ENERGETIC COUPLING OF LIGAND BINDING AND CONFORMATIONAL CHANGE IN PHOSPHOENOLPYR

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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.