ENERGETIC COUPLING OF LIGAND BINDING AND CONFORMATIONAL CHANGE IN PHOSPHOENOLPYR

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级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酸激酶在新陈代谢中起着重要的作用，作为一种通用的促糖酶在糖异生和甘油异生中发挥作用。此外，最近的研究表明，PEPCK在葡萄糖刺激的胰腺胰岛素释放途径中发挥了作用。我们的工作重点是了解PEPCK执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，通过设计用于活性位点抑制的化合物来对物种内不同的PEPCK同工酶以及物种间的酶进行特定的调节将是困难的，如果不是不可能的话。因此，我们对构象采样在PEPCK中作用的理解的扩展可以提供在疾病和感染的治疗中对特定的PEPCK同工酶进行变构调节的能力。

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.