The "magic methyl effect" refers to the ability of an appropriately placed methyl group to dramatically alter the biological properties of a compound. This makes selective alkylation of molecules highly desirable. Thus, methyltransferases (MTs), enzymes catalyzing regioselective methylation of nucleophilic atoms on small molecules, possess an immense synthetic potential which has yet to be exploited. Nevertheless, their application is limited to date, for good reasons; (i) insufficient understanding of the sequence-function relationship that could lead to desired enzymes, and (ii) limited access to efficient regeneration systems for the methyl donor. Herein results on our recent efforts to highlight the synthetic potential of MTs will be presented. Isoeugenol 4-O-MT of Clarkia breweri was used as a case‑study enzyme to identify the residues responsible for the exhibited substrate scope and regioselectivity, especially considering the high homology to the caffeic acid 3-O-methyltransferase from the same organism. Using this information, we were able to get access to variants with altered substrate scope and regioselectivity against flavonoids via semi-rational design. However, to expand the synthetic potential in an industrial scale, an easy regeneration system for the methyl donor should be implemented. In our group we developed a simple regeneration assay that provides access to the natural methyl donor (S)-adenosyl-L-methionine (SAM) and several of its analogues. Using this cascade we could prove in a mg scale the preparation of SAM analogues, but also the transfer of ethyl and allyl groups to desired target compounds using O‑MTs. Such advances are expected to open new horizons for the application of MTs in organic synthesis to access building blocks, high-added value modified natural products and pharmaceuticals.
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