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Nat Chem Biol. 2015 Sep;11(9):705-12. doi: 10.1038/nchembio.1870. Epub 2015 Aug 3.

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

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Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.
Faculty of Science and Engineering, Waseda University Center for Advanced Biomedical Sciences, Tokyo, Japan.
1] Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland. [2] Kekulé Institute of Organic Chemistry and Biochemistry, Bonn, Germany.
Institut Pasteur, Collection des Cyanobactéries, Paris, France.
Laboratory of Aquatic Natural Products Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.


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.

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