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

Author

Listed:
  • Alhosna Benjdia

    (INRA, ChemSyBio
    AgroParisTech, ChemSyBio)

  • Stéphane Pierre

    (INRA, ChemSyBio
    AgroParisTech, ChemSyBio)

  • Carmen Gherasim

    (University of Michigan Medical School)

  • Alain Guillot

    (INRA, ChemSyBio
    AgroParisTech, ChemSyBio)

  • Manon Carmona

    (INRA, ChemSyBio
    AgroParisTech, ChemSyBio)

  • Patricia Amara

    (Metalloproteins Unit, Institut de Biologie Structurale)

  • Ruma Banerjee

    (University of Michigan Medical School)

  • Olivier Berteau

    (INRA, ChemSyBio
    AgroParisTech, ChemSyBio)

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.

Suggested Citation

  • Alhosna Benjdia & Stéphane Pierre & Carmen Gherasim & Alain Guillot & Manon Carmona & Patricia Amara & Ruma Banerjee & Olivier Berteau, 2015. "The thiostrepton A tryptophan methyltransferase TsrM catalyses a cob(II)alamin-dependent methyl transfer reaction," Nature Communications, Nature, vol. 6(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9377
    DOI: 10.1038/ncomms9377
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    Cited by:

    1. Kevin B. Reed & Sierra M. Brooks & Jordan Wells & Kristin J. Blake & Minye Zhao & Kira Placido & Simon d’Oelsnitz & Adit Trivedi & Shruti Gadhiyar & Hal S. Alper, 2024. "A modular and synthetic biosynthesis platform for de novo production of diverse halogenated tryptophan-derived molecules," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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