Fluorinated S-Adenosylmethionine as a Reagent for Enzyme-Catalyzed Fluoromethylation

Strategic replacement of protons with fluorine atoms or functional groups with fluorine-containing fragments has proven a powerful strategy to optimize the activity of therapeutic compounds. For this reason, the synthetic chemistry of organofluorides has been the subject of intense development and innovation for many years. By comparison, the literature on fluorine biocatalysis still makes for a slim chapter. Herein we introduce S-adenosylmethionine (SAM) dependent methyltransferases as a new tool for the production of fluorinated compounds. We demonstrate the ability of halide methyltransferases to form fluorinated SAM (S-adenosyl-S-(fluoromethyl)-L-homocysteine) from S-adenosylhomocysteine and fluoromethyliodide. Fluorinated SAM (F-SAM) is too unstable for isolation, but is accepted as a substrate by C-, N- and O-specific methyltransferases for enzyme-catalyzed fluoromethylation of small molecules.

Automated summary

Strategically replacing protons with fluorine atoms or functional groups has proven to be an effective way to optimize the activity of therapeutic compounds, leading to intense development in the field of organofluorides. However, literature on fluorine biocatalysis is still limited, with the introduction of SAM-dependent methyltransferases as a new tool for producing fluorinated compounds being a key innovation in the field. This approach demonstrates the ability of halide methyltransferases to form unstable fluorinated SAM, accepted as a substrate by specific methyltransferases for enzyme-catalyzed fluoromethylation of small molecules.