HK3 is one of four highly homologous hexokinase isoforms in mammalian cells. This protein has a molecular weight of 100 kDa and is composed of two highly similar 50-kDa domains at its N- and C-terminals. This high similarity, along with the[clarification needed] and 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. Like with HK1, only the C-terminal domain possesses catalytic ability, whereas the N-terminal domain is predicted to contain glucose and G6P binding sites, as well as a 32-residue region essential for proper protein folding. Moreover, the catalytic activity depends on the interaction between the two terminal domains. Unlike HK1 and HK2, HK3 lacks a mitochondrial binding sequence at its N-terminal.
As a cytoplasmic isoform of hexokinase and a member of the sugar kinase family, HK3 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 HK3 as negative feedback, though inorganic phosphate can relieve G6P inhibition. Inorganic phosphate can also directly regulate HK3, and the double regulation may better suit its anabolic functions. By phosphorylating glucose, HK3 effectively prevents glucose from leaving the cell and, thus, commits glucose to energy metabolism. Compared to HK1 and HK2, HK3 possesses a higher affinity for glucose and will bind the substrate even at physiological levels, though this binding may be attenuated by intracellular ATP. Uniquely, HK3 can be inhibited by glucose at high concentrations. HK3 is also less sensitive to G6P inhibition.
Despite its lack of mitochondrial association, HK3 also functions to protect the cell against apoptosis. Overexpression of HK3 has resulted in increased ATP levels, decreased reactive oxygen species (ROS) production, attenuated reduction in the mitochondrial membrane potential, and enhanced mitochondrial biogenesis. Overall, HK3 may promote cell survival by controlling ROS levels and boosting energy production. Currently, only hypoxia is known to induce HK3 expression through a HIF-dependent pathway. The inducible expression of HK3 indicates its adaptive role in metabolic responses to changes in the cellular environment.
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