Hexokinase 2 also known as HK2 is an enzyme which in humans is encoded by the HK2 gene on chromosome 2. Hexokinases phosphorylate glucose to produce glucose-6-phosphate (G6P), the first step in most glucose metabolism pathways. This gene encodes hexokinase 2, the predominant form found in skeletal muscle. It localizes to the outer membrane of mitochondria. Expression of this gene is insulin-responsive, and studies in rat suggest that it is involved in the increased rate of glycolysis seen in rapidly growing cancer cells. [provided by RefSeq, Apr 2009] Structure HK2 is one of four highly homologous hexokinase isoforms in mammalian cells. Gene The HK2 gene spans approximately 50 kb and consists of 18 exons. There is also an HK2 pseudogene integrated into a long interspersed nuclear repetitive DNA element located on the X chromosome. Though its DNA sequence is similar to the cDNA product of the actual HK2 mRNA transcript, it lacks an open reading frame for gene expression. Protein This gene encodes a 100-kDa, 917-residue enzyme with highly similar N- and C-terminal domains that each form half of the protein. This high similarity, along with the existence of a 50-kDa hexokinase (HK4), suggests that the 100-kDa hexokinases originated from a 50-kDa precursor via gene duplication and tandem ligation. Both N- and C-terminal domains possess catalytic ability and can be inhibited by G6P, though the C-terminal domain demonstrates lower affinity for ATP and is only inhibited at higher concentrations of G6P. Despite there being two binding sites for glucose, it is proposed that glucose binding at one site induces a conformational change which prevents a second glucose from binding the other site. Meanwhile, the first 12 amino acids of the highly hydrophobic N-terminal serve to bind the enzyme to the mitochondria, while the first 18 amino acids contribute to the enzyme’s stability. Function As an isoform of hexokinase and a member of the sugar kinase family, HK2 catalyzes the rate-limiting and first obligatory step of glucose metabolism, which is the ATP-dependent phosphorylation of glucose to G6P. Physiological levels of G6P can regulate this process by inhibiting HK2 as negative feedback, though inorganic phosphate (Pi) can relieve G6P inhibition. Pi can also directly regulate HK2, and the double regulation may better suit its anabolic functions. By phosphorylating glucose, HK2 effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism. Moreover, its localization and attachment to the OMM