UniProt functional annotation for P14618



	UniProt functional annotation for P14618

UniProt code: P14618.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP (PubMed:15996096, PubMed:1854723). 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, PubMed:1854723). The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival (PubMed:15996096, PubMed:1854723). In addition to its role in glycolysis, also regulates transcription (PubMed:18191611, PubMed:21620138). Stimulates POU5F1-mediated transcriptional activation (PubMed:18191611). Promotes in a STAT1-dependent manner, the expression of the immune checkpoint protein CD274 in ARNTL/BMAL1-deficient macrophages (By similarity). Also acts 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 general role in caspase independent cell death of tumor cells (PubMed:17308100). {ECO:0000250|UniProtKB:P52480, ECO:0000269|PubMed:15996096, ECO:0000269|PubMed:17308100, ECO:0000269|PubMed:18191611, ECO:0000269|PubMed:1854723, ECO:0000269|PubMed:21620138}.

Catalytic activity: Reaction=ATP + pyruvate = ADP + H(+) + phosphoenolpyruvate; Xref=Rhea:RHEA:18157, ChEBI:CHEBI:15361, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:58702, ChEBI:CHEBI:456216; EC=2.7.1.40; Evidence={ECO:0000269|PubMed:15996096, ECO:0000269|PubMed:1854723};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000305|PubMed:23530218};

Cofactor: Name=K(+); Xref=ChEBI:CHEBI:29103; Evidence={ECO:0000305|PubMed:23530218};

Activity regulation: Isoform M2 is allosterically activated by D- fructose 1,6-bisphosphate (FBP). Inhibited by oxalate and 3,3',5- triiodo-L-thyronine (T3). The activity of the tetrameric form is inhibited by PML. 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. 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. {ECO:0000269|PubMed:15996096, ECO:0000269|PubMed:18298799, ECO:0000269|PubMed:18337815, ECO:0000269|PubMed:1854723, ECO:0000269|PubMed:23064226, ECO:0000269|PubMed:2813362}.

Biophysicochemical properties: Kinetic parameters: KM=2.7 mM for phosphoenolpyruvate (at 32 degrees Celsius, pH 8.0) {ECO:0000269|PubMed:15996096, ECO:0000269|PubMed:1854723}; KM=0.17 mM for phosphoenolpyruvate (in the presence of 2 mM D- fructose 1,6-bisphosphate (FBP), at 32 degrees Celsius, pH 8.0) {ECO:0000269|PubMed:15996096, ECO:0000269|PubMed:1854723}; KM=0.34 mM for ADP (at 32 degrees Celsius, pH 8.0) {ECO:0000269|PubMed:15996096, ECO:0000269|PubMed:1854723}; KM=0.24 mM for ADP (in the presence of 2 mM FBP, at 32 degrees Celsius, pH 8.0) {ECO:0000269|PubMed:15996096, ECO:0000269|PubMed:1854723}; KM=0.13 mM for phosphoenolpyruvate (in the presence of 2 mM FBP, at 25 degrees Celsius) {ECO:0000269|PubMed:15996096, ECO:0000269|PubMed:1854723}; KM=0.63 mM for ADP (in the presence of 2 mM FBP, at 25 degrees Celsius) {ECO:0000269|PubMed:15996096, ECO:0000269|PubMed:1854723}; pH dependence: Optimum pH for T3 binding is 6.0-6.5. Increase in pH causes T3 binding to drop, does not bind T3 above pH 9.0 or below pH 5.0. {ECO:0000269|PubMed:15996096, ECO:0000269|PubMed:1854723};

Pathway: Carbohydrate degradation; glycolysis; pyruvate from D- glyceraldehyde 3-phosphate: step 5/5.

Subunit: 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. The monomeric form binds T3. Tetramer formation induces pyruvate kinase activity. The tetrameric form has high affinity for the substrate and is associated within the glycolytic enzyme complex. Exists in a nearly inactive dimeric form in tumor cells and the dimeric form has less affinity for the substrate. Binding to certain oncoproteins such as HPV-16 E7 oncoprotein can trigger dimerization. FBP stimulates the formation of tetramers from dimers. Interacts with HERC1, POU5F1 and PML. Interacts (isoform M2) with EGLN3; the interaction hydroxylates PKM under hypoxia and enhances binding to HIF1A. Interacts (isoform M2) with HIF1A; the interaction is enhanced by binding of EGLN3, promoting enhanced transcription activity under hypoxia. Interacts (isoform M2, but not isoform M1) with TRIM35; this interaction prevents FGFR1-dependent tyrosine phosphorylation (PubMed:25263439). Interacts with JMJD8 (PubMed:27199445). {ECO:0000269|PubMed:12650930, ECO:0000269|PubMed:15996096, ECO:0000269|PubMed:18191611, ECO:0000269|PubMed:18298799, ECO:0000269|PubMed:18337815, ECO:0000269|PubMed:1854723, ECO:0000269|PubMed:21483450, ECO:0000269|PubMed:21620138, ECO:0000269|PubMed:23064226, ECO:0000269|PubMed:25263439, ECO:0000269|PubMed:27199445, ECO:0000269|PubMed:2813362}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:25263439}. Nucleus {ECO:0000269|PubMed:17308100, ECO:0000269|PubMed:18191611}. Note=Translocates to the nucleus in response to different apoptotic stimuli. Nuclear translocation is sufficient to induce cell death that is caspase independent, isoform-specific and independent of its enzymatic activity. {ECO:0000269|PubMed:17308100}.

Tissue specificity: Specifically expressed in proliferating cells, such as embryonic stem cells, embryonic carcinoma cells, as well as cancer cells. {ECO:0000269|PubMed:18191611}.

Ptm: ISGylated. {ECO:0000269|PubMed:16139798}.

Ptm: Under hypoxia, hydroxylated by EGLN3. {ECO:0000269|PubMed:21620138}.

Ptm: Acetylation at Lys-305 is stimulated by high glucose concentration, it decreases enzyme activity and promotes its lysosomal- dependent degradation via chaperone-mediated autophagy. {ECO:0000269|PubMed:21700219, ECO:0000269|Ref.11}.

Ptm: FGFR1-dependent tyrosine phosphorylation is reduced by interaction with TRIM35. {ECO:0000269|PubMed:25263439}.

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.

Similarity: Belongs to the pyruvate kinase family. {ECO:0000305}.

Sequence caution: Sequence=BAG57589.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Glycolytic enzyme that catalyzes the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP (PubMed:15996096, PubMed:1854723). 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, PubMed:1854723). The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival (PubMed:15996096, PubMed:1854723). In addition to its role in glycolysis, also regulates transcription (PubMed:18191611, PubMed:21620138). Stimulates POU5F1-mediated transcriptional activation (PubMed:18191611). Promotes in a STAT1-dependent manner, the expression of the immune checkpoint protein CD274 in ARNTL/BMAL1-deficient macrophages (By similarity). Also acts 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 general role in caspase independent cell death of tumor cells (PubMed:17308100). {ECO:0000250\|UniProtKB:P52480, ECO:0000269\|PubMed:15996096, ECO:0000269\|PubMed:17308100, ECO:0000269\|PubMed:18191611, ECO:0000269\|PubMed:1854723, ECO:0000269\|PubMed:21620138}.


Catalytic activity:		Reaction=ATP + pyruvate = ADP + H(+) + phosphoenolpyruvate; Xref=Rhea:RHEA:18157, ChEBI:CHEBI:15361, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:58702, ChEBI:CHEBI:456216; EC=2.7.1.40; Evidence={ECO:0000269\|PubMed:15996096, ECO:0000269\|PubMed:1854723};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000305\|PubMed:23530218};
Cofactor:		Name=K(+); Xref=ChEBI:CHEBI:29103; Evidence={ECO:0000305\|PubMed:23530218};
Activity regulation:		Isoform M2 is allosterically activated by D- fructose 1,6-bisphosphate (FBP). Inhibited by oxalate and 3,3',5- triiodo-L-thyronine (T3). The activity of the tetrameric form is inhibited by PML. 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. 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. {ECO:0000269\|PubMed:15996096, ECO:0000269\|PubMed:18298799, ECO:0000269\|PubMed:18337815, ECO:0000269\|PubMed:1854723, ECO:0000269\|PubMed:23064226, ECO:0000269\|PubMed:2813362}.
Biophysicochemical properties:		Kinetic parameters: KM=2.7 mM for phosphoenolpyruvate (at 32 degrees Celsius, pH 8.0) {ECO:0000269\|PubMed:15996096, ECO:0000269\|PubMed:1854723}; KM=0.17 mM for phosphoenolpyruvate (in the presence of 2 mM D- fructose 1,6-bisphosphate (FBP), at 32 degrees Celsius, pH 8.0) {ECO:0000269\|PubMed:15996096, ECO:0000269\|PubMed:1854723}; KM=0.34 mM for ADP (at 32 degrees Celsius, pH 8.0) {ECO:0000269\|PubMed:15996096, ECO:0000269\|PubMed:1854723}; KM=0.24 mM for ADP (in the presence of 2 mM FBP, at 32 degrees Celsius, pH 8.0) {ECO:0000269\|PubMed:15996096, ECO:0000269\|PubMed:1854723}; KM=0.13 mM for phosphoenolpyruvate (in the presence of 2 mM FBP, at 25 degrees Celsius) {ECO:0000269\|PubMed:15996096, ECO:0000269\|PubMed:1854723}; KM=0.63 mM for ADP (in the presence of 2 mM FBP, at 25 degrees Celsius) {ECO:0000269\|PubMed:15996096, ECO:0000269\|PubMed:1854723}; pH dependence: Optimum pH for T3 binding is 6.0-6.5. Increase in pH causes T3 binding to drop, does not bind T3 above pH 9.0 or below pH 5.0. {ECO:0000269\|PubMed:15996096, ECO:0000269\|PubMed:1854723};
Pathway:		Carbohydrate degradation; glycolysis; pyruvate from D- glyceraldehyde 3-phosphate: step 5/5.
Subunit:		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. The monomeric form binds T3. Tetramer formation induces pyruvate kinase activity. The tetrameric form has high affinity for the substrate and is associated within the glycolytic enzyme complex. Exists in a nearly inactive dimeric form in tumor cells and the dimeric form has less affinity for the substrate. Binding to certain oncoproteins such as HPV-16 E7 oncoprotein can trigger dimerization. FBP stimulates the formation of tetramers from dimers. Interacts with HERC1, POU5F1 and PML. Interacts (isoform M2) with EGLN3; the interaction hydroxylates PKM under hypoxia and enhances binding to HIF1A. Interacts (isoform M2) with HIF1A; the interaction is enhanced by binding of EGLN3, promoting enhanced transcription activity under hypoxia. Interacts (isoform M2, but not isoform M1) with TRIM35; this interaction prevents FGFR1-dependent tyrosine phosphorylation (PubMed:25263439). Interacts with JMJD8 (PubMed:27199445). {ECO:0000269\|PubMed:12650930, ECO:0000269\|PubMed:15996096, ECO:0000269\|PubMed:18191611, ECO:0000269\|PubMed:18298799, ECO:0000269\|PubMed:18337815, ECO:0000269\|PubMed:1854723, ECO:0000269\|PubMed:21483450, ECO:0000269\|PubMed:21620138, ECO:0000269\|PubMed:23064226, ECO:0000269\|PubMed:25263439, ECO:0000269\|PubMed:27199445, ECO:0000269\|PubMed:2813362}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:25263439}. Nucleus {ECO:0000269\|PubMed:17308100, ECO:0000269\|PubMed:18191611}. Note=Translocates to the nucleus in response to different apoptotic stimuli. Nuclear translocation is sufficient to induce cell death that is caspase independent, isoform-specific and independent of its enzymatic activity. {ECO:0000269\|PubMed:17308100}.
Tissue specificity:		Specifically expressed in proliferating cells, such as embryonic stem cells, embryonic carcinoma cells, as well as cancer cells. {ECO:0000269\|PubMed:18191611}.
Ptm:		ISGylated. {ECO:0000269\|PubMed:16139798}.
Ptm:		Under hypoxia, hydroxylated by EGLN3. {ECO:0000269\|PubMed:21620138}.
Ptm:		Acetylation at Lys-305 is stimulated by high glucose concentration, it decreases enzyme activity and promotes its lysosomal- dependent degradation via chaperone-mediated autophagy. {ECO:0000269\|PubMed:21700219, ECO:0000269\|Ref.11}.
Ptm:		FGFR1-dependent tyrosine phosphorylation is reduced by interaction with TRIM35. {ECO:0000269\|PubMed:25263439}.
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.
Similarity:		Belongs to the pyruvate kinase family. {ECO:0000305}.
Sequence caution:		Sequence=BAG57589.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};