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Glucokinase Regulatory ProteinThe glucokinase regulatory protein (GKRP) is a protein produced in hepatocytes (liver cells) to bind glucokinase (GK), thereby controlling both activity and intracellular location of this key enzyme of glucose metabolism. One of the important functions of GKRP is to maintain a reserve supply of GK in the nuclei for rapid release into the cytoplasm as the glucose begins to rise during a meal. GKRP is a 68 kD protein of 626 amino acids. It is coded for by a 19 exon gene on the short arm of chromosome 2 (2p23). In hepatocytes of various mammals, GKRP has always been found in molar excess of the amount of GK, but the GKRP:GK ratio varies according to diet, insulin sufficiency, and other factors. Free GKRP shuttles between the nucleus and the cytoplasm. It may be attached to the microfilament cytoskeleton. GKRP competes with glucose to bind with GK, but inactivates it when bound. In conditions of low glucose, GKRP then pulls the GK into the nucleus. Rising amounts of glucose coming into the hepatocyte prompt the GKRP to rapidly release GK to return to the cytoplasm. Fructose and sorbitol can both be converted to fructose-1-phosphate, which inhibits GKRP and frees GK. Fructose-6-phosphate binds to the same site of GKRP, but enhances the ability of GKRP to bind and inactivate GK. The glucokinase of "knockout mice" who lack GKRP is entirely found in the cytoplasm. They do not respond rapidly to glucose, exhibiting impaired glucose tolerance. Mutations of the GKRP gene in humans have been sought as possible forms of monogenic diabetes, but no examples have yet been discovered. Trace amounts of GKRP have also been detected in lung, in pancreatic islet cells, and in periventricular neurons of the hypothalamus in rats, but physiological function and significance in these organs are unknown. GKRP was discovered by Emile van Schaftingen and reported in 1989. References Van Schaftingen E (1989). A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose-6-phosphate and fructose-1-phosphate. Eur J Biochem 179:179-184. For more recent reviews, see Matschinsky FM, Magnuson MA, eds. Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Basel:Karger, 2004. ISBN 3-8055-7744-3.
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