The thiostrepton A tryptophan methyltransferase TsrM catalyses a cob(II)alamin-dependent methyl transfer reaction

Alhosna Benjdia, Stéphane Pierre, Carmen Gherasim, Alain Guillot, Manon Carmona, Patricia Amara, Ruma Banerjee and Olivier Berteau ()
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Alhosna Benjdia: INRA, ChemSyBio
Stéphane Pierre: INRA, ChemSyBio
Carmen Gherasim: University of Michigan Medical School
Alain Guillot: INRA, ChemSyBio
Manon Carmona: INRA, ChemSyBio
Patricia Amara: Metalloproteins Unit, Institut de Biologie Structurale
Ruma Banerjee: University of Michigan Medical School
Olivier Berteau: INRA, ChemSyBio

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a novel class of natural products including several antibiotics and bacterial toxins. In countless RiPP biosynthetic pathways, cobalamin-dependent radical SAM (B12/rSAM) enzymes play a pivotal role. In the biosynthetic pathway of the antibiotic and anti-cancer agent thiostrepton A, TsrM, a B12/rSAM enzyme, catalyses the transfer of a methyl group to an electrophilic carbon atom of tryptophan. Here we show that methylcob(III)alamin is the probable physiological enzyme cofactor, and cob(II)alamin rather than cob(I)alamin is a key reaction intermediate. Furthermore, we establish that TsrM and a triple-alanine mutant alkylate cob(II)alamin efficiently leading to the synthesis of MeCbl. Exploiting TsrM substrate ambiguity, we demonstrate that TsrM does not catalyse substrate H-atom abstraction like most radical SAM enzymes. Based on these data, we propose an unprecedented radical-based C-methylation mechanism, which further expands the chemical versatility of rSAM enzymes.

Date: 2015
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DOI: 10.1038/ncomms9377

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