Structures and Mechanisms of Glutamine Dependent Enzymes

谷氨酰胺依赖性酶的结构和机制

• 批准号: 6680695
• 负责人: Vincent Jo Davisson
• 金额: $ 27.77万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6680695
• 关键词: X ray crystallography; active sites; ammonia; biochemistry; biophysics; catalyst; chemical kinetics; conformation; enzyme mechanism; enzyme structure; enzyme substrate; glutaminase; glutamine; guanosine monophosphate; hydrolysis; imidazole; ligands; nitrogen metabolism; protein protein interaction; site directed mutagenesis; stop flow technique

DESCRIPTION (provided by applicant): Scientific Focus The long-term goals of this project are to establish a molecular basis for the interdomain communication in glutamine amidotransferases that relates their dynamic properties to the control of their catalytic efficiencies. This investigation aims to delineate the major mechanistic and structural aspects of two enzymes, imidazole glycerol phosphate synthase (IGPS), and guanosine monophosphate synthetase (GMPS), which catalyze the transfer of ammonia from glutamine to a purine nucleotide acceptor substrate. The general hypothesis under consideration for the glutamine amidotransferase sub-family is that the functional link between the two active sites involves the transduction of binding and chemical energy from the acceptor active site to the glutaminase site. Furthermore, the glutamine substrate specificity and catalytic efficiency is controlled by dynamic protein-protein interactions that modulate a molecular tunnel for ammonia transfer. The proposed studies will focus upon structural and mechanistic information to define the domain interactions that control the timing of the nucleotide substrate activation and glutarnine hydrolysis steps. Significance of objectives Because of the unique chemical features present in the metabolic pathway under investigation, and the detailed comparative structural information that will emerge, this project has the potential to impact the discovery and development of new therapeutic agents. In addition, these enzymes represent important examples of convergent evolution that hold many mechanistic details of how proteins transmit specific chemical information over large distances. Overall, the combination of biochemical and biophysical approaches proposed will: a) contribute to a comprehensive knowledge regarding nitrogen metabolism and b) provide critical information for the design of new selective agents of potential pharmacological importance that target essential enzymes in ammonia metabolism.

描述（由申请人提供）： 科学重点，该项目的长期目标是为谷氨酰胺酰胺酰胺氨基转移酶的域间通信建立分子基础，该酶将其动态特性与控制其催化效率的控制联系起来。这项研究旨在描述两种酶的主要机械和结构方面，咪唑甘油磷酸合酶（IGP）和鸟苷单磷酸合成酶（GMPS），它们催化氨氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨基氨酸的转移到嘌呤核苷酸接受剂。谷氨酰胺酰胺转移酶亚元素的一般假设是，两个活性位点之间的功能联系涉及结合和化学能从受体活性位点转移到谷氨酰胺酶位点。此外，谷氨酰胺底物的特异性和催化效率受动态蛋白 - 蛋白质相互作用的控制，该蛋白质蛋白质相互作用调节分子隧道进行氨转移。拟议的研究将集中于结构和机械信息，以定义控制核苷酸底物激活和谷氨酸水解步骤的时间的域相互作用。 目标的重要性是由于所研究的代谢途径中存在的独特化学特征以及将出现的详细比较结构信息，因此该项目有可能影响新治疗剂的发现和开发。此外，这些酶代表了收敛进化的重要例子，这些酶持有许多机械详细信息，这些酶详细介绍了蛋白质如何在较大距离内传输特定的化学信息。总体而言，提出的生化和生物物理方法的结合将：a）有助于有关氮代谢的全面知识，b）为设计潜在的药理学重要性的新选择剂提供了关键信息，以靶向氨代谢中的必需酶。