Cloning and Heterologous Expression of the Epothilone Gene Cluster

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Science  28 Jan 2000:
Vol. 287, Issue 5453, pp. 640-642
DOI: 10.1126/science.287.5453.640

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The polyketide epothilone is a potential anticancer agent that stabilizes microtubules in a similar manner to Taxol. The gene cluster responsible for epothilone biosynthesis in the myxobacteriumSorangium cellulosum was cloned and completely sequenced. It encodes six multifunctional proteins composed of a loading module, one nonribosomal peptide synthetase module, eight polyketide synthase modules, and a P450 epoxidase that converts desoxyepothilone into epothilone. Concomitant expression of these genes in the actinomyceteStreptomyces coelicolor produced epothilones A and B.Streptomyces coelicolor is more amenable to strain improvement and grows about 10-fold as rapidly as the natural producer, so this heterologous expression system portends a plentiful supply of this important agent.

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