Mitapivat

The pyruvate kinase enzyme is an ATP-generating enzyme involved in the Embden–Meyerhof glycolytic pathway: it catalyzes the conversion of phosphoenolpyruvate to pyruvate in the final step of glycolysis, generating adenosine triphosphate (ATP), which is critical for cellular maintenance and survival. One of the four isoforms of pyruvate kinase - erythrocyte pyruvate kinase or PKR - is dedicated to red blood cells (RBCs). Compared to most human cells, RBCs lack the metabolic machinery required for aerobic metabolism of glucose and generation of ATP; thus, they rely on anaerobic glycolysis for ATP production. The deficiency of ATP due to glycolytic enzyme defects leads to shortened lifespan and premature destruction of RBCs in the form of chronic hemolytic anemia and ineffective erythropoiesis. Pyruvate kinase deficiency is a rare hereditary disorder affecting RBC glycolysis, caused by mutations in PKLR, the gene encoding the RBC (PKR) and liver-specific isoforms (PKL) of pyruvate kinase. Pyruvate kinase deficiency is associated with a build-up of 2,3-disphosphoglycerate (2,3-DPG), an upstream metabolite in glycolysis, and deficient ATP levels.

Erythrocyte pyruvate kinase is an allosterically regulated homotetrameric enzyme that is normally activated by fructose bisphosphate (FBP) in an allosteric fashion. Mitapivat is also an allosteric pyruvate kinase activator but binds to a different allosteric site from FBP on the PKR tetramer. This allows for the activation of both wild-type and mutant forms of erythrocyte pyruvate kinase, including those not induced by FBP. Upon binding to pyruvate kinase, mitapivat stabilizes the active tetrameric form of the enzyme and enhances its affinity for its substrate, phosphoenolpyruvate. Mitapivat upregulates erythrocyte pyruvate kinase activity, increases ATP production, and reduces levels of 2,3-DPG.