Enzymatic Fluoromethylation as a Tool for ATP-Independent Ligation

Jiaming Peng; Gregory R Hughes; Manuel  M Müller; Florian  P. Seebeck

doi:10.1002/anie.202312104

Enzymatic Fluoromethylation as a Tool for ATP-Independent Ligation

Jiaming Peng, Gregory R Hughes, Manuel M Müller^*, Florian P. Seebeck^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

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.

Original language	English
Article number	e202312104
Pages (from-to)	e202312104
Journal	ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume	63
Issue number	1
Early online date	13 Nov 2023
DOIs	https://doi.org/10.1002/anie.202312104
Publication status	Published - 2 Jan 2024

Keywords

fluorine biocatalysis, methyltransferase biocatalysis, native chemical ligation, protein synthesis, post translational modification

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10.1002/anie.202312104Licence: CC BY

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abstract = "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.",

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note = "Funding Information: This project was supported by the Swiss National Science Foundation (project 182023), the Wellcome Trust and the Royal Society (Sir Henry Dale Fellowship 202250/Z/16/Z to MMM). We thank Dr. Michael Pfeffer from Analytical Team at University of Basel for measuring HRMS samples of coenzyme A and his technical support for HRMS, and The King's College London Chemistry Department Facility for mass spectrometry services. Funding Information: This project was supported by the Swiss National Science Foundation (project 182023), the Wellcome Trust and the Royal Society (Sir Henry Dale Fellowship 202250/Z/16/Z to MMM). We thank Dr. Michael Pfeffer from Analytical Team at University of Basel for measuring HRMS samples of coenzyme A and his technical support for HRMS, and The King's College London Chemistry Department Facility for mass spectrometry services. Publisher Copyright: {\textcopyright} 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.",

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Enzymatic Fluoromethylation as a Tool for ATP-Independent Ligation

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