P-2 抗腫瘍抗生物質ビセニスタチンの生合成酵素の機能解析とその応用(ポスター発表の部)

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Vicenistatin, an antitumor antibiotic isolated from Streptomyces halstedii HC 34, is composed of amino sugar vicenisamine and 20-membered vicenilactam. We are interested in the biosynthesis of vicenistatin, and its whole gene cluster (vin) has been already identified to elucidate the biosynthetic pathway of vicenistatin. In the present study, we report the functional analysis of glycosyltransferase (VinC) and thioesterase (TE) domain involved in vicenistatin biosynthesis. Recently, we identified that VinC is a glycosyltransferase which catalyzes the glycosylation of dTDP-vicenisamine and vicenilactam. In order to construct structurally diverse glycosides, VinC was applied to trans-glycosylation with structurally diverse glycosyl donors and acceptors. At first, several dTDP-sugars were attempted as glycosyl donor with vicenilactam. As a result, 2-deoxy sugars, D-mycarose and 2-deoxy-D-glucose, were recognized and transferred to vicenilactam. Furthermore, VinC was found to catalyze trans-glycosylation of vicenisamine to structurally unrelated aglycons including β-estradiol, brefeldin A and so on. A recognition mechanism was estimated by the comparison of structures between vicenilactam and accepted aglycons. Next, VinC was subjected to a new method to prepare unnatural glycosides. This method is composed of two reactions; in situ generation of NDP-sugar from natural glycoside by reverse reaction, which is subsequently transferred to a targeted acceptor by itself. In fact, preparation of respective vicenisaminides by this method was successfully demonstrated. A macrocyclization/enzyme release of polyketides from polyketide synthase is essential reaction. This cyclorelease is usually catalyzed by TE domain, and as to a macrolactone formation, it is identified that the isolated TE domain retains a capacity of cyclization. However, there has been no information to the macrolactam formation in polyketide biosynthesis. In vin cluster, the functional domain homologous to TE was identified in the last module of VinP4, and this functional domain (VinP4-TE) is expected to catalyze a macrolactamization. Actually, the catalytic function with VinP4-TE from N-acetyl-cysteamine thioester of seco-vicenilactam to vicenilactam was identified as a macrolactamization. This is the first example that thioesterase domain is able to catalyze the cyclization to form macrolactam in polyketide biosynthesis.
天然有機化合物討論会の論文
2005-09-15

P-2 抗腫瘍抗生物質ビセニスタチンの生合成酵素の機能解析とその応用(ポスター発表の部)

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