Pyruvate kinase isozymes M1/M2 (PKM1/M2), also known as pyruvate kinase muscle isozyme (PKM), pyruvate kinase type K, cytosolic thyroid hormone-binding protein (CTHBP), thyroid hormone-binding protein 1 (THBP1), or opa-interacting protein 3 (OIP3), is an enzyme that in humans is encoded by the PKM2 gene. PKM2 is an isoenzyme of the glycolytic enzyme pyruvate kinase. Depending upon the different metabolic functions of the tissues, different isoenzymes of pyruvate kinase are expressed. PKM2 is expressed in some differentiated tissues, such as lung, fat tissue, retina, and pancreatic islets, as well as in all cells with a high rate of nucleic acid synthesis, such as normal proliferating cells, embryonic cells, and especially tumor cells.
Discovery The discovery of PKM2 began with laboratory observations made by Otto Heinrich Warburg, a German physiologist and Nobel Laureate in Physiology or Medicine in 1931. Warburg's experiments show that the cells exhibit dependence on glucose and are capable of fermentation, even under aerobic conditions. These observations are known as the Warburg effect. Subsequent research on the metabolic demands of cancer cells, studies have been directed towards the investigation of specific subtypes of pyruvate kinase, notably M1 and M2.
Structure Two isozymes are encoded by the PKM gene: PKM1 and PKM2. The M-gene consists of 12 exons and 11 introns. PKM1 and PKM2 are different splicing products of the M-gene (exon 9 for PKM1 and exon 10 for PKM2) and solely differ in 23 amino acids within a 56-amino acid stretch (aa 378–434) at their carboxy terminus.
Function Pyruvate kinase catalyzes the last step within glycolysis, the dephosphorylation of phosphoenolpyruvate to pyruvate, and is responsible for net ATP production within the glycolytic sequence. In contrast to mitochondrial respiration, energy regeneration by pyruvate kinase is independent from oxygen supply and allows survival of the organs under hypoxic conditions often found in solid tumors. The involvement of this enzyme in a variety of pathways, protein–protein interactions, and nuclear transport suggests its potential to perform multiple nonglycolytic functions with diverse implications, although multidimensional role of this protein is as yet not fully explored. However, a functional role in angiogenesis the so-called process of blood vessel formation by interaction and regulation of Jmjd8 has been shown.
Localization
Tissue The PKM1 isozyme is expressed in organs that are strongly dependent upon a high rate of energy regeneration, such as muscle and brain.
Cellular PKM2 is enzyme pyruvate kinase M2 (PKM2) and a transcriptional coactivator of STAT1 responsible for the induction of the protein PD-L1 expression and its regulation in tumor and immune cells. In the lactate production, the upregulated PKM2 is required and it leads to its contribution in inflammatory response, organ injury and septic death As a consequence, the removal of PKM2 in myeloid cells, administration of anti-PD-L1 or supplementation with recombinant interleukin -1 (IL-7) eases the microbial clearance, inhibits T cell apoptosis, reduce multiple organ dysfunction and reduce septic death in Bmal1-deficient mice.
Subcellular PKM2 is a cytosolic enzyme that is associated with other glycolytic enzymes, i.e., hexokinase, glyceraldehyde 3-P dehydrogenase, phosphoglycerate kinase, phosphoglyceromutase, enolase, and lactate dehydrogenase within a so-called glycolytic enzyme complex. However, PKM2 contains an inducible nuclear localization signal in its C-terminal domain. The role of PKM2 within the nucleus is complex, since pro-proliferative but also pro-apoptotic stimuli have been described. On the one hand, nuclear PKM2 was found to participate in the phosphorylation of histone 1 by direct phosphate transfer from PEP to histone 1. On the other hand, nuclear translocation of PKM2 induced by a somatostatin analogue, H2O2, or UV light has been linked with caspase-independent programmed cell death.
Clinical significance
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