ROLE OF DYNAMICS IN PEPCK MEDIATED CATALYSIS

动力学在 PEPCK 介导催化中的作用

• 批准号: 8167407
• 负责人: TODD HOLYOAK
• 金额: $ 25.54万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 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/8167407
• 关键词: Biological; Blood Glucose; Catalysis; Chronic; Computer Retrieval of Information on Scientific Projects Database; Crystallography; Development; Diabetes Mellitus; Disease; Engineering; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Funding; Goals; Grant; Hyperglycemia; Institution; Lead; Mediating; Motion; Phosphoenolpyruvate Carboxylase; Play; Process; Property; Proteins; Reaction; Research; Research Personnel; Resources; Role; Source; Time; United States National Institutes of Health; base; catalyst; design; diabetic; inhibitor/antagonist; mutant; novel

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. Diabetes-associated hyperglycemia is the underlying cause of all of the chronic complications arising from a prolonged diabetic condition. The enzyme phosphoenolpyruvate carboxykinase (PEPCK) plays a key role in the elevated blood glucose levels observed during diabetes-associated hyperglycemia. Our studies focus on understanding how PEPCK catalyzes its biological reaction and how it leads to the development of effective inhibitors of this enzyme as potent anti-hyperglycemic agents. Our application's long-term goals are to understand the role that the inherent dynamic properties of protein catalysts play in the process of enzyme mediated catalysis. The results of these studies will have broad reaching implications in the ability to design novel protein based catalysts, as well as advance our ability to design potent and selective inhibitors of biologically important enzymes in the treatment of disease. By utilizing the enzyme phosphoenolpyruvate carboxykinase our studies will lead directly to the development of selective inhibitors of this enzyme to treat diabetes-associated hyperglycemia. To achieve these goals, we will combine the strengths of x-ray crystallography and NMR to characterize not only the conformational changes that occur during catalysis, but also the time scale in which these motions occur. By correlating these structural and dynamics studies with the ability of the enzyme to carry out catalysis in both the wild-type enzyme and in mutants engineered to upset the dynamic processes, we will achieve a more thorough understanding of the particular roles that these dynamic changes play in the catalytic cycle.

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 对于中心来说，它不一定是研究者的机构。 糖尿病相关的高血糖是长期糖尿病引起的所有慢性并发症的根本原因。磷酸烯醇丙酮酸羧激酶 (PEPCK) 在糖尿病相关高血糖期间观察到的血糖水平升高中发挥着关键作用。我们的研究重点是了解 PEPCK 如何催化其生物反应，以及它如何导致开发该酶的有效抑制剂作为有效的抗高血糖药物。我们应用的长期目标是了解蛋白质催化剂的固有动态特性在酶介导的催化过程中发挥的作用。这些研究的结果将对设计新型蛋白质催化剂的能力产生广泛的影响，并提高我们设计治疗疾病的生物重要酶的有效和选择性抑制剂的能力。通过利用磷酸烯醇丙酮酸羧激酶，我们的研究将直接导致该酶的选择性抑制剂的开发，以治疗与糖尿病相关的高血糖。为了实现这些目标，我们将结合 X 射线晶体学和 NMR 的优势，不仅可以表征催化过程中发生的构象变化，还可以表征这些运动发生的时间尺度。通过将这些结构和动力学研究与酶在野生型酶和经过改造以扰乱动态过程的突变体中进行催化的能力相关联，我们将更全面地了解这些动态变化所发挥的特定作用在催化循环中。