Structural Basis for Non-radical Catalysis by TsrM, a Radical SAM Methylase

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2021 Jan 19

PMID 33462497

Citations 27

Authors

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

Affiliations

Soon will be listed here.

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 5'-deoxyadenosyl 5'-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.

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