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


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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Figure 1: Selected structures of structurally related macrolides and their biological sources.
Figure 2: Unifying model for the biosynthesis of the actin-inhibitors misakinolide A, tolytoxin and luminaolides.
Figure 3: Colocalization of 'Entotheonella' and misakinolide A using a combination of CARD-FISH and HR-IMS.
Figure 4: HPLC profiles of test reactions investigating PS-catalyzed tetrahydropyran formation.
Figure 5: Evolutive relationships of the rhizopodin (riz), luminaolide (lum), scytophycin and tolytoxin (tto) and misakinolide (mis) PKS systems.

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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.

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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.

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Correspondence to Jörn Piel.

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Supplementary Note, Supplementary Results, Supplementary Figures 1–26 and Supplementary Tables 1–6. (PDF 2339 kb)

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Ueoka, R., Uria, A., Reiter, S. et al. Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms. Nat Chem Biol 11, 705–712 (2015).

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