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Publication Abstract from PubMed

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.

Structural basis for non-radical catalysis by TsrM, a radical SAM methylase.,Knox HL, Chen PY, Blaszczyk AJ, Mukherjee A, Grove TL, Schwalm EL, Wang B, Drennan CL, Booker SJ Nat Chem Biol. 2021 Apr;17(4):485-491. doi: 10.1038/s41589-020-00717-y. Epub 2021 , Jan 18. PMID:33462497^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.