Structural basis for non-radical catalysis by TsrM, a radical SAM methylase

Hayley L. Knox, Percival Yang Ting Chen, Anthony J. Blaszczyk, Arnab Mukherjee, Tyler L. Grove, Erica L. Schwalm, Bo Wang, Catherine L. Drennan, Squire J. Booker

Research output: Contribution to journalArticlepeer-review

Abstract

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.]

Original languageEnglish (US)
Pages (from-to)485-491
Number of pages7
JournalNature Chemical Biology
Volume17
Issue number4
DOIs
StatePublished - Apr 2021

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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