1 遺伝子解析に基づくポリケチド抗生物質halstoctacosanolideの単離、構造決定(口頭発表の部)

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Natural products produced by microorganism have been contributing to our life. Especially in a medicinal field, various bioactive natural products play important roles. However, even now more variety of compounds has been strongly demanded for establishment of the tailor-made medicine and for problem of drug resistance. The recent remarkable advances in genetic technology allow us to estimate the putative function of enzymes. In this research, a methodology of search for new natural compounds based on gene information was developed. Streptomyces halstedii HC34 is a producer of polyketide antitumor antibiotic vicenistatin. During the analysis of vicenistatin biosynthetic genes, the polyketide synthase (PKS) genes, which are different from vicenistatin, were cloned from S. halstedii. This strongly suggested that S. halstedii produced a new polyketide, which led us to start the isolation study. The inspection of the fermentation broth of S. halstedii resulted in isolating new polyketide compounds, halstoctacosanolides A and B. By several NMR experiments, those structures were determined to have a 28-membered macrolactone. The deduced structures are identical with the partial structure predicted by domain pattern of the cloned PKSs. Further, the whole halstoctacosanolide biosynthetic gene cluster (his cluster), which had remained unidentified part, was clarified. The complete hls cluster spanning 100kbp include nine genes, and these genes encode seven PKSs (hlsA-G) and two cytochrome P450 monooxygenases (hlsH, 1). The module structures of these PKS genes well reflect the chemical structure of halstoctacosanolides. Then, the gene disruptions of each P450 gene were carried out. The prepared hlsH gene mutant lost the productivity of halstoctacosanolide A, and the hlsI gene mutant did not produce halstoctacosanolides A and B. These results clearly indicated that HlsH and HlsI were responsible for the oxidation at C-4 and C-32, respectively. Furthermore, a new derivative, halstoctacosanolide C, was successfully isolated from the hlsI mutant and the structure was determined as 32-deoxyhalstoctacosanolide B.
天然有機化合物討論会の論文
2006-09-15

1 遺伝子解析に基づくポリケチド抗生物質halstoctacosanolideの単離、構造決定(口頭発表の部)

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