Hexokinase-1 (HK1) (HK1)

Hexokinase-1 (HK1) is a critical glycolytic enzyme that catalyzes the first and rate-limiting step of glucose metabolism by phosphorylating glucose to glucose-6-phosphate [1, 6]. As the primary "housekeeping" isoform of the hexokinase family, HK1 is ubiquitously expressed, with high concentrations in the brain, kidneys, and red blood cells, where it maintains a constant energy supply [1, 4]. A significant portion of HK1 is localized to the outer mitochondrial membrane through interaction with the voltage-dependent anion channel (VDAC), a positioning that facilitates the direct use of mitochondrial ATP for glycolysis and provides potent anti-apoptotic signals [1, 13]. In clinical contexts, HK1 overexpression is a hallmark of the Warburg effect in many cancers, while its deficiency is a known cause of hereditary non-spherocytic hemolytic anemia [1, 9]. Beyond metabolism, HK1 acts as a moonlighting protein in innate immunity, functioning as a pattern recognition receptor for bacterial peptidoglycan to activate the NLRP3 inflammasome [6, 8]. Therapeutic strategies targeting HK1 include inhibitors such as 2-deoxyglucose, lonidamine, and 3-bromopyruvate, although the ubiquitous nature of HK1 presents significant challenges for achieving tumor-specific inhibition without affecting vital organs like the brain [2, 10, 12].

Other names

Hexokinase IHexokinase type IHexokinase-ABrain form hexokinaseHK IHXK1HKDHMSNR

Drugs targeting Hexokinase-1 primarily act through competitive inhibition of the glucose binding site, direct enzymatic inhibition, or by inducing the dissociation of the enzyme from the outer mitochondrial membrane, thereby disrupting the coupling of glycolysis with oxidative phosphorylation and promoting apoptosis.