抗肿瘤醌那霉素的生物合成机制解析及其改造

项目名称： 抗肿瘤醌那霉素的生物合成机制解析及其改造

项目编号： No.31300033

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 蒋明

作者单位： 上海交通大学

项目金额： 24万元

中文摘要： Diazobenzo[b]fluorens是一类结构复杂和作用机制新颖的抗菌抗肿瘤化合物。Kinamycin（醌那霉素）是其中的代表化合物。醌那霉素的早期生物合成研究显示了其碳骨架的聚酮合成机制，其部分生物合成基因簇也被发现。不过醌那霉素后修饰部分的研究还很缺乏，只是通过一些变异菌株的合成产物推测了部分后修饰反应的顺序。本项目拟在前人的工作基础上，通过基因组信息分析，基因敲除与回补、体外酶学表征，发现完整的醌那霉素合成基因簇，并揭示其生物合成机制，包括碳骨架的氧化重排以及生物合成机制从未报道过的重氮基团的生物催化。在了解生物合成途径的基础上，通过合理调整代谢途径，改善酶的功能，提高醌那霉素的产量；利用酶的进化改变醌那霉素合成途径中酶的底物特异性，利用合成生物学对生物合成途径进行重新组装，引进其它合成途径中的功能元件，合成结构改变的醌那霉素衍生物。

中文关键词： 醌那霉素；生物合成基因簇；异源表达；乙酰转移酶；重氮键

英文摘要： Natural products have been a good source on modern medicines especially in providing small molecular drugs for infectious diseases and cancer. Lomaiviticin and kinamycin, which are isolated from various strains of Streptomyces and Salinispora, have a common structure of a highly oxidized tetracyclic carbon skeleton with a diazo functional group and belong to a small family of natural product, diazobenzo[b]fluorines. This family of natural products has a very good antibacterial and anticancer activities. They are nano-molar inhibitors of several cancer cell-lines through a unique mechanism. A clear understanding of the mechanism of their biological function has not been reported. The powerful biological activity and new mechanism of action of this family natural product attract numerous researchers to study their chemical synthesis and biosynthesis in order to study their unique mode of action and to produce some modified compound to improve their biological activity and. Since 2006, a series of total synthesis works of diazo[b]benzofluorene natural products have been reported although with a relatively low efficiency. Biosynthesis provides another choice to get those natural products. And synthetic biology is powerful tool to get unnatural natural product. However, the biosynthesis of this family of natural prod

英文关键词： kinamycin；biosynthetic pathway；heterologous production；acetyltransferase；diazo