PKM

This gene encodes a protein involved in glycolysis. The encoded protein is a pyruvate kinase that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate to ADP, generating ATP and pyruvate. This protein has been shown to interact with thyroid hormone and may mediate cellular metabolic effects induced by thyroid hormones. This protein has been found to bind Opa protein, a bacterial outer membrane protein involved in gonococcal adherence to and invasion of human cells, suggesting a role of this protein in bacterial pathogenesis. Several alternatively spliced transcript variants encoding a few distinct isoforms have been reported. [provided by RefSeq, May 2011]
Diseases associated with PKM include Pyruvate Kinase Deficiency Of Red Cells and Bardet-Biedl Syndrome 18. Among its related pathways are glycolysis (BioCyc) and Innate Immune System. Gene Ontology (GO) annotations related to this gene include RNA binding and MHC class II protein complex binding. An important paralog of this gene is PKLR.
Catalyzes the final rate-limiting step of glycolysis by mediating the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP (PubMed:15996096, 1854723, 20847263).
The ratio between the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production (PubMed:15996096, 1854723, 20847263).
The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival (PubMed:15996096, 1854723, 20847263). KPYM_HUMAN,P14618
[Isoform M2]: Isoform specifically expressed during embryogenesis that has low pyruvate kinase activity by itself and requires allosteric activation by D-fructose 1,6-bisphosphate (FBP) for pyruvate kinase activity (PubMed:18337823, 20847263).
In addition to its pyruvate kinase activity in the cytoplasm, also acts as a regulator of transcription in the nucleus by acting as a protein kinase (PubMed:18191611, 21620138, 22056988, 22306293, 22901803, 24120661).
Translocates into the nucleus in response to various signals, such as EGF receptor activation, and homodimerizes, leading to its conversion into a protein threonine- and tyrosine-protein kinase (PubMed:22056988, 22306293, 22901803, 24120661, 26787900).
Catalyzes phosphorylation of STAT3 at 'Tyr-705' and histone H3 at 'Thr-11' (H3T11ph), leading to activate transcription (PubMed:22306293, 22901803, 24120661).
Its ability to activate transcription plays a role in cancer cells by promoting cell proliferation and promote tumorigenesis (PubMed:18337823, 22901803, 26787900).
Promotes the expression of the immune checkpoint protein CD274 in BMAL1-deficient macrophages (By similarity).
May also act as a translation regulator for a subset of mRNAs, independently of its pyruvate kinase activity: associates with subpools of endoplasmic reticulum-associated ribosomes, binds directly to the mRNAs translated at the endoplasmic reticulum and promotes translation of these endoplasmic reticulum-destined mRNAs (By similarity).
Plays a role in caspase independent cell death of tumor cells (PubMed:17308100). KPYM_HUMAN,P14618
[Isoform M1]: Pyruvate kinase isoform expressed in adult tissues, which replaces isoform M2 after birth (PubMed:18337823).
In contrast to isoform M2, has high pyruvate kinase activity by itself and does not require allosteric activation by D-fructose 1,6-bisphosphate (FBP) for activity (PubMed:20847263).
[Isoform M2]: Isoform M2 is allosterically activated by D-fructose 1,6-bisphosphate (FBP) (PubMed:15996096, 18337815, 1854723, 2813362).
Inhibited by oxalate and 3,3',5-triiodo-L-thyronine (T3) (PubMed:15996096).
The activity of the tetrameric form is inhibited by PML (PubMed:18298799).
Selective binding to tyrosine-phosphorylated peptides releases the allosteric activator FBP, leading to inhibition of PKM enzymatic activity, this diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors (PubMed:18337815).
Glycolytic flux are highly dependent on de novo biosynthesis of serine and glycine, and serine is a natural ligand and allosteric activator of isoform M2 (PubMed:23064226).
Acetylation at Lys-433 promotes its translocation into the nucleus and homodimerization, promoting the protein kinase activity (PubMed:24120661).
[Isoform M1]: Has high pyruvate kinase activity by itself and does not require allosteric activation by D-fructose 1,6-bisphosphate (FBP) for activity.
pyruvate kinase,muscle (see THBP2),glycolysis,energy pathway,tetramer of 50-60kDa subunit,generating ATP from ADP,with two alternatively spliced isoforms,M2 widely expressed and M1,predominantly expressed in mature striated muscle and brain
thyroid hormone binding protein 1 (p55),same as PDI & P4HB
Cytoplasm {ECO:0000269 PubMed:25263439, 26787900, 27573352, 32268273}
Nucleus {ECO:0000269 PubMed:17308100, 18191611, 22056988, 22901803, 24120661, 26787900, 27573352, 32268273}
Note: Translocates to the nucleus in response to various signals, such as EGF receptor activation or apoptotic stimuli (PubMed:17308100, 22056988, 24120661). Nuclear translocation is promoted by acetylation by EP300 (PubMed:24120661). Deacetylation by SIRT6 promotes its nuclear export in a process dependent of XPO4, thereby suppressing its ability to activate transcription and promote tumorigenesis (PubMed:26787900) {ECO:0000269 PubMed:17308100, 22056988, 24120661, 26787900}
Quaternary structure:
[Isoform M2]: Monomer and homotetramer; exists as a monomer in the absence of D-fructose 1,6-bisphosphate (FBP), and reversibly associates to form a homotetramer in the presence of FBP (PubMed:15996096, 18298799, 18337815, 1854723, 23064226, 2813362).
The monomeric form binds 3,3',5-triiodo-L-thyronine (T3) (PubMed:15996096).
Tetramer formation induces pyruvate kinase activity (PubMed:15996096, 18298799, 18337815, 1854723, 23064226, 2813362).
The tetrameric form has high affinity for the substrate and is associated within the glycolytic enzyme complex (PubMed:15996096, 18298799, 18337815, 1854723, 23064226, 2813362).
FBP stimulates the formation of tetramers from dimers (PubMed:15996096, 18298799, 18337815, 1854723, 23064226, 2813362).
Homodimer; exists in a dimeric form in tumor cells and the dimeric form has less affinity for the phosphoenolpyruvate substrate (PubMed:22306293, 24120661).
The homodimer converts into a protein kinase (PubMed:22306293, 24120661).
Interacts with HERC1, POU5F1 and PML (PubMed:12650930, 18191611).
Interacts with EGLN3; the interaction hydroxylates PKM under hypoxia and enhances binding to HIF1A (PubMed:21483450, 21620138).
Interacts with HIF1A; the interaction is enhanced by binding of EGLN3, promoting enhanced transcription activity under hypoxia (PubMed:21620138).
Interacts with TRIM35; this interaction prevents FGFR1-dependent tyrosine phosphorylation (PubMed:25263439).
Interacts with JMJD8 (PubMed:27199445).
Interacts with TRAF4 (PubMed:32268273).
Interacts with (phosphorylated) CTNNB1; leading to activate transcription (PubMed:22056988).
Interacts with TSC22D2; the interaction results in reduced nuclear levels of PKM isoform M2, leading to repression of cyclin CCND1 transcription and reduced cell growth (PubMed:27573352).
Miscellaneous:
There are 4 isozymes of pyruvate kinase in mammals (L, R, M1, M2) encoded by 2 different genes: PKLR and PKM.
The L and R isozymes are generated from the PKLR by differential splicing of RNA; the M1 and M2 forms are produced from the PKM gene by differential splicing.
L type is major isozyme in the liver, R is found in red cells, M1 is the main form in muscle, heart and brain, and M2 is found in early fetal tissues as well as in most cancer cells.