Additive activation of glucokinase by the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and the chemical activator LY2121260
| Autor: | Anke Brix, Sigurd Lenzen, Sara Langer, H Schmitt, Simone Baltrusch |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Phosphofructokinase-2
Mannoheptulose 030209 endocrinology & metabolism Biology Carbohydrate metabolism Biochemistry Cell Line law.invention 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine law Glucokinase Insulin Secretion Humans Insulin Phosphofructokinase 2 Sulfones Enzyme Inhibitors 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences Activator (genetics) Heptoses Recombinant Proteins Enzyme Activation Thiazoles Glucose Enzyme chemistry Recombinant DNA Phosphorylation |
| Zdroj: | Biochemical Pharmacology. 83:1300-1306 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2012.01.020 |
| Popis: | The glucose phosphorylating enzyme glucokinase plays a crucial role in stimulus-secretion coupling in pancreatic beta cells and in glucose metabolism in liver. Glucose mediates a shift of the enzyme's conformational equilibrium towards the closed conformation with high glucokinase activity. Further activation of glucokinase is endogenously mediated by interaction with the bisphosphatase domain (FBPase-2) of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/FBPase-2) and can be achieved also by a new class of glucokinase activators (GKA), chemical compounds that might be suited for type 2 diabetes therapy. While FBPase-2 increased only the phosphorylating capacity of glucokinase, the GKA LY2121260 augmented in addition the affinity of glucokinase for glucose. PFK-2/FBPase-2 but not LY2121260 antagonized glucokinase inhibition by the competitive glucokinase inhibitor mannoheptulose at increasing glucose concentrations. Interestingly, an additive activation of glucokinase was observed by use of recombinant FBPase-2 together with LY2121260. This new crucial observation could be confirmed with cellular extracts containing the glucokinase and PFK-2/FBPase-2 proteins. Addition of LY2121260 resulted in a further significant increase in glucokinase activity. Because the glucokinase-PFK-2/FBPase-2 complex was conserved under LY2121260 treatment as shown by size exclusion chromatography a concerted action of both activators towards the closed active glucokinase conformation can be anticipated. Thus, as a result of the additive effect of both activators on glucokinase activity, the largest increase of glucose-induced insulin secretion was observed in the combined presence of PFK-2/FBPase-2 and LY2121260. |
| Databáze: | OpenAIRE |
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