pyruvaatkinase

Pyruvate kinase (Dutch: pyruvaatkinase) is a cytosolic glycolytic enzyme that catalyzes the final step of glycolysis: the transfer of a phosphate from phosphoenolpyruvate (PEP) to ADP to form pyruvate and ATP. This reaction is rate-limiting and helps link glycolysis to energy production and to downstream pathways such as fermentation or aerobic metabolism.

In humans, pyruvate kinase exists as tissue-specific isoforms produced by different genes and alternative splicing. The PKLR gene encodes liver (PKL) and red blood cell (PKR) isoforms, while the PKM gene yields PKM1 and PKM2 through alternative splicing. PKL and PKR are predominantly expressed in liver and erythrocytes, respectively; PKM1 is common in muscle and brain, whereas PKM2 is prevalent in proliferating tissues and many cancer cells. PKM2 can exist as an inactive dimer or an active tetramer, enabling metabolic flexibility in response to cellular conditions.

Regulation of pyruvate kinase is allosteric and linked to cellular energy status. Fructose-1,6-bisphosphate (FBP) strongly activates PK to promote glycolytic flux, while high levels of ATP and certain amino acids such as alanine inhibit PK, slowing glycolysis when energy is abundant. The oligomeric state, post-translational modifications, and tissue-specific expression further modulate activity, particularly for PKM2 in cancer biology.

Clinical significance includes pyruvate kinase deficiency, most commonly due to mutations in PKLR, which causes congenital non-spherocytic hemolytic anemia. The deficiency reduces erythrocyte ATP, leading to hemolysis, anemia, and related complications. Diagnosis relies on reduced PK activity and genetic testing, with treatment focusing on supportive care and management of anemia.

Overall, pyruvate kinase plays a central role in energy metabolism, with isoform diversity contributing to tissue-specific energy needs and disease processes, including cancer metabolism and inherited anemias.