Hexokinase 1 (HK1) and Hexokinase 2 (HK2) (HK1/HK2)

Hexokinase 1 (HK1) and Hexokinase 2 (HK2) are the primary enzymes responsible for the first step of glucose metabolism, catalyzing the ATP-dependent phosphorylation of glucose to glucose-6-phosphate [UniProt: P19367, P52789]. HK1 is ubiquitously expressed and provides a basal level of glucose catabolism, whereas HK2 is typically restricted to insulin-sensitive tissues but is highly upregulated in many cancers to support the Warburg effect [PubMed: 32117781]. Both isoforms can bind to the voltage-dependent anion channel (VDAC) on the outer mitochondrial membrane, which grants them preferential access to mitochondrial ATP and helps suppress apoptosis by stabilizing the mitochondrial membrane [PubMed: 19249211]. Because cancer cells rely heavily on HK2 for rapid energy production and survival, it has become a significant therapeutic target. However, the high structural similarity between HK1 and HK2 makes selective inhibition difficult, raising concerns about potential toxicity in healthy tissues like the brain and red blood cells where HK1 is essential [PubMed: 29445144]. Current pharmacological approaches include glucose analogs like 2-deoxy-D-glucose and small molecules like lonidamine that disrupt both the enzymatic activity and the mitochondrial association of these proteins [PubMed: 27551501]. Additionally, HK2 is being investigated for its role in inflammatory diseases and metabolic disorders like type 2 diabetes [PubMed: 31063715]. Monitoring HK activity via FDG-PET imaging remains a gold standard for assessing tumor metabolic activity and response to therapy in clinical settings [PubMed: 32117781].

Other names

HK1HK2Hexokinase type IHexokinase type IIHK IHK IIBrain hexokinaseMuscle hexokinase

Inhibition of the phosphorylation of glucose to glucose-6-phosphate through competitive or non-competitive mechanisms, and/or the displacement of the enzyme from the mitochondrial voltage-dependent anion channel (VDAC) to induce apoptosis [PubMed: 32117781, 19249211].