Pyruvate kinase, liver and red blood cell isoforms (PKLR)

Pyruvate kinase, liver and red blood cell isoforms (PKLR) is an enzyme encoded by the PKLR gene and is expressed predominantly in the liver and erythrocytes. It catalyzes the final and rate-limiting step of glycolysis by transferring a phosphate from phosphoenolpyruvate (PEP) to ADP, generating pyruvate and ATP. The enzyme is essential for energy production, as mature red blood cells rely exclusively on glycolysis for ATP due to their lack of mitochondria. Deficiency of PKLR activity—typically from pathogenic genetic variants—causes pyruvate kinase deficiency, the most common enzymatic cause of chronic nonspherocytic hemolytic anemia. Disease severity varies from mild to life-threatening anemia. PKLR deficiency is inherited in an autosomal recessive manner. Over 200 pathogenic variants are described, most leading to reduced enzyme stability or function. Allosteric regulation by fructose-1,6-bisphosphate, alanine, and divalent cations is critical for enzyme activity. Some PKLR gene variants confer protection against malaria and show population-specific differences due to evolutionary selection. Diagnosis is made by measuring pyruvate kinase activity and through genetic testing. No curative therapy exists; management is supportive, though novel allosteric activators (e.g., mitapivat) are in clinical development[1][2][3][4][5][6][7][8][9].

Other names

PK1PKLPKRPKRLpyruvate kinase 1pyruvate kinase isozyme R/Lpyruvate kinase type Lpyruvate kinase, liver and blood cellpyruvate kinase, liver and RBCR-type/L-type pyruvate kinasered cell/liver pyruvate kinaseRPKKPYR_HUMAN[3]

Allosteric activation of pyruvate kinase to enhance function in deficient states (for mitapivat); generally, drugs may modulate (activate) enzyme activity to restore glycolytic flux and red blood cell ATP levels