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

Pyruvate kinase liver and red blood cell (PKLR) is a critical glycolytic enzyme that catalyzes the final rate-limiting step of the Embden-Meyerhof pathway, converting phosphoenolpyruvate (PEP) to pyruvate with the simultaneous generation of adenosine triphosphate (ATP) [4, 5, 21]. Encoded by the PKLR gene, this target yields two tissue-specific isoforms, PKL (liver) and PKR (erythrocytes), through the use of alternative promoters [13, 15]. In mature red blood cells, which lack mitochondria, PKR is the sole source of ATP required to maintain cellular integrity, ion pump activity, and membrane flexibility; thus, its deficiency leads to premature hemolysis and hereditary nonspherocytic hemolytic anemia [13, 22]. Beyond its role in energy production, PKLR activity also regulates the levels of 2,3-diphosphoglycerate (2,3-DPG), an allosteric modulator of hemoglobin-oxygen affinity [3, 21]. Therapeutic targeting of PKLR primarily involves small-molecule allosteric activators, such as mitapivat and etavopivat, which stabilize the active tetrameric form of the enzyme to enhance glycolytic flux [2, 7, 16]. These drugs are used or investigated to improve red blood cell health and survival in patients with pyruvate kinase deficiency, sickle cell disease, and thalassemia [3, 14, 16].

Other names

Pyruvate kinase L/RPK-LPK-RR-type/L-type pyruvate kinasePyruvate kinase 1KPYRPKLPKRRed cell/liver pyruvate kinase

Allosteric activation of the pyruvate kinase tetramer to increase enzymatic activity and protein stability, thereby increasing cellular ATP production and decreasing 2,3-diphosphoglycerate (2,3-DPG) levels [1, 2, 14].