Glucokinase

Glucokinase (GK), ATP:D-hexose 6-phosphotransferase (EC 2.7.1.1), is a glycolytic enzyme expressed mainly in the insulin-secreting pancreatic beta-cells and hepatocytes where it catalyzes the first rate limiting reaction in glycolysis; using ATP to phosphorylate glucose to glucose-6-phosphate. This enzyme is distinguished from other members of the mammalian hexokinase family by its lower affinity for glucose (Km = 8 mM versus 0.02 - 0.2 mM for hexokinases), its molecular size (50 kDa versus 100 kDa), its lack of physiologically relevant product inhibition by glucose-6-phosphate and its cooperative/sigmoidal kinetic behavior with respect to glucose. The cooperative behavior is unusual in that glucokinase functions as a monomer with a single active site. Several kinetic models have been proposed for its sigmoidal behavior. Generally, the short-term regulation of GK activity is dependent on the substrate glucose causing activation of the enzyme through a "mnemonic mechanism" as the enzyme relaxes relatively slowly from the high to low activity state. Therefore, it "remembers" its interaction with glucose analogues for a time after the release of the products. Mutations in the glucokinase (GK) gene may be the most common cause of non-insulin-dependent diabetes mellitus (NIDDM) identified to date. Over 40 different mutations in GK gene have been linked to a subtype of NIDDM called maturity-onset diabetes of the young type 2 or MODY-2.