NICOTINAMIDASES AS ANTIBIOTIC TARGETS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 烟酰胺腺嘌呤二核苷酸（NAD）是一种普遍存在于 它不仅是氧化还原反应中必不可少的辅助因子，而且还可以作为 腺苷二磷酸核糖（ADPR）供体。“NAD消耗”酶，包括 ADP-核糖基转移酶、聚ADP-核糖基聚合酶、cADP-核糖合成酶和 Sir 2蛋白脱乙酰基酶，可以快速消耗细胞NAD储备，并且在此过程中 生产烟酰胺。不仅需要补充NAD库， 但是产生的烟酰胺可以作为这些NAD消耗的反馈抑制剂， 内切酶虽然哺乳动物可以直接使用烟酰胺来回收NAD，但大多数较低 生物体必须首先使用烟酰胺酶将其转化为烟酸。不 烟酰胺酶不仅在NAD再循环中发挥重要作用，它还可以作为一种 通过控制烟酰胺的细胞水平来调节NAD消耗酶。 此外，这种酶已被证明可以催化结核杆菌的转化， 将前药吡嗪酰胺转化为其活性形式吡嗪酸。完成结构研究 到目前为止，关于底物结合在该活性位点的信息很少。 酵素对配体结合的深入研究将提供这方面的重要信息 酶的活性位点，从而更深入地了解酶的机理 并为结构指导的药物设计工作提供必要的细节。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Nicotinamide adenine dinucleotide (NAD) is a molecule that is ubiquitous throughout all of life and is essential not only as a cofactor in redox reactions, but can also act as an adenosine diphosphate ribose (ADPR) donor. 'NAD consuming' enzymes, including ADP-ribosyl transferase, poly-ADP-ribosyl polymerase, cADP-ribose synthetase, and Sir2 protein deacetylase, can rapidly deplete cellular NAD stocks and in the process produce nicotinamide. Not only is it necessary for the NAD pool to be replenished, but the nicotinamide produced can act as a feedback inhibitor of these NAD consuming enzymes. While mammals can use nicotinamide directly to recycle NAD, most lower organisms must first convert it into nicotinic acid using a nicotinamidase enzyme. Not only does nicotinamidase play an essential role in NAD recycling, it can also act as a regulator of the NAD consuming enzymes by controlling cellular levels of nicotinamide. In addition, this enzyme has been shown to catalyze the conversion of the tuberculosis prodrug, pyrazinamide, into its active form, pyrazinoic acid. Structural studies completed to date have provided little information about substrate binding in the active site of this enzyme. A thorough study of ligand binding will provide crucial information about this enzyme's active site allowing for a deeper understanding of the mechanistic enzymology and providing essential details for structure-guided drug design efforts.