GLUTAMINE DEPENDENT NAD+ SYNTHETASE FROM MYCOBACTERIUM TUBERCULOSIS

来自结核分枝杆菌的谷氨酰胺依赖性 NAD 合成酶

• 批准号: 7955172
• 负责人: Nicole A LaRonde
• 金额: $ 0.39万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955172
• 关键词: Active Sites; Amino Acids; Ammonia; Anabolism; Catalysis; Cell division; Cells; Coenzymes; Computer Retrieval of Information on Scientific Projects Database; Enzymes; Funding; Glutamates; Glutaminase; Glutamine; Goals; Grant; Human; Hydrolysis; Immune response; Institution; Knowledge; Ligase; Link; Longevity; Metabolic; Mycobacterium tuberculosis; Oxidation-Reduction; Pathway interactions; Production; Proteins; Purines; Pyrimidine; Pyrimidines; Reaction; Recycling; Research; Research Personnel; Resources; Role; Signal Transduction; Solvents; Source; United States National Institutes of Health; cofactor; nicotinic acid adenine dinucleotide; purine; pyridine nucleotide; structural biology

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. Substrate channeling is defined as the transfer of a metabolite from an active site to another without exchanging in the solvent. Although in several cases substrate channeling is controversial and far from being settled, it has been experimentally implicated in the reactions catalyzed by the ubiquitous multidomain enzymes of the glutamine amidotransferase (GAT) superfamily. These enzymes catalyze key metabolic reactions in protein, amino acid, cofactor, purine and pyrimidine biosyntheses, all of which have in common the hydrolysis of glutamine to glutamate and ammonia in the glutaminase active site. The ammonia produced is transfered through an inter-domain tunnel (the ammonia tunnel) to a second active site in the acceptor domain (a synthase or synthetase domain). NAD+ synthetase represents an unprecented and uncharacterized class of the GAT superfamily. It catalyzes the ATP-dependent transformation of nicotinic acid adenine dinucleotide (NaAD+) to NAD+ , the last step of the de novo biosynthesis of NAD+. NAD+ is historically known as the cofactor of enzymes involved in reduction-oxidation reactions. An emerging and important role for NAD+ is as source of molecules involved in cell signaling, cell division, cell longevity and immune response. While in humans NAD+ is obtained either from de novo biosynthesis or from the pyridine nucleotide recycling pathways, in M. tuberculosis NAD+ production relies entirely on the de novo biosynthetic pathway. The main goal of this project is to establish a link between catalysis and local dynamics in the protein and to characterize the mechanisms of interdomain signaling and of ammonia transfer in NAD+ synthetase. This project will contribute to the basic knowledge of substrate channeling and enzyme catalysis.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 底物通道是指代谢产物在溶剂中不发生交换而从一个活性位点转移到另一个活性位点。虽然在一些情况下，底物通道是有争议的，远未解决，它已被实验牵连的反应催化的无处不在的多结构域酶的谷氨酰胺酰胺转移酶（GAT）超家族。这些酶催化蛋白质、氨基酸、辅因子、嘌呤和嘧啶生物合成中的关键代谢反应，所有这些都具有在谷氨酰胺酶活性位点将谷氨酰胺水解为谷氨酸和氨的共同点。所产生的氨通过域间隧道（氨隧道）转移到受体域（合酶或合成酶域）中的第二活性位点。NAD+合成酶代表了GAT超家族中一个未知的和未表征的类别。催化烟酸腺嘌呤二核苷酸（NaAD+）向NAD+的ATP依赖性转化，这是NAD+从头生物合成的最后一步。NAD+在历史上被认为是参与还原-氧化反应的酶的辅因子。NAD+的一个新兴的重要作用是作为参与细胞信号传导、细胞分裂、细胞寿命和免疫应答的分子的来源。而在人类中，NAD+是从从头生物合成或从吡啶核苷酸再循环途径获得的，在M.结核病NAD+的产生完全依赖于从头生物合成途径。该项目的主要目标是建立蛋白质中催化和局部动力学之间的联系，并表征NAD+合成酶中结构域间信号传导和氨转移的机制。本计画将有助于对底物通道及酵素催化之基础知识之了解。