page_title: Tumor M2-PK
section_title: Tetrameric and dimeric PKM2
hierarchical_section_title: Tumor M2-PK / Tetrameric and dimeric PKM2
caption_attribution_description: Effect of the tetrameric and dimeric form of M2-PK on cell metabolism
context_page_description: Tumor M2-PK is a synonym for the dimeric form of the pyruvate kinase isoenzyme type M2, a key enzyme within tumor metabolism. Tumor M2-PK can be elevated in many tumor types, rather than being an organ-specific tumor marker such as PSA. Increased stool levels are being investigated as a method of screening for colorectal tumors, and EDTA plasma levels are undergoing testing for possible application in the follow-up of various cancers.
  Sandwich ELISAs based on two monoclonal antibodies which specifically recognize Tumor M2-PK are available for the quantification of Tumor M2-PK in stool and EDTA-plasma samples respectively. As a biomarker, the amount of Tumor M2-PK in stool and EDTA-plasma reflects the specific metabolic status of the tumors.
context_section_description: Pyruvate kinase catalyzes the last step within the glycolytic sequence, the dephosphorylation of phosphoenolpyruvate to pyruvate and is responsible for net energy production within the glycolytic pathway. Depending upon the different metabolic functions of the tissues, different isoenzymes of pyruvate kinase are expressed.
  M2-PK (PKM2) is the predominant pyruvate kinase isoform in proliferating cells, such as fibroblasts, embryonic cells and adult stem cells and most human tissue, including lung, bladder, kidney and thymus; M2-PK is upgregulated in many human tumors.
  M2-PK can occur in two different forms in proliferating cells:
  a tetrameric form, which consists of four subunits
  a dimeric form, consisting of two subunits.
  The tetrameric form of M2-PK has a high affinity to its substrate, phosphoenolpyruvate (PEP), and is highly active at physiological PEP concentrations. Furthermore, the tetrameric form of M2-PK is associated with several other glycolytic enzymes within the so-called glycolytic enzyme complex. Due to the close proximity of the enzymes, the association within the glycolytic enzyme complex leads to a highly effective conversion of glucose to lactate. 
  When M2-PK is mainly in the highly active tetrameric form, which is the case in most normal cells, glucose is mostly converted to lactate, with the attendant production of energy.
  In contrast, the dimeric form of M2-PK has a low affinity for phosphoenolpyruvate, being nearly inactive at physiological PEP concentrations. When M2-PK is mainly in the dimeric form, which is the case in tumor cells, all phosphometabolites above pyruvate kinase accumulate and are channelled into synthetic processes which branch off from glycolytic intermediates, such as nucleic acids, phospholipids and amino acids, important cell building blocks for highly proliferating cells such as tumor cells.
  As a consequence of the key position of pyruvate kinase within glycolysis, the tetramer : dimer ratio of M2-PK determines whether glucose carbons are converted to pyruvate and lactate, along with the production of energy (tetrameric form), or channelled into synthetic processes (dimeric form). In tumor cells M2-PK is mainly in the dimeric form. Therefore, the dimeric form of M2-PK has been termed Tumor M2-PK.
  The dimerization of M2-PK in tumor cells is induced by the direct interaction of M2-PK with different oncoproteins.
  However, the tetramer : dimer ratio of M2-PK is not constant.
  Oxygen starvation or highly accumulated glycolytic intermediates, such as fructose 1,6-bisphosphate (fructose 1,6-P2) or the amino acid serine, induce the reassociation of the dimeric form of M2-PK to the tetrameric form. Consequently, due to the activation of M2-PK, glucose is converted to pyruvate and lactate under the production of energy until the fructose 1,6-P2 levels drop below a certain threshold value, which allows the dissociation of the tetrameric form of M2-PK to the dimeric form. Thereafter, the cycle of oscillation starts again when the fructose 1,6-P2 levels reach a certain upper threshold value which induces the tetramerization of M2-PK.
  When M2-PK is mainly in the less active dimeric form, energy is produced by the degradation of the amino acid glutamine to aspartate, pyruvate and lactate, which is termed glutaminolysis.
  In tumor cells the increased rate of lactate production in the presence of oxygen is termed the Warburg effect.
caption: Metabolic consequences of the tetrameric and dimeric forms of M2-PK
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