Pilot--Structure and Function in the Regulation of Glucokinase by GKRP

Morehouse College, Atlanta GA

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Abstract

The research proposed here has three specific aims which speak to the potential for therapy in the management of Non-Insulin Dependent Diabetes Mellitus (NIDDM);these include the following: (1) to determine the three-dimensional structure of rat liver glucokinase regulatory protein in the presence of fructose-1 -phosphate and in the presence of fructose-6-phosphate using protein X-ray crystallography, (2) to develop assays to test the ability of the beta-islet isoform of glucokinase regulatory protein to inhibit glucokinase in the presence and absence of hexose phosphates, (3) to use crystallographic data to model the necessary interactions and structural features required for formation of the glucokinase/glucokinase regulatory protein complex that leads to nuclear compartmentalization in hepatocytes and/or precludes compartmentalization in beta-islet cells, (4) to determine whether the beta-islet isoform of glucokinase regulatory protein can facilitate nuclear transport and/or to determine the structural characteristics which preclude this facilitation as compared to hepatic glucokinase regulatory protein, and (5) to determine the effect of glucokinase phosphorylation on glucokinase regulatory protein recognition in both hepatic and beta-islet cells. Long-term objectives of this work involve the establishment of a Center for Endocrine Disorders and Enteric Infectious Diseases at Morehouse College (CEDEID) for the advancement of interdisciplinary research toward the management of chronic endocrine disease and enteric infection. As it relates to public health, the enzyme called glucokinase, regulates two key functions that go awry in diabetic patients: secretion of insulin by the pancreas and absorption of glucose by the liver. Understanding glucokinase activity, may yield important insights into how to normalize blood glucose and may lead to the discovery of new therapeutic agents.