Hexokinase 1, 2, and 3 (HK1-3)

Hexokinases I-III (HK1, HK2, and HK3) are a group of high-affinity enzymes that catalyze the first step of glucose metabolism by phosphorylating glucose into glucose-6-phosphate (UniProt: P19367, P52789). HK1 is ubiquitously expressed and essential for maintaining basal energy levels in most tissues, particularly the brain and red blood cells. HK2 is primarily expressed in insulin-responsive tissues like muscle and adipose, but it is frequently overexpressed in cancer cells to drive the high glycolytic rates known as the Warburg effect (PubMed: 21132124). These enzymes, especially HK2, often associate with the voltage-dependent anion channel (VDAC) on the outer mitochondrial membrane, which helps coordinate glycolysis with oxidative phosphorylation and provides a survival advantage by suppressing apoptosis (PubMed: 19473913). Targeting hexokinases, particularly HK2, is a strategy in oncology aimed at metabolic exhaustion of tumor cells. Experimental drugs like 2-deoxy-D-glucose and lonidamine act by inhibiting the catalytic activity or displacing the enzyme from the mitochondria (PubChem: CID 10822). However, the high structural similarity between HK1 and HK2 poses a significant challenge for developing selective inhibitors that do not cause systemic toxicity in glucose-dependent organs (StatPearls: NBK537031).

Other names

Hexokinase type I, II, and IIIHK I-IIIATP:D-hexose 6-phosphotransferaseHigh-affinity hexokinases

Inhibition of the phosphorylation of glucose to glucose-6-phosphate, thereby limiting glycolytic flux; some agents also induce the dissociation of hexokinase from the voltage-dependent anion channel (VDAC) on the outer mitochondrial membrane to trigger apoptosis (PubMed: 19473913).