Abstract
Genes for biosynthesis of a Streptomyces sp. FR-008 heptaene macrolide
antibiotic with antifungal and mosquito larvicidal activity were
cloned in Escherichia coli using heterologous DNA probes. The cloned
genes were implicated in heptaene biosynthesis by gene replacement.
The FR-008 antibiotic contains a 38-membered, polyketide-derived
macrolide ring. Southern hybridization using probes encoding domains
of the type I modular erythromycin polyketide synthase (PKS) showed
that the Streptomyces sp. FR-008 PKS gene cluster contains repeated
sequences spanning c. 105kb of contiguous DNA; assuming c. 5 kb
for each PKS module, this is in striking agreement with the expectation
for the 21-step condensation process required for synthesis of the
FR-008 carbon chain. The methods developed for transformation and
gene replacement in Streptomyces sp. FR-008 make it possible to
genetically manipulate polyene macrolide production, and may later
lead to the biosynthesis of novel polyene macrolides.
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