title: Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms.
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.
authors.affiliation: Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.
authors.forename: Reiko
authors.initials: R
authors.lastname: Ueoka
authors.affiliation: Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.
authors.forename: Agustinus R
authors.initials: AR
authors.lastname: Uria
authors.affiliation: Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.
authors.forename: Silke
authors.initials: S
authors.lastname: Reiter
authors.affiliation: Faculty of Science and Engineering, Waseda University Center for Advanced Biomedical Sciences, Tokyo, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Mori
authors.affiliation: 1] Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland. [2] Kekulé Institute of Organic Chemistry and Biochemistry, Bonn, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Karbaum
authors.affiliation: Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.
authors.forename: Eike E
authors.initials: EE
authors.lastname: Peters
authors.affiliation: Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.
authors.forename: Eric J N
authors.initials: EJ
authors.lastname: Helfrich
authors.affiliation: Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.
authors.forename: Brandon I
authors.initials: BI
authors.lastname: Morinaka
authors.affiliation: Institut Pasteur, Collection des Cyanobactéries, Paris, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Gugger
authors.affiliation: Faculty of Science and Engineering, Waseda University Center for Advanced Biomedical Sciences, Tokyo, Japan.
authors.forename: Haruko
authors.initials: H
authors.lastname: Takeyama
authors.affiliation: Laboratory of Aquatic Natural Products Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsunaga
authors.affiliation: Institute of Microbiology, Eigenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland.
authors.forename: Jörn
authors.initials: J
authors.lastname: Piel
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D005075:Biological Evolution; D000458:Cyanobacteria / Q000235:genetics / Q000378:metabolism*; D020564:Deltaproteobacteria / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D005810:Multigene Family; D010455:Peptides; D048630:Polyketide Synthases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D061065:Polyketides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011714:Pyrans / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism; D013559:Symbiosis; D047232:Theonella / Q000382:microbiology
chemical_list: D000199:Actins; D001426:Bacterial Proteins; D018942:Macrolides; D010455:Peptides; D061065:Polyketides; D011714:Pyrans; D054852:Small Molecule Libraries; C104924:bistheonellide A; C068527:tolytoxin; D048630:Polyketide Synthases