Identification of the Putative Bryostatin Polyketide Synthase Gene Cluster from “Candidatus Endobugula sertula”, the Uncultivated Microbial Symbiont of the Marine Bryozoan Bugula neritina

The bryostatins are protein kinase C modulators with unique structural features and potential anticancer and neurological activities. These complex polyketides were isolated from the marine bryozoan Bugula neritina, but recent studies indicate that they are produced by the uncultured symbiotic bacte...

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Bibliographic Details
Published in:Journal of natural products (Washington, D.C.) D.C.), 2007-01, Vol.70 (1), p.67-74
Main Authors: Sudek, Sebastian, Lopanik, Nicole B, Waggoner, Laura E, Hildebrand, Mark, Anderson, Christine, Liu, Haibin, Patel, Amrish, Sherman, David H, Haygood, Margo G
Format: Article
Language:English
Subjects:
Animals
Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents
Applied microbiology
Base Sequence
Biological and medical sciences
Bryostatins
Bryozoa - chemistry
Bryozoa - genetics
Bugula neritina
California
Chemotherapic agents
DNA - chemistry
DNA - isolation & purification
Endobugula sertula
Fundamental and applied biological sciences. Psychology
Macrolides - chemistry
Macrolides - metabolism
Macrolides - pharmacology
Microbiology
Molecular Sequence Data
Molecular Structure
Polyketide Synthases - genetics
Polyketide Synthases - isolation & purification
Polyketide Synthases - metabolism
Protein Kinase C - drug effects
RNA - chemistry
RNA - isolation & purification
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Summary:The bryostatins are protein kinase C modulators with unique structural features and potential anticancer and neurological activities. These complex polyketides were isolated from the marine bryozoan Bugula neritina, but recent studies indicate that they are produced by the uncultured symbiotic bacterium “Candidatus Endobugula sertula” (“E. sertula”). Here we present the putative biosynthetic genes:  five modular polyketide synthase (PKS) genes, a discrete acyltransferase, a β-ketosynthase, a hydroxy-methyl-glutaryl CoA synthase (HMG-CS), and a methyltransferase. The cluster was sequenced in two closely related “E. sertula” strains from different host species. In one strain the gene cluster is contiguous, while in the other strain it is split into two loci, with one locus containing the PKS genes and the other containing the accessory genes. Here, we propose a hypothesis for the biosynthesis of the bryostatins. Thirteen PKS modules form the core macrolactone ring, and the pendent methyl ester groups are added by the HMG-CS gene cassette. The resulting hypothetical compound bryostatin 0 is the common basis for the 20 known bryostatins. As “E. sertula” is to date uncultured, heterologous expression of this biosynthetic gene cluster has the potential of producing the bioactive bryostatins in large enough quantities for development into a pharmaceutical.
ISSN:0163-3864
1520-6025
DOI:10.1021/np060361d