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. 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 promotes the coupling of glycolysis to mitochondrial oxidative phosphorylation, which greatly enhances ATP production to meet the cell’s energy demands. Specifically, HK2 binds VDAC to trigger opening of the channel and release mitochondrial ATP to further fuel the glycolytic process.