NICOTINAMIDASES AS ANTIBIOTIC TARGETS

烟酰胺酶作为抗生素靶点

• 批准号: 8361651
• 负责人: STEVEN E EALICK
• 金额: $ 0.11万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361651
• 关键词: Active Sites; Adenosine Diphosphate Ribose; Antibiotics; Binding; Cyclic ADP-Ribose; Deacetylase; Drug Design; Enzymatic Biochemistry; Enzymes; Feedback; Funding; Grant; Life; Ligand Binding; Ligase; Lower Organism; Mammals; National Center for Research Resources; Niacinamide; Nicotinamidase; Nicotinamide adenine dinucleotide; Nicotinic Acids; Oxidation-Reduction; Play; Polymerase; Principal Investigator; Process; Prodrugs; Proteins; Pyrazinamide; Reaction; Recycling; Research; Research Infrastructure; Resources; Role; Source; Structure; Transferase; Tuberculosis; United States National Institutes of Health; cofactor; cost; inhibitor/antagonist; pyrazinoic acid; structural biology

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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 烟酰胺腺嘌呤二核苷酸(NAD)是一种在整个过程中普遍存在的分子 它不仅是氧化还原反应中的一个辅助因子，而且还可以作为 二磷酸腺苷核糖(ADPR)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 Sir2蛋白脱乙酰酶，可以迅速耗尽细胞内的NAD储备，并在此过程中 产生烟酰胺。不仅需要补充NAD池， 但产生的烟酰胺可以作为这些NAD消费的反馈抑制物 酵素。虽然哺乳动物可以直接使用烟酰胺来循环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循环中起着关键作用，它还可以作为一种 通过控制细胞烟酰胺水平来调节NAD消耗酶。 此外，这种酶已被证明可以催化结核杆菌的转化。 前体药物，吡津酰胺，转化为其活性形式，吡津酸。结构研究已完成 到目前为止，几乎没有提供关于底物在这个活性部位结合的信息 酵素。对配体结合的深入研究将提供有关这方面的重要信息。 酶的活性部位有助于更深入地了解酶的作用机理 并为以结构为导向的药物设计工作提供必要的细节。