Pyruvate kinase muscle isozyme (PKM) (PKM)

Pyruvate kinase muscle isozyme (PKM) is a key glycolytic enzyme that catalyzes the conversion of phosphoenolpyruvate and ADP to pyruvate and ATP (UniProt P14618). The PKM gene produces two main isoforms, PKM1 and PKM2, via alternative splicing; PKM1 is typically found in high-energy demanding tissues, while PKM2 is predominantly expressed in proliferating cells and many cancers (NCBI Gene 5315). In cancer, PKM2 often exists as a low-activity dimer, which allows glycolytic intermediates to be diverted into biosynthetic pathways to support rapid growth, a phenomenon known as the Warburg effect (PubMed 22037306). Additionally, PKM2 can function as a protein kinase and transcriptional co-activator in the nucleus, influencing cell cycle progression and gene expression (PubMed 22901813). Therapeutic interventions target PKM2 using either inhibitors to block glycolysis or allosteric activators, such as TEPP-46, to stabilize the active tetrameric form and reduce the availability of biosynthetic precursors (PubMed 22976226). Mitapivat, an activator of the related PKR isoform, has also sparked interest in the PKM space for metabolic disorders (ClinicalTrials.gov NCT03548220).

Other names

PKM2PKM1Pyruvate kinase 2/3Cytosolic thyroid hormone-binding proteinTHBP1CTHBPOpa-interacting protein 3OIP-3M2-PK

Allosteric activation to stabilize the tetrameric state or inhibition of enzymatic activity to disrupt metabolic flux.