Hexokinase 2, Lactate dehydrogenase A, and Pyruvate dehydrogenase E1 component subunit alpha (HK2, LDHA, PDHA)

Hexokinase 2 (HK2), Lactate dehydrogenase A (LDHA), and Pyruvate dehydrogenase E1 component subunit alpha (PDHA) are critical enzymes involved in the metabolic reprogramming of cancer cells, a phenomenon known as the Warburg effect (Liberti & Locasale, 2016). HK2 (UniProt P52789) catalyzes the first committed step of glycolysis by phosphorylating glucose to glucose-6-phosphate, often being overexpressed and bound to mitochondria in malignant cells to ensure a high glycolytic rate (Pathania et al., 2009). LDHA (UniProt P00338) facilitates the final step of aerobic glycolysis by converting pyruvate to lactate, which regenerates NAD+ to sustain high glycolytic flux and contributes to an acidic tumor microenvironment (Granchi et al., 2010). PDHA (UniProt P08559) is the primary regulatory subunit of the pyruvate dehydrogenase complex, which controls the conversion of pyruvate into acetyl-CoA for entry into the tricarboxylic acid (TCA) cycle; its activity is frequently suppressed in cancer to divert carbon sources away from oxidative phosphorylation. Together, these enzymes represent a coordinated metabolic network that supports the biosynthetic and energetic demands of rapid tumor proliferation. Therapeutic strategies targeting this triad involve inhibiting HK2 and LDHA to starve the cell of energy and intermediates, or activating PDHA (often by inhibiting its regulatory kinases with drugs like Dichloroacetate) to force cancer cells back into mitochondrial respiration, potentially inducing oxidative stress and apoptosis (Stacpoole, 1989).

Other names

HKIIHexokinase type IILDH-ALDH-MLDH-5PDHA1PDHE1-APyruvate dehydrogenase alpha

Inhibition of glucose phosphorylation (HK2); inhibition of pyruvate-to-lactate conversion (LDHA); and activation of the pyruvate dehydrogenase complex (PDHA) via inhibition of pyruvate dehydrogenase kinases (PDKs).