Aberle, BenjaminKowalczyk, DanielMassini, SimonEgler‐Kemmerer, Alexander‐N.Gergel, SebastianHammer, Stephan C.Hauer, Bernhard2023-10-122023-10-1220231433-78511521-37731868998266http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-ds-136017http://elib.uni-stuttgart.de/handle/11682/13601http://dx.doi.org/10.18419/opus-13582Terpenoids are built from isoprene building blocks and have numerous biological functions. Selective late-stage modification of their carbon scaffold has the potential to optimize or transform their biological activities. However, the synthesis of terpenoids with a non-natural carbon scaffold is often a challenging endeavor because of the complexity of these molecules. Herein we report the identification and engineering of (S)-adenosyl-l-methionine-dependent sterol methyltransferases for selective C-methylation of linear terpenoids. The engineered enzyme catalyzes selective methylation of unactivated alkenes in mono-, sesqui- and diterpenoids to produce C11, C16 and C21 derivatives. Preparative conversion and product isolation reveals that this biocatalyst performs C-C bond formation with high chemo- and regioselectivity. The alkene methylation most likely proceeds via a carbocation intermediate and regioselective deprotonation. This method opens new avenues for modifying the carbon scaffold of alkenes in general and terpenoids in particular.eninfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/4.0/540article2023-07-11