SAM-dependent methyltransferases: from chemoenzymatic natural product synthesis to industrial application

Covering: up to 2026Over the past decades, research on S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTs) has led to their emergence as highly selective biocatalysts for late-stage methylation reactions, serving as new tools within the chemoenzymatic synthesis of complex natural products and chemical scaffolds. Studies focussing on the identification of novel MTs, their engineering and process optimisation, have not only expanded the accessible chemical space for biocatalytic methylations but have also significantly improved their applicability for reactions conducted at preparative scale. This includes innovations in enzyme-coupled SAM recycling systems and SAM analogue generation which have additionally enabled alkylation beyond methyl transfer. Structure-guided MT mutagenesis campaigns, together with the development of novel activity assays, have contributed to the expansion of the catalytic repertoire of MTs, thereby unlocking new reactivities. This highlight article provides a brief overview of recent developments in MT biocatalysis, with particular focus on their application in the chemoenzymatic synthesis of natural products at preparative scale. Current limitations associated with MT biocatalysis are examined, and future opportunities for the implementation of MT-catalysed transformations in industrial applications are discussed.