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A natural prodrug activation mechanism in nonribosomal peptide synthesis

Nature Chemical Biology volume 7, pages 888–890 (2011)Cite this article

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Abstract

We have identified a new mechanism for the cleavage and activation of nonribosomally made peptides and peptide-polyketide hybrids that are apparently operational in several different bacteria. This process includes the cleavage of a precursor molecule by a membrane-bound and D-asparagine–specific peptidase, as shown here in the biosynthesis of the antibiotic xenocoumacin from Xenorhabdus nematophila.

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Figure 1: Xenocoumacins and prexenocoumacins produced from Xenorhabdus nematophila.
Figure 2: Transformation of prexenocoumacin B (4) by E. coli.
Figure 3: XcnG homologs and their domain architecture.

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Acknowledgements

The authors thank A. Venneri for technical assistance. D.R., P.G. and H.B.B. are grateful to the Deutsche Forschungsgemeinschaft (DFG) for financial support. Work in H.B.B.'s lab is additionally supported by the Frankfurt Initiative for Microbial Sciences (FIMS), the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 223328 (GameXP), and by the research funding program “LOEWE – Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz” of Hessen's Ministry of Higher Education, Research, and the Arts. Support by the DFG-EXC115 (Cluster of Excellence Macromolecular Complexes at the Goethe-University Frankfurt), DFG-SFB807 (Transport and Communication across Biological Membranes) and FIMS is gratefully acknowledged by K.M.P. M.T. is financially supported by the LOEWE program of Hessen's Ministry of Higher Education, Research, and the Arts.

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Authors and Affiliations

  1. Molecular Biotechnology, Institute for Molecular Biosciences, Goethe University Frankfurt, Frankfurt, Germany

    Daniela Reimer, Peter Grün & Helge B Bode

  2. Institute of Biochemistry, Goethe University Frankfurt, Frankfurt, Germany

    Klaas M Pos

  3. Cluster of Excellence Frankfurt - Macromolecular Complexes, Goethe University Frankfurt, Frankfurt, Germany

    Klaas M Pos

  4. Biodiversity and Climate Research Centre (BiK-F), Frankfurt, Germany

    Marco Thines

  5. Department of Biological Sciences, Institute of Ecology, Evolution and Diversity, Goethe University Frankfurt, Frankfurt, Germany

    Marco Thines

Authors
  1. Daniela Reimer
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  2. Klaas M Pos
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  3. Marco Thines
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  4. Peter Grün
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  5. Helge B Bode
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Contributions

D.R. and H.B.B. designed experiments; D.R. and P.G. performed experiments; D.R. and H.B.B. analyzed experimental data, K.M.P. performed XcnG homology modeling; and M.T. performed XcnA and XcnG phylogenetic analysis. D.R., K.M.P., M.T. and H.B.B. wrote the paper.

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Correspondence to Helge B Bode.

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The authors declare no competing financial interests.

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Reimer, D., Pos, K., Thines, M. et al. A natural prodrug activation mechanism in nonribosomal peptide synthesis. Nat Chem Biol 7, 888–890 (2011). https://doi.org/10.1038/nchembio.688

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