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Autocatalytic backbone N-methylation in a family of ribosomal peptide natural products

Nature Chemical Biology volume 13, pages 833–835 (2017)Cite this article

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Abstract

Peptide backbone N-methylation, as seen in cyclosporin A, has been considered to be exclusive to nonribosomal peptides. We have identified the first post-translationally modified peptide or protein harboring internal α-N-methylations through discovery of the genetic locus for the omphalotins, cyclic N-methylated peptides produced by the fungus Omphalotus olearius. We show that iterative autocatalytic activity of an N-methyltransferase fused to its peptide substrate is the signature of a new family of ribosomally encoded metabolites.

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Figure 1: Omphalotin A: natural product and encoding genetic locus.
Figure 2: Observed methylation states of wild-type and hybrid omphalotin precursors.

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Change history

  • 14 June 2017

    In the version of this article initially published online, the side chain of tryptophan was drawn incorrectly in the structure of omphalotin A depicted in Figure 1a and the graphical abstract. The error has been corrected in the print, PDF and HTML versions of this article.

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Acknowledgements

We thank M. Aebi for helpful discussions and continuous support, J. Thorner for helpful suggestions regarding the manuscript, the functional genomics center Zürich for ESI–TOF–MS measurements, A. Brachmann for help with HPLC–MS/MS HCD measurements, A. Imani for performing cell-free experiments and C.W. Lin for help with HPLC–MS/MS ETD measurements. We are grateful to L. Nagy and F. Martin for sharing unpublished genome and transcriptome data of Dendrothele bispora CBS 962.96 and Marasmius fiardii PR-910, respectively, produced and made publicly available by the US Department of Energy Joint Genome Institute (DOE JGI). This work was supported by ETH Zürich (M.K. and J.P.), the University of Minnesota (M.F.F.), the Swiss National Science Foundation (31003A_146992) (J.P.), and the EU 7th framework program (SYNPEPTIDE) (J.P.).

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Authors and Affiliations

  1. Department of Biology, Institute of Microbiology, Eidgenössische Technische Hochschule (ETH) Zürich, Zürich, Switzerland

    Niels S van der Velden, Noemi Kälin, Maximilian J Helf, Jörn Piel & Markus Künzler

  2. Department of Biochemistry, Molecular Biology, and Biophysics and BioTechnology Institute, University of Minnesota Twin Cities, St. Paul, Minnesota, USA

    Michael F Freeman

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  1. Niels S van der Velden
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Contributions

M.K. initiated and supervised the project. M.F.F. and N.S.v.d.V. designed the experiments. N.S.v.d.V. and N.K. conducted the experiments. N.S.v.d.V., M.F.F. and M.J.H. analyzed the data. All authors discussed the results. M.F.F., N.S.v.d.V. and M.K. wrote the manuscript. J.P. edited the manuscript and provided experimental expertise.

Corresponding authors

Correspondence to Michael F Freeman or Markus Künzler.

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Competing interests

M.K., M.F.F., N.S.v.d.V., N.K. and J.P. are inventors on European Patent application no. EP16164245.9 (PCT/EP2017/058327) filed by ETH Zürich titled “Novel multiply Backbone N-methyl transferase and use thereof.”

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–2 and Supplementary Figures 1–6 (PDF 6681 kb)

Supplementary Note

Mass spectra supporting the structural assignment of peptides described in this study. (PDF 15750 kb)

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van der Velden, N., Kälin, N., Helf, M. et al. Autocatalytic backbone N-methylation in a family of ribosomal peptide natural products. Nat Chem Biol 13, 833–835 (2017). https://doi.org/10.1038/nchembio.2393

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