A natural prodrug activation mechanism in nonribosomal peptide synthesis

Journal name:
Nature Chemical Biology
Volume:
7,
Pages:
888–890
Year published:
DOI:
doi:10.1038/nchembio.688
Received
Accepted
Published online

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.

At a glance

Figures

  1. Xenocoumacins and prexenocoumacins produced from Xenorhabdus nematophila.
    Figure 1: Xenocoumacins and prexenocoumacins produced from Xenorhabdus nematophila.

    (a) Structures of xenocoumacin-1 (1), xenocoumacin-2 (2) and prexenocoumacins A–E (37). (b) ESI-HPLC-MS analysis (base peak chromatograms) of (I) X. nematophila HGB081-δxcnG-xnc1_2228::cat, (II) HGB081-δxcnG and (III) wild-type HGB081. The positions of 1–7 and of peptide masses (X) resulting from xcn1_2228 are indicated. The peak at 11.4 min is xenortide A (ref. 22). All chromatograms are scaled to the same intensity.

  2. Transformation of prexenocoumacin B (4) by E. coli.
    Figure 2: Transformation of prexenocoumacin B (4) by E. coli.

    Depicted are the relative amounts of 1 (black squares), 2 (black diamonds) and 4 (white triangles) in E. coli DH10B expressing (a) xcnG, (b) xcnG and xcnMN and (c) xbJ1_2693. Mean values and s.d. of two independent experiments are shown.

  3. XcnG homologs and their domain architecture.
    Figure 3: XcnG homologs and their domain architecture.

    Depicted are the domain architectures of XcnG (X. nematophila), the homologs Bpum_0630 (B. pumilius SAFR-032), CLM0371 (C. botulinum A2 strain Kyoto), C2452 (E. coli CFT073), CKO_00875 (Citrobacter koseri ATCC BAA-895), XbJ1_2693 (X. bovienii SS-2004), ZmaM (Bacillus thuringiensis serovar Berliner ATCC 10792) and Plarl_010100010772 (Paenibacillus larvae subsp. larvae BRL-230010), and possible interaction partners of XcnG in X. nematophila, which may supplement the ABC transporter function in the putative XcnG–ABC transporter complex. Peptidase homologs can be classified into two proposed domain architecture types. Type I consist of a signal sequence (red), specific for the transport of the protein into the periplasm, a peptidase domain (blue) and three C-terminal transmembrane helices (dark green). Type II consists of a signal sequence, a peptidase domain, nine transmembrane helices (light green) and an ABC transporter domain (yellow) located in the cytoplasm. TMH, transmembrane helices.

Compounds

9 compounds View all compounds
  1. Xenocoumacin 1
    Compound 1 Xenocoumacin 1
  2. Xenocoumacin 2
    Compound 2 Xenocoumacin 2
  3. Prexenocoumacin A
    Compound 3 Prexenocoumacin A
  4. Prexenocoumacin B
    Compound 4 Prexenocoumacin B
  5. Prexenocoumacin C
    Compound 5 Prexenocoumacin C
  6. Prexenocoumacin D
    Compound 6 Prexenocoumacin D
  7. Prexenocoumacin E
    Compound 7 Prexenocoumacin E
  8. Amicoumacin A
    Compound 8 Amicoumacin A
  9. Zwittermicin A
    Compound 9 Zwittermicin A

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Author information

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

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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The authors declare no competing financial interests.

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Supplementary information

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