S-adenosylmethionine-dependent methyltransferases form a large family of enzymes that can catalyse regio-, chemo- and stereospecific methylation of complex natural products. These enzymes could be very useful tools for the chemoenzymatic production and diversification of natural or artificial compounds. Despite this potential, in vitro applications of methyltransferases are limited by their requirement for S-adenosylmethionine as a stoichiometric methyl donor. The chemical complexity, instability, high cost and poor atom economy of this reagent prevent preparative in vitro methylation reactions from becoming routine protocols in natural product research and viable options for process development. In this Article we demonstrate that C-, N- and O-specific methyltransferases can be combined with halide methyltransferases to form enzyme cascades that require only catalytic concentrations of S-adenosylmethionine and use methyl iodide as the stoichiometric methyl donor.
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The primary data that support the plots within this paper and other findings of this study are available from the corresponding author on reasonable request.
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C.L. was a recipient of an SSSTC and CSC postdoctoral fellowship. F.P.S. is supported by the ‘Professur für Molekulare Bionik’. This project was supported by the European Research Council (ERC-2013-StG 336559) and ‘Innovationsraum Biokatalyse’. The authors thank A. Maurer for ESI-HRMS measurements.
The authors have submitted a patent application (European patent EP18193563) protecting the methodology described in this manuscript.
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Liao, C., Seebeck, F.P. S-adenosylhomocysteine as a methyl transfer catalyst in biocatalytic methylation reactions. Nat Catal 2, 696–701 (2019). https://doi.org/10.1038/s41929-019-0300-0
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