M TUBERCULOSIS ADENOSINE KINASE AND ANTI-MICROBIAL NUCLEOSIDE ANALOGS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。结核分枝杆菌是一种机会性感染病原体，在世界范围内引起结核病和发病率和死亡率。耐多药（MDR）菌株的出现和艾滋病相关结核感染导致迫切需要开发新的有效的结核病治疗药物。来自结核分枝杆菌的腺苷激酶（Mtb-AK）最近被确定为负责一组核苷类似物抗结核分枝杆菌的生物激活。我们的长期目标是通过利用嘌呤回收途径中的关键酶Mtb-AK对核苷前药的特异性激活来开发新的抗细菌药物。我们的具体目标是：1)表征不同形式的Mtb-AK的晶体结构，洗脱结核分枝杆菌中腺苷磷酸化和腺苷类似物生物活化的酶反应机制。2)表征酶对底物偏好的结构基础，以及mmb - ak能更有效和选择性激活的核苷类似物的结构特征。3)利用先导的腺苷类似物表征Mtb-AK复合物的结构，为核苷类似物的优化提供结构基础。

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.