Activating Compound | Comment | Organism | Structure |
---|---|---|---|
D-fructose 1,6-bisphosphate | triggers allosteric signal transduction, increases activity, binding tetramerizes the enzyme, whereas its release causes dissociation to inactive dimer | Homo sapiens |
Protein Variants | Comment | Organism |
---|---|---|
H391Y | naturally occuring mutation from a BS patient, mutation at intersubunit contact domain of the enzyme, the mutant shows 20% reduced activity compared to the wild-type enzyme, lost cooperativity and activation by fructose 1,6-bisphosphate, increased alpha-helical content, and 6fold increased PEP affinity | Homo sapiens |
K422R | naturally occuring mutation at intersubunit contact domain of the enzyme, the mutant shows 75% reduced activity compared to the wild-type enzyme, 3fold reduced PEP affinity, and increased cooperativity | Homo sapiens |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
A-Raf protein | proteins known for cellular growth and proliferation such as A-Raf and PML protein are known to downregulate PKM2 activity by interacting with it | Homo sapiens | |
human papillomavirus-16 E7 | causes dissociation of PKM2 tetramer into inactive dimer | Homo sapiens | |
lysophosphatidic acid | - |
Homo sapiens | |
additional information | poor inhibition by thyroid hormone T3. Tyr phosphorylated peptides interact with isozyme PKM2 at a site near to D-fructose 1,6-bisphosphate-binding pocket and can affect fructose 1,6-bisphosphate binding. Fibroblast growth factor receptor-dependent phosphorylation of iozyme PKM2 at Y105 causes its dimerization by the release of fructose 1,6-bisphosphate leading to Warburg effect | Homo sapiens | |
PML protein | proteins known for cellular growth and proliferation such as A-Raf and PML protein are known to downregulate PKM2 activity by interacting with it | Homo sapiens | |
Pp60v-src | causes dissociation of PKM2 tetramer into inactive dimer | Homo sapiens |
Metals/Ions | Comment | Organism | Structure |
---|---|---|---|
Mg2+ | required | Homo sapiens |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
ATP + pyruvate | Homo sapiens | - |
ADP + phosphoenolpyruvate | - |
r | |
additional information | Homo sapiens | mitogenic factor LPA, SUMO-E3 ligase, tumor endothelial marker-8, hepatitis C virus-NS5B RNA polymerase and HERC-1 via its HECT domain bind to isozyme PKM2 | ? | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | P14618 | four isozymes | - |
Posttranslational Modification | Comment | Organism |
---|---|---|
phosphoprotein | phosphorylation at Ser residues by A-Raf, a Raf kinase isozyme or by PKC delta protein kinase C isozyme, phosphorylation at Y105 by fibroblast growth factor receptor-1, break point cluster region-ABL fusion Tyr kinase, ETV6-neurotrophic Tyr kinase receptor-3, and JAK-2 mutant V617F. Fibroblast growth factor receptor-dependent phosphorylation of iozyme PKM2 at Y105 causes its dimerization by the release of fructose 1,6-bisphosphate leading to Warburg effect | Homo sapiens |
Source Tissue | Comment | Organism | Textmining |
---|---|---|---|
embryo | M2 isoform (PKM2) is exclusively expressed in embryonic and adult dividing/tumor cells | Homo sapiens | - |
additional information | M2 isoform (PKM2) is exclusively expressed in embryonic and adult dividing/tumor cells | Homo sapiens | - |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
ATP + pyruvate | - |
Homo sapiens | ADP + phosphoenolpyruvate | - |
r | |
additional information | mitogenic factor LPA, SUMO-E3 ligase, tumor endothelial marker-8, hepatitis C virus-NS5B RNA polymerase and HERC-1 via its HECT domain bind to isozyme PKM2 | Homo sapiens | ? | - |
? |
Subunits | Comment | Organism |
---|---|---|
More | the dimeric isozyme PKM2 is inactive | Homo sapiens |
tetramer | binding of fructose 1,6-bisphosphate tetramerizes the enzyme, whereas its release causes dissociation to dimer | Homo sapiens |
Synonyms | Comment | Organism |
---|---|---|
PKM2 | - |
Homo sapiens |
pyruvate kinase M2 | - |
Homo sapiens |
pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
---|---|---|---|
7 | - |
mutants H391Y and K422R | Homo sapiens |
7.4 | - |
wild-type enzyme | Homo sapiens |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
ATP | - |
Homo sapiens |
General Information | Comment | Organism |
---|---|---|
malfunction | PKM2 inhibition accumulates all upstream glycolytic intermediates as an anabolic feed for synthesis of lipids and nucleic acids. Downregulation of the enzyme activity by either phosphorylation or dissociation into dimer blocks the pyruvate production and leads in turn to an accumulation of the synthetic precursors to activate nucleic acid and lipid biosynthesis, required for cell division. The reduced cellular ATP amount as a result of PKM2 inactivation possibly activates TIGAR protein through AMPK-p53 pathway | Homo sapiens |
metabolism | pyruvate kinase catalyzes the last but rate-limiting step of glycolysis | Homo sapiens |
physiological function | tetrameric isozyme PKM2 is an allosterically regulated isoform and intrinsically designed to downregulate its activity by subunit dissociation from tetramer to dimer, which results in partial inhibition of glycolysis at the last step. Reassociation of PKM2 into active tetramer replenishes the normal catabolism as a feedback after cell division. PKM2 is a metabolic regulator, 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, overview. Downregulation of the enzyme activity by either phosphorylation or dissociation into dimer blocks the pyruvate production and leads in turn to an accumulation of the synthetic precursors to activate nucleic acid and lipid biosynthesis, required for cell division PKM2 saves the cell from nutritional stress-dependent apoptosis during cell division process | Homo sapiens |