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Structural basis for non-radical catalysis by TsrM, a radical SAM methylase
Name
nihms-1649786.pdf
Description
Accepted version
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1.92 MB
Format
Adobe PDF
Checksum (MD5)
6562e168332a4f8a2bae25644f79b8ec
Author(s)
Knox, Hayley L
Chen, Percival Yang-Ting
Blaszczyk, Anthony J
Mukherjee, Arnab
Grove, Tyler L
Schwalm, Erica L
Wang, Bo
Drennan, Catherine L
Booker, Squire J
Date Issued
2021
Journal
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Version
Author's final manuscript
Abstract
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. Tryptophan 2C methyltransferase (TsrM) methylates C2 of the indole ring of l-tryptophan during biosynthesis of the quinaldic acid moiety of thiostrepton. TsrM is annotated as a cobalamin-dependent radical S-adenosylmethionine (SAM) methylase; however, TsrM does not reductively cleave SAM to the universal 5ʹ-deoxyadenosyl 5ʹ-radical intermediate, a hallmark of radical SAM (RS) enzymes. Herein, we report structures of TsrM from Kitasatospora setae, which are the first structures of a cobalamin-dependent radical SAM methylase. Unexpectedly, the structures show an essential arginine residue that resides in the proximal coordination sphere of the cobalamin cofactor, and a [4Fe–4S] cluster that is ligated by a glutamyl residue and three cysteines in a canonical CXXXCXXC RS motif. Structures in the presence of substrates suggest a substrate-assisted mechanism of catalysis, wherein the carboxylate group of SAM serves as a general base to deprotonate N1 of the tryptophan substrate, facilitating the formation of a C2 carbanion. [Figure not available: see fulltext.]
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DOI of Published Version
10.1038/s41589-020-00717-y
