme reactions start with substrate ionization through diphosphate abstraction, followed by a cascade reaction via cationic intermediates. Based on isotopic-labelling experiments in combination with a computational study, the cyclization mechanism for sodorifen, a highly methylated sesquiterpene from the soil bacterium Serratia plymuthica, was resolved. A peculiar problem in its biosynthesis lies in the formation of several methyl groups from chain methylene carbons. The underlying mechanism involves a methyltransferase-mediated cyclization and unprecedented ring contraction with carbon extrusion from the chain to form a methyl group. A terpene cyclase subsequently catalyses a fragmentation into two reactive intermediates, followed by hydrogen transfers between them and recombination of the fragments by [4 + 3] cycloaddition. This study solves the intricate mechanistic problem of extra methyl group formation in sodorifen biosynthesis.

萜烯是天然产物中最大的一类。它们的骨架由萜烯环化酶 (TC) 通过复杂的酶促转化从无环寡聚戊二烯二磷酸酯形成。这些酶反应从通过二磷酸盐提取的底物电离开始，然后通过阳离子中间体进行级联反应。基于同位素标记实验与计算研究相结合，解决了来自土壤细菌普城沙雷氏菌的高度甲基化倍半萜索多芬的环化机制。其生物合成中的一个特殊问题在于由链亚甲基碳形成多个甲基。潜在的机制涉及甲基转移酶介导的环化和前所未有的环收缩，碳从链中挤出形成甲基。萜烯环化酶随后催化裂解成两个反应性中间体，然后在它们之间进行氢转移，并通过 [4 + 3] 环加成重组片段。这项研究解决了索多芬生物合成中额外甲基形成的复杂机制问题。