利用基因组发掘的方法在链霉菌SH-62中寻找新型天然产物的生物合成基因

从湖北省房县土壤中分离得到的链霉菌SH-62具有较好的抗细菌和抗真菌活性。基因组测序分析发现该链霉菌中含有非常丰富的天然产物生物合成基因的资源。本项目研究希望利用基因组测序所获得的信息，采用基因组发掘的方法，在链霉菌SH-62中寻找新的天然产物合成基因簇并展开相关的功能研究。通过分析基因簇中各基因的功能及组成，初步推测其对应的天然产物的化学结构类型；利用基因中断和基因敲除技术，找到负责该链霉菌发酵产物中活性化合物生物合成的基因簇；同时利用异源表达的方法，将可能的"隐形生物合成基因簇"导入遗传和代谢背景清晰的模式链霉菌中，尝试激活或提高其表达水平，从而产生新的天然产物。对这些克隆到的基因簇展开进一步的功能分析，揭示其生物合成机制，将为后期组合生物合成的研究以及新药的开发和应用奠定基础。

Streptomyces SH-62 isolated from soil in Fangxian Country, Hubei Province, exhibits strong antibacterial and antifungal activities. Genome sequence analyses of Streptomyces SH-62 disclosed that there are a lot of putative secondary metabolite gene clusters in the genome of this species and some of these clusters appear to be completely novel. Based on data from genome analyses, we plan to use genome mining techniques to reveal new natural products and their biosynthetic gene clusters from Streptomyces SH-62. According to the correspondence of catalytic enzymes to biosynthetic reactions, the putative structure type of natural products could be inferred by analyzing functions and organization of their biosynthetic genes. The biosynthetic clusters of the bioactive compounds produced by wild type Streptomyces SH-62 could be determined through gene disruption and gene knockout. Meanwhile, new natural products might be produced by heterologous expression of some cryptic gene clusters isolated from the Streptomyces SH-62 genome in the model Streptomyces host strains. Further functional study of these targeted gene clusters will disclose biosynthetic pathways of new natural products and provide more enzymatic systems for combinatorial biosynthesis.