NICOTINAMIDASES AS ANTIBIOTIC TARGETS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 烟酰胺腺嘌呤二核苷酸(NAD)是一种在整个生命周期中普遍存在的分子，它不仅是氧化还原反应中的辅助因子，而且还可以作为腺苷二磷酸核糖(ADPR)的供体。“NAD消耗”酶，包括ADP-核糖基转移酶、多聚ADP-核糖基聚合酶、cADP-核糖合成酶和Sir2蛋白去乙酰基酶，可以迅速消耗细胞内的NAD储备，并在此过程中产生烟酰胺。不仅NAD池需要补充，而且产生的烟酰胺可以作为这些NAD消耗酶的反馈抑制物。虽然哺乳动物可以直接使用烟酰胺来回收NAD，但大多数低等生物必须首先使用烟酰胺酶将其转化为烟酸。烟酰胺酶不仅在NAD循环中发挥重要作用，它还可以通过控制细胞内烟酰胺的水平来调节NAD消耗酶。此外，这种酶还被证明可以催化结核病前药吡津酰胺转化为其活性形式吡津酸。到目前为止，已完成的结构研究提供的关于该酶活性部位的底物结合的信息很少。对配体结合的深入研究将提供有关该酶活性部位的重要信息，从而能够更深入地了解该酶的作用机理，并为结构导向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. 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. 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.