M TUBERCULOSIS ADENOSINE KINASE AND ANTI-MICROBIAL NUCLEOSIDE ANALOGS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。结核分枝杆菌是一种机会性感染病原体，在世界范围内导致结核病和发病率和死亡率。多药耐药(MDR)菌株的出现和艾滋病相关的结核病感染导致了对开发新的有效的结核病治疗药物的迫切需求。来自结核分枝杆菌的腺苷激酶(Mtb-AK)最近被发现是一组核苷类似物抗结核分枝杆菌的生物激活因子。我们的长期目标是通过利用核苷前体药物Mtb-AK的特异性激活来开发新的抗分枝杆菌药物，Mtb-AK是嘌呤挽救途径中的关键酶。我们的具体目标是：1)。研究结核分枝杆菌不同形式的Mtb-AK的晶体结构，阐明参与腺苷磷酸化和腺苷类似物生物活性的酶反应机制。2)研究Mtb-AK能更有效和选择性地激活核苷类似物的底物选择的结构基础和结构特征。3)用先导腺苷类似物表征Mtb-AK络合物结构，为优化核苷类似物的结构奠定基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mycobacterium tuberculosis is an opportunistic infection pathogen that causes TB and morbidity and mortality worldwide. The emergence of multi-drug resistance (MDR) strains and the AIDS-associated TB infection has led to a critical need for the development of new and effective therapeutic agents for the TB treatment. Adenosine kinase from M. tuberculosis (Mtb-AK) has recently been identified to be responsible for the bioactivation of a group of nucleoside analogs against M. tuberculosis. Our long-term goal is to develop new antimycobacterial agents by exploiting the specific activation of a nucleoside prodrug by Mtb-AK, a key enzyme in the purine salvage pathway. Our specific aims are: 1). to characterize the crystal structure of Mtb-AK in different forms and to elute the enzyme reaction mechanism involved in adenosine phosphorylation and bioactivation of adenosine analogs in M. tuberculosis. 2) To characterize the structural basis of the enzyme's substrate preferences and the structural features of nucleoside analogs that can be activated more efficiently and selectively by Mtb-AK. 3) To characterize the Mtb-AK complex structures with the lead adenosine analogs and the structural basis for optimization of nucleoside analogs.