Glucokinase

Glucokinase is a mammalian hexokinase enzyme which facilitates the phosphorylation of glucose to glucose-6-phosphate (G6P). Alternate names for this enzyme are human hexokinase IV, hexokinase D, and ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1 (previously 2.7.1.2). The common name, glucokinase, is derived from its relative specificity for glucose and minimal reactivity with mannose and fructose, unlike hexokinases I, II, and III. Molecular weight is about 50 kD.

The phosphorylation reaction mediated by glucokinase is:

Glucose + ATP → glucose-6-phosphate + ADP

Magnesium complexed to ATP is a cofactor in the reaction. Glucokinase in cell cytoplasm is associated with the glucokinase regulatory protein, which can inhibit its catalytic efficiency. Compared to other hexokinases, glucokinase is less inhibited by the product, G6P, so it continues to work in the presence of high glucose levels. It has a single binding site, but still displays kinetic cooperativity with respect to glucose.

Although phosphorylation of glucose to G6P is the first step of glycolysis, the higher K_M of glucokinase for glucose compared to other hexokinases leaves them more important initiators of glycolysis for most cells. Phosphorylation to G6P is also the first step in glycogen synthesis in the liver.

Mammalian glucokinase is located in liver cells and pancreatic islet cells, where it serves a more specialized function as a glucose sensor. The activity of glucokinase is minimal below a threshold intracellular glucose level of 5 mmol/l (about 90 mg/dl). In these cells, most of the G6P is consumed aerobically in the citric acid cycle of the mitochondria, producing far more ATP than is consumed by the initial phosphorylation.

Glucokinase regulates insulin secretion

In islet beta cells, glucokinase activity is serves as a principal control for the secretion of insulin in response to rising levels of blood glucose. As G6P is consumed in the mitochondria, increasing amounts of ATP initiate a series of processes that result in release of insulin.

Mutations cause hypoglycemia or diabetes

Mutations of the glucokinase gene GCK can change the efficiency of glucose binding and phosphorylation, increasing or decreasing the sensitivity of beta cell insulin secretion in response to glucose. Specific mutations have been discovered that can result in excessive insulin secretion (causing a form of hyperinsulinemic hypoglycemia) or deficient insulin secretion (causing a form of diabetes referred to as MODY.

References

Mahalingam B, Cuesta-Munoz A, Davis EA, Matschinsky FM, Harrison RW, Weber IT. Structural model of human glucokinase in complex with glucose and ATP: implications for the mutants that cause hypo- and hyperglycemia. Diabetes 1999 Sep;48(9):1698-705.

Cardenas ML. Glucokinase: its regulation and role in liver metabolism. R.G. Austin:Landes Co., 1995. ISBN 1-57059-207-1; International ISBN 3-540-59285-7