结核杆菌N-乙酰谷氨酸合成酶argA的结构与功能研究

Mycobacterium tuberculosis is responsible for millions of deaths worldwide annually and nearly million new infections in China every year. Due to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) M.tuberculosis strains, tuberculosis is still widespread.Currently approved anti-TB drugs have limited effect on MDR-TB and XDR-TB patients. Therefore, developing new anti-TB drugs and exploring more effective therapies are crucial and urgent. ArgA is an N-acetylglutamate synthase, and catalyzes the initial step in L-arginine biosynthesis. It has been shown to be an essential gene for the growth of Mycobacterium tuberculosis. ArgA meets mutiple requirements for anti-TB drug targets, and was approved to be a high-confidence target for anti-TB by Karthik Raman et al. There is no crystal structure of argA published so far, and the knowledge of the mechanistic detail of argA and its regulation in mycrobacteria are limited. Thus our research will fill these gaps and strongly promote the enzymatic mechanism research of argA. Furthermore, the research of small molecule inhibitors based on structure will provide important clues and reliable structural foundation for argA-based anti-TB drug screening and vaccine development.

全世界每年都有上百万人死于结核病，我国每年新增的肺结核病人接近百万。耐多药结核杆菌(MDR-TB)和广泛耐多药结核杆菌(XDR-TB)的出现，使结核病至今仍在广为传播。现有的抗结核药物对于MDR-TB和XDR-TB病人效果十分有限，因而研发治疗结核病的新药是一项重要而急迫的工作。argA具有N-乙酰谷氨酸合成酶的功能，催化L-精氨酸生物合成的初始步骤，是结核杆菌生长必须的基因。argA符合多重抗结核病的药物靶标分子的特点，被Raman K等人研究证实为高潜力的抗结核病的药物靶标蛋白。迄今为止，尚无argA的三维结构发表，对于argA具体的催化机制和调节机制也尚不清楚，本研究项目可以填补argA结构研究的空白，也可极大推进其酶活机制的研究；而根据结构进行的的小分子抑制剂的研究，对基于argA的抗结核病的药物筛选和疫苗开发工作可以提供重要线索和可靠的结构生物学基础。