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pyruvate kinase M1/2

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Target not currently curated in GtoImmuPdb

Target id: 3006

Nomenclature: pyruvate kinase M1/2

Family: 2.7.1.40 Pyruvate kinases

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 531 15q23 PKM pyruvate kinase M1/2 6
Mouse - 531 9 32.03 cM Pkm pyruvate kinase, muscle
Rat - 531 8q24 Pkm pyruvate kinase M1/2
Gene and Protein Information Comments
Human PKM1 is 513 aa and PKM2 (also know as isoform c) is 605 aa. Mouse PKM1 and PKM2 are both 531 aa. Only one transcript and protein isoform arising from the rat gene has been reported.
Previous and Unofficial Names Click here for help
pyruvate kinase | OIP3 | PK3 | PKM2 | pyruvate kinase, muscle | THBP1
Database Links Click here for help
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
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RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction Click here for help
EC Number: 2.7.1.40
Description Reaction Reference
ATP + pyruvate <=> ADP + phosphoenolpyruvate

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Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 16 [PMID: 31977207] Small molecule or natural product Hs Activation ~7.8 pEC50 1
pEC50 ~7.8 (EC50 ~1.5x10-8 M) [1]
Description: Activation of PKM2 kinase activity (promotion of high kinase activity PKM2 tertramer formation) in vitro, by compound 5; described as AC50 in the reference,
DMAMCL Small molecule or natural product Primary target of this compound Hs Activation - - 4
[4]
Description: Direct target binding has been shown by binding of a biotinylated version of the parent molecule MCL to recombinant hPKM2 in vitro.
TEPP-46 Small molecule or natural product Immunopharmacology Ligand Hs Activation - - 3
[3]
DASA-58 Small molecule or natural product Ligand has a PDB structure Hs Activation - - 7
[7]
Inhibitors
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Ligand Sp. Action Value Parameter Reference
compound 1 [PMID: 31465224] Small molecule or natural product Hs Inhibition 6.6 pIC50 2
pIC50 6.6 (IC50 2.5x10-7 M) [2]
Description: Measuring inhibition of pyruvate kinase activity in PC-9 cells treated with compound 1.
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
mitapivat Small molecule or natural product Hs Activation >7.0 pEC50 5
pEC50 >7.0 (EC50 <1x10-7 M) [5]
Description: Activation of the PKM2 isoform.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0043312 neutrophil degranulation TAS
Immuno Process:  Tissue repair
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0043403 skeletal muscle tissue regeneration IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0043312 neutrophil degranulation TAS
General Comments
Pyruvate kinases catalyse the conversion of phosphoenol-pyruvate (PEP) to pyruvate at the final step of glycolysis. PKM is a large allosteric enzyme whose activity is modulated by binding to one or more allosteric effectors.

Two isozymes are generated from the human PKM gene by alternative splicing and are referred to as PKM1 and PKM2. PKM1 is expressed in muscle, heart and brain, as a stable tetramer that is highly active. PKM2 is expressed in early fetal tissues and in the majority of cancer cells, and exists in equilibrium between monomeric, dimeric, and tetrameric forms. The non-tetrameric forms of PKM2 are almost devoid of enzymatic activity. PKM2 found in cancer cells is mainly of the dimeric form, and this form appears to promote increased biomass production (required for oncogenesis) and can act as a nuclear transcription factor on genes that promote tumourigenesis and migration. Because of this role in cancer PKM2 is being investigated as a novel therapeutic anti-cancer target, on the premise that PKM2 activators are likely to promote tetramer formation and high pyruvate kinase activity, and decrease the nonmetabolic effects on transcriptional regulation of cell proliferation and tumorigenesis pathway genes.

References

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1. Ding Y, Xue Q, Liu S, Hu K, Wang D, Wang T, Li Y, Guo H, Hao X, Ge W et al.. (2020) Identification of Parthenolide Dimers as Activators of Pyruvate Kinase M2 in Xenografts of Glioblastoma Multiforme in Vivo. J. Med. Chem., 63 (4): 1597-1611. [PMID:31977207]

2. Hsieh IS, Gopula B, Chou CC, Wu HY, Chang GD, Wu WJ, Chang CS, Chu PC, Chen CS. (2019) Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors. J. Med. Chem., 62 (18): 8497-8510. [PMID:31465224]

3. Jiang JK, Boxer MB, Vander Heiden MG, Shen M, Skoumbourdis AP, Southall N, Veith H, Leister W, Austin CP, Park HW et al.. (2010) Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg. Med. Chem. Lett., 20 (11): 3387-93. [PMID:20451379]

4. Li J, Li S, Guo J, Li Q, Long J, Ma C, Ding Y, Yan C, Li L, Wu Z et al.. (2018) Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia. J. Med. Chem., 61 (9): 4155-4164. [PMID:29641204]

5. Saunders JO, Salituro FG, Yan S. (2011) Therapeutic compounds and compositions. Patent number: WO2011002817A1. Assignee: Agios Pharmaceuticals, Inc.. Priority date: 29/06/2009. Publication date: 06/01/2011.

6. Takenaka M, Noguchi T, Sadahiro S, Hirai H, Yamada K, Matsuda T, Imai E, Tanaka T. (1991) Isolation and characterization of the human pyruvate kinase M gene. Eur. J. Biochem., 198 (1): 101-6. [PMID:2040271]

7. Walsh MJ, Brimacombe KR, Veith H, Bougie JM, Daniel T, Leister W, Cantley LC, Israelsen WJ, Vander Heiden MG, Shen M et al.. (2011) 2-Oxo-N-aryl-1,2,3,4-tetrahydroquinoline-6-sulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg. Med. Chem. Lett., 21 (21): 6322-7. [PMID:21958545]

How to cite this page

2.7.1.40 Pyruvate kinases: pyruvate kinase M1/2. Last modified on 03/02/2020. Accessed on 02/12/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3006.