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