pyruvate kinase M1/2

Target not currently curated in GtoImmuPdb

Target id: 3006

Nomenclature: pyruvate kinase M1/2

Family: Pyruvate kinases (EC 2.7.1.40)

Gene and Protein Information
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
pyruvate kinase \| OIP3 \| PK3 \| PKM2 \| pyruvate kinase, muscle \| THBP1

Previous and Unofficial Names

pyruvate kinase | OIP3 | PK3 | PKM2 | pyruvate kinase, muscle | THBP1

Database Links
Alphafold	P14618 (Hs), P52480 (Mm), P11980 (Rn)
BRENDA	2.7.1.40
ChEMBL Target	CHEMBL1075189 (Hs), CHEMBL4994 (Rn)
Ensembl Gene	ENSG00000067225 (Hs), ENSMUSG00000032294 (Mm), ENSRNOG00000011329 (Rn)
Entrez Gene	5315 (Hs), 18746 (Mm), 25630 (Rn)
Human Protein Atlas	ENSG00000067225 (Hs)
KEGG Enzyme	2.7.1.40
KEGG Gene	hsa:5315 (Hs), mmu:18746 (Mm), rno:25630 (Rn)
OMIM	179050 (Hs)
Pharos	P14618 (Hs)
RefSeq Nucleotide	NM_001206796 (Hs), NM_182470 (Hs), NM_011099 (Mm), NM_001253883 (Mm), NM_053297 (Rn)
RefSeq Protein	NP_872270 (Hs), NP_001193725 (Hs), NP_001240812 (Mm), NP_035229 (Mm), NP_445749 (Rn)
UniProtKB	P14618 (Hs), P52480 (Mm), P11980 (Rn)
Wikipedia	PKM (Hs)

Enzyme Reaction

EC Number: 2.7.1.40
	Description	Reaction	Reference
		ATP + pyruvate <=> ADP + phosphoenolpyruvate

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Activators

Key to terms and symbols

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Ligand		Sp.	Action	Value	Parameter	Reference
compound 16 [PMID: 31977207]		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		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		Hs	Activation	-	-	3
⤷	[3]
DASA-58		Hs	Activation	-	-	7
⤷	[7]

Inhibitors

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Ligand											Sp.	Action	Value	Parameter	Reference
compound 1 [PMID: 31465224]											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

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Ligand		Sp.	Action	Value	Parameter	Reference
mitapivat		Hs	Activation	>7.0	pEC₅₀	5
⤷	pEC₅₀ >7.0 (EC₅₀ <1x10^-7 M) [5] Description: Activation of the PKM2 isoform.
compound 24 [PMID: 36723914]		Hs	Inhibition	6.9	pIC₅₀	8
⤷	pIC₅₀ 6.9 (IC₅₀ 1.22x10^-7 M) [8] Description: Inhibition of PKM2 enzymatic activity

Immuno Process Associations

Immuno Process:

Inflammation

Immuno Process:

Tissue repair

Immuno Process:

Cellular signalling

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.

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]

8. Wang J, Zhou S, Cheng Y, Cheng L, Qin Y, Zhang Z, Bi A, Xiang H, He X, Tian X et al.. (2023) Selective Covalent Targeting of Pyruvate Kinase M2 Using Arsenous Warheads. J Med Chem, 66 (4): 2608-2621. [PMID:36723914]

How to cite this page

Pyruvate kinases (EC 2.7.1.40): pyruvate kinase M1/2. Last modified on 24/02/2023. Accessed on 20/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=3006.

pyruvate kinase M1/2

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References

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