GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:17028192

From GONUTS
Jump to: navigation, search
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

Significance

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

See also

References

See Help:References for how to manage references in GONUTS.