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Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms
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Journal Article
Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms
2015
Overview
Investigations into the biosynthetic pathways of three families of actin-targeting macrolides lead to insights into their convergent or combinatorial evolution, along with the identification of the first free-living bacterial source of macroalga-derived luminaolides.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 14/32
/ 45/22
/ 45/23
/ 82/58
/ 82/83
/ Animals
/ Bacteria
/ Bacterial Proteins - chemistry
/ Bacterial Proteins - genetics
/ Bacterial Proteins - metabolism
/ Deltaproteobacteria - genetics
/ Deltaproteobacteria - metabolism
/ Enzymes
/ Microbiology and Parasitology
/ Peptides
/ Polyketide Synthases - chemistry
/ Polyketide Synthases - genetics
/ Polyketide Synthases - metabolism
/ Small Molecule Libraries - chemistry
