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J. Antibiot. 59(1): 4452, 2006
THE JOURNAL OF
ORIGINAL ARTICLE
ANTIBIOTICS
The Complete Biosynthetic Gene Cluster of the 28-Membered Polyketide Macrolactones, Halstoctacosanolides, from Streptomyces halstedii HC34
Shigehiro Tohyama, Katsumi Kakinuma, Tadashi Eguchi
Received: November 29, 2005 / Accepted: December 23, 2005 Japan Antibiotics Research Association
Abstract Halstoctacoanolides A and B are 28-membered polyketide macrolactones and were isolated from Streptomyces halstedii HC34. The biosynthetic gene cluster (hls cluster) of halstoctacosanolides was completely identied from the genome library of Streptomyces halstedii HC34. DNA sequence analysis of ca. 100 kb region revealed that there were seven type I polyketide synthases (PKSs) and two cytochrome P450 monooxygenases in this cluster. Involvement of the gene cluster in the halstoctacosanolide biosynthesis was demonstrated by the gene disruption of P450 monooxygenase genes. The mutants produced a new deoxygenated halstoctacosanolide derivative, halstoctacosanolide C, which conrmed that the hls gene cluster was essential for the biosynthesis of halstoctacosanolides.
Keywords halstoctacosanolides, biosynthetic gene cluster, polyketide synthase, P450 monooxygenase, gene disruption
Introduction
Polyketide macrolides are one of the largest bioactive natural product families. They have various complex structures and a huge variety of bioactivities have been reported for them. Three examples are the antibiotic erythromycin, immunosuppressant rapamycin and the
antitumor agent epothilone, and there are many other polyketide macrolides that are clinically important [1]. Polyketide chains are generally biosynthesized in a similar manner by the multi-modular enzymes, type I polyketide synthases (PKSs) [1]. Each module is responsible for one elongation of an extender unit and modication of the b -carbon by coordinated domains. In generally, the polyketide structures well reect the domain structure of its own biosynthetic PKSs. Because these domain structures are easily assigned from the gene information, it is now possible to predict the polyketide structure biosynthesized by PKSs when once the DNA sequences of the genes encoding PKSs are determined. Based on this context, the predictions of the polyketide productivity and the searches of new polyketide compounds from organisms having the PKS genes, especially from the major secondary metabolite producer actinomycetes, have been accomplished [2 6].
Molecular genetic studies of the actinomycetes, thus, present promising opportunities for the discovery of a new polyketide compound potentially useful for drug development.
T. Eguchi (Corresponding author), S. Tohyama, K. Kakinuma:
Department of Chemistry & Materials...