NICOTINAMIDASES AS ANTIBIOTIC TARGETS

烟酰胺酶作为抗生素靶点

• 批准号: 8169277
• 负责人: STEVEN E EALICK
• 金额: $ 0.38万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169277
• 关键词: Active Sites; Adenosine Diphosphate Ribose; Antibiotics; Binding; Computer Retrieval of Information on Scientific Projects Database; Cyclic ADP-Ribose; Deacetylase; Drug Design; Enzymatic Biochemistry; Enzymes; Feedback; Funding; Grant; Institution; Life; Ligand Binding; Ligase; Lower Organism; Mammals; Niacinamide; Nicotinamidase; Nicotinamide adenine dinucleotide; Nicotinic Acids; Oxidation-Reduction; Play; Polymerase; Process; Prodrugs; Proteins; Pyrazinamide; Reaction; Recycling; Research; Research Personnel; Resources; Role; Source; Structure; Transferase; Tuberculosis; United States National Institutes of Health; cofactor; inhibitor/antagonist; pyrazinoic acid

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 烟酰胺腺嘌呤二核苷酸 (NAD) 是一种在整个生命中普遍存在的分子，不仅作为氧化还原反应中的辅助因子至关重要，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 Sir2 蛋白脱乙酰酶，可以快速耗尽细胞 NAD 储备，并在此过程中产生烟酰胺。 不仅需要补充NAD池，而且产生的烟酰胺可以充当这些NAD消耗酶的反馈抑制剂。 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 回收中发挥重要作用，还可以通过控制烟酰胺的细胞水平来充当 NAD 消耗酶的调节剂。 此外，该酶已被证明可以催化结核病前药吡嗪酰胺转化为其活性形式吡嗪酸。 迄今为止完成的结构研究几乎没有提供有关该酶活性位点底物结合的信息。 对配体结合的彻底研究将提供有关该酶活性位点的重要信息，从而可以更深入地了解酶学机制，并为结构指导的药物设计工作提供必要的细节。