Glucokinase (GK) (GK)

Glucokinase (GK), also known as hexokinase 4 (HK4), is a member of the hexokinase family of enzymes that catalyzes the phosphorylation of glucose to glucose-6-phosphate, the first step in glycolysis. It is primarily expressed in the liver and pancreatic beta cells, where it functions as a glucose sensor due to its unique kinetic properties, including a high Km for glucose and lack of product inhibition by glucose-6-phosphate (UniProt P35557). In the pancreas, GK activity regulates the threshold for insulin secretion, while in the liver, it facilitates glucose uptake and glycogen synthesis in response to elevated blood sugar (PubMed: 21242101). Mutations in the GCK gene are associated with Maturity-Onset Diabetes of the Young type 2 (MODY2) and permanent neonatal diabetes mellitus (StatPearls: NBK549851). Therapeutic development has focused on glucokinase activators (GKAs) to treat type 2 diabetes by lowering the glucose threshold for insulin release and enhancing hepatic glucose disposal (PubMed: 30115533). Other hexokinase isoforms, particularly hexokinase 2 (HK2), are frequently upregulated in various cancers to support the high glycolytic demands of rapidly proliferating cells, a phenomenon known as the Warburg effect, making them targets for metabolic-based anti-cancer therapies (PubMed: 28652336).

Other names

Hexokinase-4Hexokinase-DHK IVHK4GCKHexokinase type IVATP-glucose phosphotransferase

Glucokinase activators (GKAs) function as allosteric modulators that increase the enzyme's affinity for glucose and its maximum reaction velocity, thereby lowering the blood glucose threshold for insulin secretion in the pancreas and promoting glucose storage in the liver (PubMed: 30115533). Conversely, hexokinase inhibitors like 2-deoxy-D-glucose act as competitive inhibitors that block the phosphorylation of glucose, primarily targeting the hexokinase 2 (HK2) isoform to inhibit the high glycolytic flux required for cancer cell survival and proliferation (PubMed: 28652336).