ENERGETIC COUPLING OF LIGAND BINDING AND CONFORMATIONAL CHANGE IN PHOSPHOENOLPYR

配体结合的能量耦合和膦酰基的构象变化

• 批准号: 8362421
• 负责人: TODD HOLYOAK
• 金额: $ 0.03万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8362421
• 关键词: Active Sites; Catalysis; Coupling; Disease; Enzymes; Funding; Gluconeogenesis; Glucose; Grant; Infection; Insulin; Isoenzymes; Ligand Binding; Metabolism; National Center for Research Resources; Pancreas; Pathway interactions; Phosphoenolpyruvate Carboxylase; Play; Principal Investigator; Process; Radiation; Regulation; Research; Research Infrastructure; Resources; Role; Sampling; Source; United States National Institutes of Health; Vertebrates; Work; cost; design; flexibility; 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. In vertebrates, phosphoenolpyruvate carboxykinase plays an important role in metabolism, operating as a general cataplerotic enzyme functioning in the gluconeogenesis and glyceroneogenesis pathways. Additionally, recent work suggests a role for PEPCK in the pathway of glucose stimulated insulin release in the pancreas. Our work focuses on understanding both the mechanism by which PEPCK carries out catalysis as well as the role of conformational flexibility in that catalytic process. As the active sites of all PEPCKs are highly conserved, the specific regulation of different PEPCK isozymes within a species as well as enzymes between species via compounds designed for active site inhibition would be difficult if not impossible. Therefore, the expansion of our understanding of the role of conformational sampling in PEPCK could provide the ability to allosterically regulate specific PEPCK isozymes in the treatment of disease and infection.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 在脊椎动物中，磷酸烯醇式丙酮酸羧激酶在代谢中起重要作用，作为一种通用的分解酶，在代谢产物生成和甘油生成途径中起作用。此外，最近的工作表明PEPCK在胰腺中葡萄糖刺激的胰岛素释放途径中的作用。我们的工作重点是了解PEPCK进行催化的机制以及构象灵活性在催化过程中的作用。由于所有PEPCK的活性位点都是高度保守的，因此通过设计用于活性位点抑制的化合物特异性调节物种内的不同PEPCK同工酶以及物种之间的酶即使不是不可能，也是困难的。因此，我们对构象取样在PEPCK中的作用的理解的扩展可以提供在疾病和感染的治疗中变构调节特定PEPCK同工酶的能力。