PMID:17028192

Citation	Futamura, M, Hosaka, H, Kadotani, A, Shimazaki, H, Sasaki, K, Ohyama, S, Nishimura, T, Eiki, J and Nagata, Y (2006) An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism. J. Biol. Chem. 281:37668-74
Abstract	Glucokinase (GK) plays a key role in the control of blood glucose homeostasis. We identified a small molecule GK activator, compound A, that increased the glucose affinity and maximal velocity (V(max)) of GK. Compound A augmented insulin secretion from isolated rat islets and enhanced glucose utilization in primary cultured rat hepatocytes. In rat oral glucose tolerance tests, orally administrated compound A lowered plasma glucose elevation with a concomitant increase in plasma insulin and hepatic glycogen. In liver, GK activity is acutely controlled by its association to the glucokinase regulatory protein (GKRP). In order to decipher the molecular aspects of how GK activator affects the shuttling of GK between nucleus and cytoplasm, the effect of compound A on GK-GKRP interaction was further investigated. Compound A increased the level of cytoplasmic GK in both isolated rat primary hepatocytes and the liver tissues from rats. Experiments in a cell-free system revealed that compound A interacted with glucose-bound free GK, thereby impairing the association of GK and GKRP. On the other hand, compound A did not bind to glucose-unbound GK or GKRP-associated GK. Furthermore, we found that glucose-dependent GK-GKRP interaction also required ATP. Given the combined prominent role of GK on insulin secretion and hepatic glucose metabolism where the GK-GKRP mechanism is involved, activation of GK has a new therapeutic potential in the treatment of type 2 diabetes.
Links	PubMed Online version:10.1074/jbc.M605186200
Keywords	Active Transport, Cell Nucleus/drug effects; Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Adenosine Triphosphate/metabolism; Adenosine Triphosphate/pharmacology; Allosteric Regulation; Animals; Benzamides/chemistry; Benzamides/pharmacology; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell-Free System; Cells, Cultured; Enzyme Activation/drug effects; Glucokinase/genetics; Glucokinase/metabolism; Glucose/metabolism; Glucose/pharmacology; Hepatocytes/drug effects; Hepatocytes/metabolism; Humans; Insulin/secretion; Islets of Langerhans/drug effects; Islets of Langerhans/secretion; Male; Rats; Rats, Wistar; Recombinant Proteins/genetics; Recombinant Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:HXK4	located_in	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
RAT:HXK4	located_in	GO:0005737: cytoplasm	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
RAT:HXK4	part_of	GO:0005634: nucleus	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
RAT:HXK4	involved_in	GO:0032024: positive regulation of insulin secretion	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
RAT:HXK4	part_of	GO:0005737: cytoplasm	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
RAT:HXK4	involved_in	GO:0005978: glycogen biosynthetic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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