|Topic:||Regulation of Hepatic Glycolytic Flux by Glucokinase .|
|Details:||A major level of control over hepatic glucokinase activity is exerted by the protein identified as glucokinase regulatory protein (GKRP) encoded by the GCKR gene. The GCKR gene is located on chromosome 2p23.3 and is composed of 20 exons that encode a protein of 625 amino acids. Expression of the GCKR gene is exclusively hepatic. During the fasting state, glucokinase is "held" in the nucleus by interaction with GKRP. This localization prevents glucokinase access to cytosolic glucose until it is released from GKRP. At sufficient intracellular levels of glucose, glucokinase is released from GKRP and can begin to phosphorylate cytosolic glucose. In addition to glucose, fructose-1-phosphate (F1P), derived from the action of hepatic fructokinase phosphorylating fructose, stimulates the release for glucokinase from GKRP. Indeed, the ability of F1P to stimulate release of glucokinase from GKRP ultimately contributes to the potentially lethal hypoglycemia associated with the fructose metabolic disorder, hereditary fructose intolerance. This latter effect results from inappropriate release of glucokinase to the cytosol leading to the phosphorylation of glucose, thereby, trapping the glucose within hepatocytes. The activity of GKRP is also regulated by binding of fructose-6-phosphate (F6P) as well as by phosphorylation. The binding of F6P to GKRP enhances the binding of GKRP to glucokinase. This essentially prevents the generation of more glucose-6-phosphate under conditions that would be associated with rising levels of F6P such as adequate glycogen stores and ATP levels within hepatocytes. The phosphorylation of GKRP occurs through the action of AMPK which results in the release of glucokinase from GKRP. The activity of AMPK rises as the energy charge falls (increasing AMP levels), therefore, it would make sense for the hepatocyte to increase energy production via glycolysis which would be enhanced by increased glucokinase activity.|
COPYRIGHT ©2019 . All Rights Reserved.