Chemoenzymatic analysis of bryostatin biosynthesis

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DESCRIPTION (provided by applicant): Bryostatins are polyketide secondary metabolites isolated from the marine bryozoan Bugula neritina. Bryostatin 1 is a very promising anti-cancer drug, and is currently undergoing Phase II clinical trials. Unfortunately, bryostatin concentrations in B. neritina are very low and, to date, there are no chemical synthetic alternatives, requiring the harvest of large amounts of the animal to obtain sufficient quantities of bryostatin for biotesting. Recent research has revealed that the bryostatins are produced by the bacterial endosymbiont, Endobugula sertula, but attempts to culture the microbe have not been successful. Consequently, the latest research effort has resulted in the identification of a polyketide synthase (PKS) gene cluster from symbiont-enriched DMA that may be responsible for bryostatin biosynthesis. However, as the organism cannot be cultured, mutation and complementation experiments that can verify whether this cluster produces bryostatin cannot be conducted. In this project, I propose to use in vitro studies with purified putative bryostatin PKS modules to determine whether this gene cluster is in fact responsible for the production of bryostatin. This research may lead to production of bryostatin by a heterologous host.