S-adenosylmethionine-dependent methyltransferases are involved in countless biological processes, including signal transduction, epigenetics, natural product biosynthesis, and detoxification. Only a handful of carboxylate methyltransferases have evolved to participate in amide bond formation. In this report we show that enzyme-catalyzed F-methylation of carboxylate substrates produces F-methyl esters that readily react with N- or S-nucleophiles under physiological conditions. We demonstrate the applicability of this approach to the synthesis of small amides, hydroxamates, and thioesters, as well as to site-specific protein modification and native chemical ligation.
This report shows that methyltransferase‐mediated fluoromethylation can activate small and large carboxylate substrates for conjugation to thiols, hydrazine, hydroxylamine or amines. This methodology to produce anhydrides offers an alternative to the much more common ATP‐dependent processes observed in nature and utilized in biocatalysis.
Keywords: Fluorine Biocatalysis; Methyltransferase Biocatalysis; Native Chemical Ligation; Post Translational Modification; Protein Synthesis.
© 2023 The Authors. Angewandte Chemie published by Wiley-VCH GmbH.