Glucokinase

Glucokinase, also called hexokinase IV, is a cytosolic enzyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate using one molecule of ATP. This step commits glucose to glycolysis, glycogen synthesis, and lipid synthesis in the liver and is essential for proper carbohydrate sensing in pancreatic beta cells. It is distinguished from hexokinases I–III by its regulatory properties and kinetic behavior.

Glucokinase has a relatively high Km for glucose (about 8–10 mM) and a high maximum velocity, enabling it to respond to rises in blood glucose with increased phosphorylation capacity. Unlike other hexokinases, it is not inhibited by glucose-6-phosphate, and its activity is modulated by the glucokinase regulatory protein (GKRP) in the liver.

In the liver, GKRP binds glucokinase at low glucose levels and sequesters it in the nucleus. Elevated glucose causes GKRP release, translocation of glucokinase to the cytoplasm, and stimulation of glycolysis and lipogenesis. In pancreatic beta cells, glucokinase acts as a glucose sensor that links glucose entry to insulin secretion. Insulin and glucose availability regulate GCK gene expression.

Clinical relevance: Mutations in GCK cause maturity-onset diabetes of the young type 2 (MODY2), typically with mild fasting hyperglycemia. Loss of glucokinase activity reduces pancreatic insulin response and hepatic glucose handling. Conversely, pharmacological glucokinase activators are studied as potential therapies for type 2 diabetes, aiming to increase hepatic glucose uptake and insulin release.

Structure and genetics: Glucokinase is a ~50-kilodalton catalytic protein that functions as a monomer and interacts with GKRP in the liver. The enzyme is encoded by the GCK gene; regulation occurs via GKRP binding and cellular localization, substrate availability, and hormonal signals.