Discovery, structure, and mechanism of a class II sesquiterpene cyclase

24 August 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Terpene cyclases (TCs), the extraordinary enzymes that create the structural diversity seen in terpene natural products, are traditionally divided into two classes. Although the structural and mechanistic features in class I TCs are well-known, the corresponding details in class II counterparts have not been fully characterized. Here, we report the genome mining discovery and structural characterization of two class II sesquiterpene cyclases (STCs) from Streptomyces. These drimenyl diphosphate synthases (DMSs) are the first STCs shown to possess β,γ-didomain architecture. High-resolution X-ray crystal structures of SsDMS in complex with both a farnesyl diphosphate and Mg2+ unveiled an induced-fit mechanism with an unprecedented Mg2+ binding mode, finally solving one of the lingering questions in class II TC enzymology. This study supports continued genome mining for novel bacterial TCs and provides new mechanistic insights into canonical class II TCs that will lead to advances in TC engineering and synthetic biology.


terpene cyclase
class II sesquiterpene cyclase
magnesium ion binding mode
drimenol natural product

Supplementary materials

Supplementary Information for Discovery, structure and mechanism of a class II sesquiterpene cyclase
The Supporting Information includes materials, methods, detailed experimental procedures, bioinformatic analysis, in vivo, in vitro, and structural characterizations of SsDMS.


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