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Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms

Nature Chemical Biology volume 11, pages 705712 (2015) | Download Citation

Abstract

Actin-targeting macrolides comprise a large, structurally diverse group of cytotoxins isolated from remarkably dissimilar micro- and macroorganisms. In spite of their disparate origins and structures, many of these compounds bind actin at the same site and exhibit structural relationships reminiscent of modular, combinatorial drug libraries. Here we investigate biosynthesis and evolution of three compound groups: misakinolides, scytophycin-type compounds and luminaolides. For misakinolides from the sponge Theonella swinhoei WA, our data suggest production by an uncultivated 'Entotheonella' symbiont, further supporting the relevance of these bacteria as sources of bioactive polyketides and peptides in sponges. Insights into misakinolide biosynthesis permitted targeted genome mining for other members, providing a cyanobacterial luminaolide producer as the first cultivated source for this dimeric compound family. The data indicate that this polyketide family is bacteria-derived and that the unusual macrolide diversity is the result of combinatorial pathway modularity for some compounds and of convergent evolution for others.

  • Compound C82H142N2O24

    Luminaolide B

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Acknowledgements

We thank T. Wakimoto and K. Takada for providing sponge samples, D. Uemura for a generous sample of luminaolide, M. Wilson for sequence analysis and naming of 'Entotheonella serta', C. Maufrais and A. Criscuolo from the Bioinformatic Plateform of the Institut Pasteur for help in ANI calculation, and J. Pernthaler for helpful discussion and for providing material for CARD-FISH experiments. We are also grateful to Y.I. Park and J.-F. Humbert for the use of cyanobacterial genomes. This work was funded by grants of the SNF (IZLSZ3_149025), and the EU (BlueGenics and BluePharmTrain) to J.P., by the Institut Pasteur to M.G., by an Alexander von Humboldt Research Fellowship to R.U. and by a DAAD fellowship to A.R.U.

Author information

Author notes

    • Reiko Ueoka
    •  & Agustinus R Uria

    These authors contributed equally to this work.

Affiliations

  1. Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.

    • Reiko Ueoka
    • , Agustinus R Uria
    • , Silke Reiter
    • , Petra Karbaum
    • , Eike E Peters
    • , Eric J N Helfrich
    • , Brandon I Morinaka
    •  & Jörn Piel
  2. Faculty of Science and Engineering, Waseda University Center for Advanced Biomedical Sciences, Tokyo, Japan.

    • Tetsushi Mori
    •  & Haruko Takeyama
  3. Kekulé Institute of Organic Chemistry and Biochemistry, Bonn, Germany.

    • Petra Karbaum
  4. Institut Pasteur, Collection des Cyanobactéries, Paris, France.

    • Muriel Gugger
  5. Laboratory of Aquatic Natural Products Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.

    • Shigeki Matsunaga

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Contributions

R.U. isolated and characterized polyketides from cyanobacteria, A.R.U. performed the genetic work on misakinolide, S.R. performed the phylogenetic studies, T.M. and H.T. conducted the single-cell experiments, P.K. expressed and assayed the misakinolide PS domain, B.I.M. characterized the PS product, E.E.P. conducted the CARD-FISH experiments, E.J.N.H. performed MS analysis including imaging, M.G. cultivated and sequenced cyanobacteria and performed ANI calculations, S.M. provided and analyzed sponge chemotypes, J.P. analyzed PKS sequences and predicted polyketide structures, all authors designed research, analyzed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jörn Piel.

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https://doi.org/10.1038/nchembio.1870

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