Structures and Mechanisms of Glutamine Dependent Enzymes

描述（由申请人提供）： 的科学聚焦 这个项目的长期目标是建立一个分子基础的谷氨酰胺酰胺转移酶的结构域间的通信，涉及到他们的动态特性，以控制他们的催化效率。这项调查的目的是描绘两种酶，咪唑甘油磷酸合成酶（IGPS），和鸟苷一磷酸合成酶（GMPS），催化氨从谷氨酰胺转移到嘌呤核苷酸受体底物的主要机制和结构方面。对于谷氨酰胺转移酶亚家族考虑的一般假设是，两个活性位点之间的功能连接涉及从受体活性位点到谷氨酰胺酶位点的结合和化学能的转导。此外，谷氨酰胺底物特异性和催化效率由动态蛋白质-蛋白质相互作用控制，所述动态蛋白质-蛋白质相互作用调节氨转移的分子隧道。拟议的研究将集中在结构和机械信息，以确定域的相互作用，控制核苷酸底物激活和谷氨酰胺水解步骤的时间。 目标的意义 由于正在研究的代谢途径中存在独特的化学特征，以及将出现的详细的比较结构信息，该项目有可能影响新治疗药物的发现和开发。此外，这些酶代表了趋同进化的重要例子，这些趋同进化包含了蛋白质如何远距离传递特定化学信息的许多机制细节。总体而言，生物化学和生物物理方法的组合建议将：a）有助于全面了解氮代谢和B）提供关键信息的设计新的选择剂的潜在药理学的重要性，在氨代谢的目标必需酶。

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.