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Post-translational modification of ribosomally synthesized peptides by a radical SAM epimerase in Bacillus subtilis

Nature Chemistry volume 9, pages 698–707 (2017)Cite this article

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Abstract

Ribosomally synthesized peptides are built out of L-amino acids, whereas D-amino acids are generally the hallmark of non-ribosomal synthetic processes. Here we show that the model bacterium Bacillus subtilis is able to produce a novel type of ribosomally synthesized and post-translationally modified peptide that contains D-amino acids, and which we propose to call epipeptides. We demonstrate that a two [4Fe–4S]-cluster radical S-adenosyl-L-methionine (SAM) enzyme converts L-amino acids into their D-counterparts by catalysing Cα-hydrogen-atom abstraction and using a critical cysteine residue as the hydrogen-atom donor. Unexpectedly, these D-amino acid residues proved to be essential for the activity of a peptide that induces the expression of LiaRS, a major component of the bacterial cell envelope stress-response system. Present in B. subtilis and in several members of the human microbiome, these epipeptides and radical SAM epimerases broaden the landscape of peptidyl structures accessible to living organisms.

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Figure 1: YydG is a radical SAM enzyme that catalyses the modification of the YydF peptide.
Figure 2: YydG catalyses hydrogen-atom transfer to the peptide backbone.
Figure 3: YydG catalyses amino acid epimerization.
Figure 4: Activity of YydG mutants.
Figure 5: Proposed mechanism of the radical SAM peptide epimerase YydG.
Figure 6: Activity of the epipeptides on B. subtilis.

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Acknowledgements

This work was supported by grants from European Research Council (Consolidator Grant 617053 to O.B.). High-resolution MS analyses were performed on the INRA PAPPSO proteomics platform.

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Authors and Affiliations

  1. Micalis Institute (UMR 1319), ChemSyBio, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, 78350, France

    Alhosna Benjdia, Alain Guillot, Pauline Ruffié & Olivier Berteau

  2. Inserm U982, PRIMACEN, University of Rouen Normandy, F-76130, Mont-Saint-Aignan, France

    Jérôme Leprince

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  1. Alhosna Benjdia
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Contributions

A.B. and O.B. conceived and designed the experiments; A.B., A.G., P.R., J.L. and O.B. performed the experiments; A.B., A.G, J.L. and O.B. analysed the data; A.B. and O.B. co-wrote the manuscript.

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Correspondence to Olivier Berteau.

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Benjdia, A., Guillot, A., Ruffié, P. et al. Post-translational modification of ribosomally synthesized peptides by a radical SAM epimerase in Bacillus subtilis. Nature Chem 9, 698–707 (2017). https://doi.org/10.1038/nchem.2714

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