PKM

Summary

PKM (pyruvate kinase M1/2, HGNC:9021) is a protein-coding gene on chromosome 15q23, encoding Pyruvate kinase PKM (P14618). Catalyzes the final rate-limiting step of glycolysis by mediating the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. It is a selective cancer dependency (DepMap: 87.7% of cell lines).

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.

Source: NCBI Gene 5315 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 79 total
• Druggable target: yes — 59 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 87.7% of screened cell lines
• MANE Select transcript: NM_002654

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9021
Approved symbol	PKM
Name	pyruvate kinase M1/2
Location	15q23
Locus type	gene with protein product
Status	Approved
Aliases	THBP1, OIP3, PK3
Ensembl gene	ENSG00000067225
Ensembl biotype	protein_coding
OMIM	179050
Entrez	5315

Gene structure

Transcript identifiers

Ensembl transcripts: 92 — 80 protein_coding, 9 retained_intron, 3 nonsense_mediated_decay

ENST00000319622, ENST00000335181, ENST00000389093, ENST00000561609, ENST00000562784, ENST00000562997, ENST00000563275, ENST00000563986, ENST00000564178, ENST00000564276, ENST00000564440, ENST00000564993, ENST00000565143, ENST00000565154, ENST00000565184, ENST00000566809, ENST00000567087, ENST00000567118, ENST00000568459, ENST00000568743, ENST00000569050, ENST00000569857, ENST00000570166, ENST00000698740, ENST00000698741, ENST00000891959, ENST00000891960, ENST00000891961, ENST00000891962, ENST00000891963, ENST00000891964, ENST00000891965, ENST00000891966, ENST00000891967, ENST00000891968, ENST00000891969, ENST00000891970, ENST00000891971, ENST00000891972, ENST00000891973, ENST00000891974, ENST00000891975, ENST00000891976, ENST00000891977, ENST00000891978, ENST00000891979, ENST00000891980, ENST00000891981, ENST00000891982, ENST00000891983, ENST00000891984, ENST00000933430, ENST00000933431, ENST00000933432, ENST00000933433, ENST00000933434, ENST00000933435, ENST00000933436, ENST00000933437, ENST00000933438, ENST00000933439, ENST00000933440, ENST00000933441, ENST00000933442, ENST00000933443, ENST00000933444, ENST00000933445, ENST00000933446, ENST00000969834, ENST00000969835, ENST00000969836, ENST00000969837, ENST00000969838, ENST00000969839, ENST00000969840, ENST00000969841, ENST00000969842, ENST00000969843, ENST00000969844, ENST00000969845, ENST00000969846, ENST00000969847, ENST00000969848, ENST00000969849, ENST00000969850, ENST00000969851, ENST00000969852, ENST00000969853, ENST00000969854, ENST00000969855, ENST00000969856, ENST00000969857

RefSeq mRNA: 9 — MANE Select: NM_002654 NM_001206796, NM_001206797, NM_001206798, NM_001206799, NM_001316318, NM_001411081, NM_002654, NM_182470, NM_182471

CCDS: CCDS32284, CCDS32285, CCDS73752, CCDS92035, CCDS92036, CCDS92037

Canonical transcript exons

ENST00000335181 — 11 exons

Exon	Start	End
ENSE00001546931	72231116	72231190
ENSE00003475296	72207127	72207277
ENSE00003522795	72218944	72219110
ENSE00003535056	72209673	72209859
ENSE00003563330	72199029	72199756
ENSE00003566465	72210347	72210478
ENSE00003590685	72208621	72208891
ENSE00003618390	72202454	72202620
ENSE00003632285	72200474	72200655
ENSE00003647308	72206728	72206880
ENSE00003790251	72217409	72217500

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 99.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1430.5897 / max 9440.0730, expressed in 1829 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150810	1409.4891	1829
150796	5.3390	1506
150792	3.4639	1451
150799	3.2492	1344
150790	2.6910	1322
150798	2.1008	1117
150793	1.3116	919
150795	0.7017	414
150797	0.6172	341
207581	0.5688	284

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.76	gold quality
cerebellar hemisphere	UBERON:0002245	99.73	gold quality
right frontal lobe	UBERON:0002810	99.73	gold quality
prefrontal cortex	UBERON:0000451	99.70	gold quality
metanephros cortex	UBERON:0010533	99.69	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.68	gold quality
cerebellar cortex	UBERON:0002129	99.67	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.67	gold quality
islet of Langerhans	UBERON:0000006	99.66	gold quality
right adrenal gland	UBERON:0001233	99.65	gold quality
right adrenal gland cortex	UBERON:0035827	99.65	gold quality
muscle of leg	UBERON:0001383	99.64	gold quality
gastrocnemius	UBERON:0001388	99.64	gold quality
left adrenal gland	UBERON:0001234	99.63	gold quality
stromal cell of endometrium	CL:0002255	99.61	gold quality
ventricular zone	UBERON:0003053	99.61	gold quality
apex of heart	UBERON:0002098	99.60	gold quality
left adrenal gland cortex	UBERON:0035825	99.59	gold quality
monocyte	CL:0000576	99.57	gold quality
right atrium auricular region	UBERON:0006631	99.55	gold quality
nucleus accumbens	UBERON:0001882	99.54	gold quality
cerebellum	UBERON:0002037	99.54	gold quality
adrenal cortex	UBERON:0001235	99.53	gold quality
dorsal root ganglion	UBERON:0000044	99.52	gold quality
adrenal gland	UBERON:0002369	99.52	gold quality
cardiac atrium	UBERON:0002081	99.51	gold quality
pons	UBERON:0000988	99.48	gold quality
descending thoracic aorta	UBERON:0002345	99.48	gold quality
right testis	UBERON:0004534	99.43	gold quality
leukocyte	CL:0000738	99.42	gold quality

Single-cell (SCXA)

Detected in 28 experiment(s), a significant marker in 18.

Experiment	Marker?	Max mean expression
E-GEOD-106540	yes	3115.24
E-HCAD-5	yes	2642.19
E-MTAB-4850	yes	2201.05
E-CURD-89	yes	2037.49
E-MTAB-8498	yes	547.63
E-MTAB-8142	yes	77.36
E-CURD-122	yes	65.68
E-HCAD-35	yes	49.68
E-HCAD-4	yes	41.00
E-HCAD-10	yes	39.71
E-CURD-46	yes	27.49
E-MTAB-9221	yes	19.07
E-HCAD-1	yes	18.71
E-MTAB-10042	yes	16.60
E-CURD-88	yes	9.82

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ASCL1, BMAL1, CLOCK, CREB1, HIF1A, MYC, NEUROG1, NFKB, PPARG, SP1, SP3, SREBF1, ZBTB7A

miRNA regulators (miRDB)

42 targeting PKM, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-4780	98.57	64.75	611
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-9851-5P	97.57	67.49	1067
HSA-MIR-6865-3P	97.54	64.67	684

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 87.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• measurement of fecal Tumor M2-PK concentrations might provide an interesting screening tool for colorectal cancer (PMID:12820312)
• With the fuzzy logic method and a tumor marker panel (including the new marker Tumor M2-PK), a useful diagnostic tool for the detection of progression in lung cancer patients is available (PMID:12820320)
• phosphorylated at tyrosine residues in breast cancer patients; did not find any evidence that this phosphorylation is initiated by the oncoprotein HER-2/neu (PMID:12820337)
• The X-ray structure of tumor specific PKM2 complexed with Mg2+, K+, inhibitor oxalate, and allosteric activator fructose 1,6-bisphosphate has been determined, and its unique structural characteristics relative to other known isoforms have been analyzed. (PMID:15996096)
• PanK4 interacts with Pkm2 and thereby may modulate the glucose metabolism through regulating the activity of Pkm2. (PMID:16132722)
• PK can function as an autoimmune target and that this immunoreactivity may be associated with Tourette syndrome, obsessive compulsive disorder, and associated disorders (PMID:17011640)
• A sensitive and specific tumor marker for colorectal cancer, seen in older adults. (PMID:17406361)
• An elevated level in this enzyme on admission in suspected periampullary cancer is a predictor of adverse prognosis in periampullary cancer. (PMID:17414054)
• PKM2 exists in either an active tetrameric form which has high affinity for its substrate phosphoenolpyruvate (PEP) or a less active dimeric form which has low affinity for its substrate. (PMID:18298799)
• results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells (PMID:18337815)
• expression of pyruvate kinase M2 isoenzyme was found in 53% 0f granulosa cell tumors of the ovary (PMID:18394773)
• aberrant reduction of miR-133a and miR-133b was associated with the dysregulation of M2-type pyruvate kinase (PKM2) in squamous cell carcinoma (SCC) of the tongue. (PMID:18464261)
• NS5B interacted with M2 type pyruvate kinase but not L type pyruvate kinase. (PMID:18519040)
• Data confirmed the cancer-associated expression of the PKM2 variant with primary colon cancer and colon cancer cell lines, with PKM2 expressed at high levels in colon cancer and in colon cancer cell lines. (PMID:18789002)
• fecal pyruvate kinase M2 is an inferior biological marker of inflammatory bowel disease when compared with fecal calprotectin (PMID:19097497)
• Differential behavior of missense mutations in the intersubunit contact domain of the human pyruvate kinase M2 isozyme. (PMID:19265196)
• The gene ratio test with the PKM2 gene for survival of patients with malignant pleural mesothelioma has robust predictive value. (PMID:19401544)
• Pyruvate kinase M2 and prednisolone resistance in acute lymphoblastic leukemia. (PMID:19734428)
• Complete lack of M2-PK expression was observed in benign pancreatic ducts, premalignant lesions and cancer. (PMID:19754967)
• Tumor-M2-PK may have a role in diagnosing pancreatic ductal adenocarcinoma. (PMID:19820423)
• Studies suggest that regulation of PKM2 seems to be pivotal for regulating glycolysis in proliferating cells. regulation of PKM2 seems to be pivotal for regulating glycolysis in proliferating cells. (PMID:19920249)
• Data show that oncogenic forms of fibroblast growth factor receptor type 1 inhibit the pyruvate kinase M2 (PKM2) isoform by direct phosphorylation of PKM2 tyrosine residue 105 (Y(105)). (PMID:19920251)
• human gliomas overexpress c-Myc, PTB, hnRNPA1 and hnRNPA2 in a manner that correlates with PKM2 expression (PMID:20010808)
• the association of PKM2 and HSPD1, two differentially expressed proteins, with MDR were analyzed, and the results showed that they could contribute considerably to the cisplatin resistance in ovarian cancer cell (PMID:20082317)
• splicing repressors hnRNP A1 and A2, as well as the polypyrimidine-tract-binding protein PTB, contribute to control of pyruvate kinase isoform M1 and M2 expression (PMID:20133837)
• human pyruvate kinase M2 isozyme dominant mutations promote cellular growth and polyploidy (PMID:20304929)
• Increased M2 pyruvate kinase is associated with cervical cancer progression. (PMID:20332442)
• M2PK has a role in preventing, and pAkt has a role in enhancing progression of breast cancer (PMID:20592362)
• human glioblastoma cells with high levels of PKM2 expressed lower levels of miR-326, suggestive of endogenous regulation of PKM2 by miR-326. (PMID:20667897)
• Overexpression of PKM2 is associated with recurrences in chordomas. (PMID:20721957)
• histidine-phosphorylated PGAM1 correlated with expression of PKM2 in cancer cell lines; decreased pyruvate kinase activity in PKM2-expressing cells allows PEP-dependent histidine phosphorylation of PGAM1 and may provide an alternate glycolytic pathway (PMID:20847263)
• This review aims to provide an overview of the involvement of human PKM2 in various physiological pathways with possible functional implications. (PMID:20857498)
• inhibition of PKM2 by PRL contributes to the PRL-stimulated cell (PMID:20962042)
• A study on the relationship between prothymosin alpha kinase(ProTalphaK) activity and pyruvate kinase isoforms confirmed that the M2 isoform is the enzyme responsible for ProTalphaK activity in proliferating cells. (PMID:20977946)
• Components of the mTOR/HIF1alpha/Myc-hnRNPs/PKM2 glycolysis signaling network could be targeted for the treatment of cancer caused by an aberrant RTK/PI3K/AKT/mTOR signaling pathway (PMID:21325052)
• Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1alpha and PKM2 coactivator function; PKM2 participates in a positive feedback loop that promotes HIF-1 transactivation and reprograms glucose metabolism in cancer cells. (PMID:21620138)
• Data show that pyruvate kinase M2 (PKM2) was a binding partner of death-associated protein kinase (DAPk). (PMID:21725354)
• Exons are the key determinants of PK-M splicing isoform ratios. (PMID:22044881)
• findings show, in lung cancer cells, increases in intracellular ROS caused inhibition of PKM2 through oxidation of Cys(358);regulatory properties of PKM2 may confer an additional advantage to cancer cells by allowing them to withstand oxidative stress (PMID:22052977)
• epidermal growth factor receptor (EGFR) activation induces translocation of PKM2, but not PKM1, into the nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of beta-catenin (PMID:22056988)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	pkma	ENSDARG00000099730
danio_rerio	pkmb	ENSDARG00000099860
mus_musculus	Pkm	ENSMUSG00000032294
rattus_norvegicus	Pkm	ENSRNOG00000011329
rattus_norvegicus	Pkml1	ENSRNOG00000047276
rattus_norvegicus		ENSRNOG00000063421
drosophila_melanogaster	CG2964	FBGN0031462
drosophila_melanogaster	CG7362	FBGN0038258
drosophila_melanogaster	CG7069	FBGN0038952
drosophila_melanogaster	PyK	FBGN0267385
caenorhabditis_elegans	pyk-1	WBGENE00009126
caenorhabditis_elegans		WBGENE00014001

Paralogs (1): PKLR (ENSG00000143627)

Protein

Protein identifiers

Pyruvate kinase PKM — P14618 (reviewed: P14618)

Alternative names: Cytosolic thyroid hormone-binding protein, Opa-interacting protein 3, Pyruvate kinase 2/3, Pyruvate kinase muscle isozyme, Threonine-protein kinase PKM2, Thyroid hormone-binding protein 1, Tumor M2-PK, Tyrosine-protein kinase PKM2, p58

All UniProt accessions (15): P14618, A0A804F6T5, A0A804F729, A0A8V8TMM5, A0A8V8TNX9, B4DNK4, H3BN34, H3BQ34, H3BQZ3, H3BT25, H3BTJ2, H3BTN5, H3BU13, H3BUW1, V9HWB8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the final rate-limiting step of glycolysis by mediating the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP. 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. The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival. 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. 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. 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. Catalyzes phosphorylation of STAT3 at ‘Tyr-705’ and histone H3 at ‘Thr-11’ (H3T11ph), leading to activate transcription. Its ability to activate transcription plays a role in cancer cells by promoting cell proliferation and promote tumorigenesis. Promotes the expression of the immune checkpoint protein CD274 in BMAL1-deficient macrophages. 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. Plays a role in caspase independent cell death of tumor cells. Pyruvate kinase isoform expressed in adult tissues, which replaces isoform M2 after birth. 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.

Subunit / interactions. 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 3,3’,5-triiodo-L-thyronine (T3). Tetramer formation induces pyruvate kinase activity. The tetrameric form has high affinity for the substrate and is associated within the glycolytic enzyme complex. FBP stimulates the formation of tetramers from dimers. Homodimer; exists in a dimeric form in tumor cells and the dimeric form has less affinity for the phosphoenolpyruvate substrate. The homodimer converts into a protein kinase. Interacts with HERC1, POU5F1 and PML. Interacts with EGLN3; the interaction hydroxylates PKM under hypoxia and enhances binding to HIF1A. Interacts with HIF1A; the interaction is enhanced by binding of EGLN3, promoting enhanced transcription activity under hypoxia. Interacts with TRIM35; this interaction prevents FGFR1-dependent tyrosine phosphorylation. Interacts with JMJD8. Interacts with TRAF4. Interacts with (phosphorylated) CTNNB1; leading to activate transcription. 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. (Microbial infection) Binding to certain oncoproteins such as HPV-16 E7 oncoprotein promotes homodimerization.

Subcellular location. Cytoplasm. Nucleus Cytoplasm.

Tissue specificity. Specifically expressed in proliferating cells, such as embryonic stem cells, embryonic carcinoma cells, as well as cancer cells. Expressed in adult tissues. Not expressed in tumor cells.

Post-translational modifications. ISGylated. Under hypoxia, hydroxylated by EGLN3. Acetylation at Lys-305 is stimulated by high glucose concentration, it decreases enzyme activity and promotes its lysosomal-dependent degradation via chaperone-mediated autophagy. Acetylated at Lys-433 by EP300, leading to impair phosphoenolpyruvate substrate-binding and promote its homodimerization and subsequent translocation to the nucleus. Deacetylation at Lys-433 by SIRT6 promotes its nuclear export into the cytoplasm, leading to suppress its nuclear localization and oncogenic function. S-nitrosylation at Cys-423 and Cys-424 inhibits homotetramerization and pyruvate kinase activity. S-nitrosylation is indirectly inhibited by AKR1A1 which degrades S-nitroso-CoA, a cofactor required to S-nitrosylate proteins. FGFR1-dependent tyrosine phosphorylation is reduced by interaction with TRIM35.

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. Acetylation at Lys-433 promotes its translocation into the nucleus and homodimerization, promoting the protein kinase activity. Has high pyruvate kinase activity by itself and does not require allosteric activation by D-fructose 1,6-bisphosphate (FBP) for activity.

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

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.

Isoforms (3)

UniProt ID	Names	Canonical?
P14618-1	M2, M2-PK, PKM2	yes
P14618-2	M1, M1-PK, PKM1
P14618-3	3

RefSeq proteins (9): NP_001193725, NP_001193726, NP_001193727, NP_001193728, NP_001303247, NP_001398010, NP_002645, NP_872270, NP_872271 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001697	Pyr_Knase	Family
IPR011037	Pyrv_Knase-like_insert_dom_sf	Homologous_superfamily
IPR015793	Pyrv_Knase_brl	Domain
IPR015795	Pyrv_Knase_C	Domain
IPR015806	Pyrv_Knase_insert_dom_sf	Homologous_superfamily
IPR015813	Pyrv/PenolPyrv_kinase-like_dom	Homologous_superfamily
IPR018209	Pyrv_Knase_AS	Active_site
IPR036918	Pyrv_Knase_C_sf	Homologous_superfamily
IPR040442	Pyrv_kinase-like_dom_sf	Homologous_superfamily

Pfam: PF00224, PF02887

Enzyme classification (BRENDA):

• EC 2.7.1.40 — pyruvate kinase (BRENDA: 141 organisms, 129 substrates, 587 inhibitors, 274 Km, 57 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PHOSPHOENOLPYRUVATE	0.0003–4.58	114
ADP	0.0002–14.1	67
GDP	0.026–2.2	5
CDP	2.53–9	3
PYRUVATE	0.025–0.48	3
UDP	0.41–2.4	3
IDP	0.193–4	2
ATP	0.35	1

Catalyzed reactions (Rhea), 3 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)
• pyruvate + ATP = phosphoenolpyruvate + ADP + H(+) (RHEA:18157)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (146 total): strand 30, modified residue 28, helix 24, binding site 21, turn 10, mutagenesis site 10, sequence conflict 10, cross-link 4, region of interest 2, site 2, splice variant 2, initiator methionine 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

61 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6B6U	X-RAY DIFFRACTION	1.35
3GR4	X-RAY DIFFRACTION	1.6
6NU5	X-RAY DIFFRACTION	1.6
6NUB	X-RAY DIFFRACTION	1.7
8G2E	X-RAY DIFFRACTION	1.84
6WP3	X-RAY DIFFRACTION	1.84
3GQY	X-RAY DIFFRACTION	1.85
6WP4	X-RAY DIFFRACTION	1.9
3ME3	X-RAY DIFFRACTION	1.95
3G2G	X-RAY DIFFRACTION	2
3H6O	X-RAY DIFFRACTION	2
9HIA	X-RAY DIFFRACTION	2.02
3BJF	X-RAY DIFFRACTION	2.03
3U2Z	X-RAY DIFFRACTION	2.1
5X1V	X-RAY DIFFRACTION	2.1
8HMS	X-RAY DIFFRACTION	2.1
6JFB	X-RAY DIFFRACTION	2.12
6WP5	X-RAY DIFFRACTION	2.17
9HIB	X-RAY DIFFRACTION	2.17
8X4R	X-RAY DIFFRACTION	2.18
1ZJH	X-RAY DIFFRACTION	2.2
6NU1	X-RAY DIFFRACTION	2.25
7L21	X-RAY DIFFRACTION	2.29
4QGC	X-RAY DIFFRACTION	2.3
4B2D	X-RAY DIFFRACTION	2.3
4G1N	X-RAY DIFFRACTION	2.3
4QG8	X-RAY DIFFRACTION	2.3
6V74	X-RAY DIFFRACTION	2.32
4JPG	X-RAY DIFFRACTION	2.33
4QG9	X-RAY DIFFRACTION	2.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14618-F1	96.94	0.96

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 270 (transition state stabilizer); 433 (crucial for phosphotyrosine binding)

Ligand- & substrate-binding residues (21): 113; 114; 120; 207; 270; 272; 295; 296; 296; 328; 432–437; 464 …

Post-translational modifications (32): 2, 3, 37, 41, 62, 66, 89, 97, 100, 105, 127, 148, 166, 166, 175, 195, 266, 270, 305, 322 …

Mutagenesis-validated functional residues (10):

Position	Phenotype
367	abolishes both pyruvate kinase and protein kinase activities.
399	impaired homotetramerization, leading to homodimerization and subsequent activation of the protein kinase activity.
403	significant reduction in hydroxylation and in pkm-mediated transcriptional activity of hif1a; when associated with a-408
408	significant reduction in hydroxylation and in pkm-mediated transcriptional activity of hif1a; when associated with a-403
423–424	abolished s-nitrosylation, leading to increased pyruvate kinase activity.
433	abolished interaction with phosphorylated ctnnb1. impaired phosphorylation of histone h3.
433	mimics acetylation, promoting homodimerization and activation of the protein kinase activity.
433	abolished acetylation by ep300. abolished deacetylation by sirt6.
437	unable to bind fbp but still activated by serine.
464	abolishes serine binding and allosteric activation.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-9764725	Negative Regulation of CDH1 Gene Transcription
R-HSA-70171	Glycolysis
R-HSA-70268	Pyruvate metabolism
R-HSA-9861718	Regulation of pyruvate metabolism
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 461 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, MODY_HIPPOCAMPUS_POSTNATAL, REACTOME_INNATE_IMMUNE_SYSTEM, SHIPP_DLBCL_VS_FOLLICULAR_LYMPHOMA_UP, HARRIS_HYPOXIA, GOCC_SECRETORY_GRANULE, MODULE_151, AMIT_EGF_RESPONSE_60_HELA, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (9): glycolytic process (GO:0006096), programmed cell death (GO:0012501), cellular response to insulin stimulus (GO:0032869), positive regulation of transcription by RNA polymerase II (GO:0045944), canonical glycolysis (GO:0061621), positive regulation of sprouting angiogenesis (GO:1903672), positive regulation of cytoplasmic translation (GO:2000767), chromatin remodeling (GO:0006338), regulation of translation (GO:0006417)

GO Molecular Function (20): magnesium ion binding (GO:0000287), transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), mRNA binding (GO:0003729), protein serine/threonine kinase activity (GO:0004674), protein tyrosine kinase activity (GO:0004713), non-membrane spanning protein tyrosine kinase activity (GO:0004715), pyruvate kinase activity (GO:0004743), ATP binding (GO:0005524), MHC class II protein complex binding (GO:0023026), potassium ion binding (GO:0030955), histone H3T11 kinase activity (GO:0035402), protein homodimerization activity (GO:0042803), cadherin binding (GO:0045296), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (14): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), rough endoplasmic reticulum (GO:0005791), cytosol (GO:0005829), vesicle (GO:0031982), secretory granule lumen (GO:0034774), extracellular exosome (GO:0070062), sperm principal piece (GO:0097228), extracellular vesicle (GO:1903561), ficolin-1-rich granule lumen (GO:1904813), cilium (GO:0005929)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Innate Immune System	1
Regulation of CDH1 Gene Transcription	1
Glucose metabolism	1
Aerobic respiration and respiratory electron transport	1
Pyruvate metabolism	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
positive regulation of DNA-templated transcription	2
protein kinase activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
membrane-bounded organelle	2
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
signal transduction	1
cell death	1
response to insulin	1
cellular response to peptide hormone stimulus	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
glucokinase activity	1
glyceraldehyde-3-phosphate dehydrogenase (NAD+) (phosphorylating) activity	1
glucose catabolic process	1
glycolytic process through glucose-6-phosphate	1
sprouting angiogenesis	1
positive regulation of angiogenesis	1
regulation of sprouting angiogenesis	1
cytoplasmic translation	1
positive regulation of translation	1
regulation of cytoplasmic translation	1
chromatin organization	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
metal ion binding	1

Protein interactions and networks

STRING

5580 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PKM	HIF1A	Q16665	995
PKM	CTNNB1	P35222	990
PKM	POU5F1	P31359	966
PKM	CD44	P16070	964
PKM	PGAM1	P18669	934
PKM	PGAM4	Q8N0Y7	897
PKM	LDHA	P00338	891
PKM	PTBP1	P26599	877
PKM	ENO1	P06733	869
PKM	PGAM2	P15259	844
PKM	FGFR1	P11362	842
PKM	TPI1	P00938	836
PKM	ALDOA	P04075	836
PKM	GAPDH	P00354	830
PKM	KDM8	Q8N371	826

IntAct

294 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PKM	HTT	psi-mi:“MI:0915”(physical association)	0.670
PKM	E7	psi-mi:“MI:0915”(physical association)	0.650
CHEK2	PPM1G	psi-mi:“MI:0914”(association)	0.560
PKM	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
RYBP	PKM	psi-mi:“MI:0915”(physical association)	0.560
BOD1	PKM	psi-mi:“MI:0915”(physical association)	0.560
PKM		psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	PKM	psi-mi:“MI:0915”(physical association)	0.560
PKM	SPRED1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (747): PKM (Affinity Capture-MS), PKM (Affinity Capture-MS), POLE2 (Two-hybrid), NXT2 (Two-hybrid), LNX1 (Two-hybrid), PKM (Affinity Capture-MS), PKM (Affinity Capture-MS), PKM (Affinity Capture-MS), PKM (Affinity Capture-MS), PKM (Affinity Capture-MS), SUMO1 (Reconstituted Complex), PKM (Affinity Capture-MS), PKM (Affinity Capture-MS), AGL (Co-fractionation), AKR1A1 (Co-fractionation)

ESM2 similar proteins: A2VCW9, A5DFH6, A7SG73, O35567, O62619, O65595, P00548, P00931, P00937, P09556, P11974, P11979, P11980, P14618, P14965, P21593, P22200, P31335, P31939, P32431, P43230, P43619, P46794, P52480, P54113, P54887, P54888, Q01378, Q01637, Q0VCK0, Q19264, Q42586, Q42806, Q42942, Q42954, Q5NVN0, Q5R5C2, Q6BYI4, Q6IUR4, Q71HN5

Diamond homologs: B0B7Q0, O05118, O08309, O30853, O44006, O51323, O62619, O65595, O94122, P00548, P00549, P0AD61, P0AD62, P0CE21, P11974, P11979, P11980, P12928, P14618, P21599, P22200, P22360, P30613, P30614, P30615, P30616, P31865, P34038, P43924, P46614, P47458, P51181, P51182, P52480, P52489, P53657, P55964, P57404, P70789, P73534

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
CREB1	“up-regulates quantity by expression”	PKM	“transcriptional regulation”
SREBF1	“up-regulates quantity by expression”	PKM	“transcriptional regulation”
PKM	up-regulates	STAT3	phosphorylation
L-serine	“up-regulates activity”	PKM	“chemical activation”
PIM2	“up-regulates quantity by stabilization”	PKM	phosphorylation
Shikonin	“down-regulates activity”	PKM	“chemical inhibition”
Alkannin	“down-regulates activity”	PKM	“chemical inhibition”
PKM	“down-regulates quantity”	phosphonatoenolpyruvate	“chemical modification”
PKM	“up-regulates quantity”	pyruvate	“chemical modification”
PKM	“up-regulates activity”	“HIF-1 complex”	binding
EGLN3	“up-regulates activity”	PKM	hydroxylation
CyclinD3/CDK6	“down-regulates activity”	PKM	phosphorylation
TRIB2	“up-regulates activity”	PKM	phosphorylation
MAPK8	“up-regulates activity”	PKM	phosphorylation
CDC25A	“up-regulates activity”	PKM	dephosphorylation
PTPN6	“down-regulates activity”	PKM	dephosphorylation
ACP1	“up-regulates activity”	PKM	dephosphorylation
EGFR	“down-regulates activity”	PKM	phosphorylation
PKM	“up-regulates activity”	RBBP8	phosphorylation
CDK6	“down-regulates activity”	PKM	phosphorylation
PKM	“up-regulates activity”	STAT3	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 150 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	5	16.0×	2e-03
autophagosome maturation	5	15.7×	2e-03
mitophagy	5	14.2×	3e-03
autophagosome assembly	6	12.0×	2e-03
MAPK cascade	6	8.2×	8e-03
positive regulation of apoptotic process	10	5.1×	3e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	10	4.7×	6e-03
protein ubiquitination	12	4.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

79 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	6
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

1788 predictions. Top by Δscore:

Variant	Effect	Δscore
15:72199752:CTTGC:C	acceptor_gain	1.0000
15:72199753:TTGC:T	acceptor_gain	1.0000
15:72199754:TGC:T	acceptor_gain	1.0000
15:72199755:GC:G	acceptor_gain	1.0000
15:72199756:CC:C	acceptor_gain	1.0000
15:72199757:C:CC	acceptor_gain	1.0000
15:72200470:GTACC:G	donor_loss	1.0000
15:72200472:A:AC	donor_gain	1.0000
15:72200472:AC:A	donor_gain	1.0000
15:72200473:C:CC	donor_gain	1.0000
15:72200473:CC:C	donor_gain	1.0000
15:72200473:CCA:C	donor_gain	1.0000
15:72200473:CCAA:C	donor_gain	1.0000
15:72200509:T:TA	donor_gain	1.0000
15:72200524:T:TA	donor_gain	1.0000
15:72200651:CAGAC:C	acceptor_gain	1.0000
15:72200652:AGAC:A	acceptor_gain	1.0000
15:72200653:GAC:G	acceptor_gain	1.0000
15:72200661:A:AC	acceptor_gain	1.0000
15:72200666:A:C	acceptor_gain	1.0000
15:72202641:C:CT	acceptor_gain	1.0000
15:72202642:A:T	acceptor_gain	1.0000
15:72203100:T:TA	donor_gain	1.0000
15:72206722:ACTCA:A	donor_loss	1.0000
15:72206723:CTCAC:C	donor_loss	1.0000
15:72206724:TCA:T	donor_loss	1.0000
15:72206725:CACCA:C	donor_loss	1.0000
15:72206726:A:AC	donor_gain	1.0000
15:72206726:AC:A	donor_gain	1.0000
15:72206726:ACCAG:A	donor_loss	1.0000

AlphaMissense

3483 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:72202608:C:G	A385P	1.000
15:72206765:C:A	G368V	1.000
15:72206765:C:T	G368E	1.000
15:72206766:C:A	G368W	1.000
15:72206766:C:G	G368R	1.000
15:72206766:C:T	G368R	1.000
15:72206771:G:T	A366D	1.000
15:72206786:A:G	L361P	1.000
15:72206789:A:C	M360R	1.000
15:72206789:A:T	M360K	1.000
15:72206813:A:T	V352D	1.000
15:72206817:C:G	A351P	1.000
15:72206822:G:T	A349D	1.000
15:72206828:T:A	D347V	1.000
15:72206829:C:G	D347H	1.000
15:72206830:A:C	S346R	1.000
15:72206830:A:T	S346R	1.000
15:72206832:T:G	S346R	1.000
15:72206876:A:G	L331P	1.000
15:72207131:G:A	T328I	1.000
15:72207134:G:T	A327D	1.000
15:72207136:A:C	C326W	1.000
15:72207137:C:T	C326Y	1.000
15:72207138:A:G	C326R	1.000
15:72207163:G:C	C317W	1.000
15:72207164:C:T	C317Y	1.000
15:72207188:G:T	A309D	1.000
15:72207221:C:T	G298D	1.000
15:72207222:C:G	G298R	1.000
15:72207224:A:G	L297P	1.000

dbSNP variants (sampled 300 via entrez): RS1000107033 (15:72209197 T>C,G), RS1000246117 (15:72200374 G>A,T), RS1000298235 (15:72222166 T>A), RS1000313739 (15:72215027 C>T), RS1000391207 (15:72221788 T>G), RS1000486082 (15:72206472 T>C), RS1000494879 (15:72229207 A>G,T), RS1000812679 (15:72231543 G>A), RS1000885943 (15:72226532 AAAAATAAAATAAAAT>A,AAAAAT,AAAAATAAAAT,AAAAATAAAATAAAATAAAAT,AAAAATAAAATAAAATAAAATAAAAT,AAAAATAAAATAAAATAAAATAAAATAAAAT), RS1001010387 (15:72204366 A>T), RS1001040747 (15:72210992 T>C), RS1001110568 (15:72210636 C>G), RS1001160007 (15:72231711 C>A,G,T), RS1001274371 (15:72221208 C>A,T), RS1001301068 (15:72208525 C>A)

Disease associations

OMIM: gene MIM:179050 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010083_289	Hemoglobin levels	1.000000e-14
GCST90011899_150	Aspartate aminotransferase levels	4.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1075189 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

59 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 809,845 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1094	FELBAMATE	4	10,652
CHEMBL1096	AMLEXANOX	4	4,195
CHEMBL1200930	RABEPRAZOLE SODIUM	4	3,361
CHEMBL1201039	BENZTHIAZIDE	4	37,839
CHEMBL129	ZIDOVUDINE	4	4,996
CHEMBL1382627	SULFADIAZINE, SILVER	4	561,177
CHEMBL1401	NITAZOXANIDE	4	9,504
CHEMBL1448	NICLOSAMIDE	4	14,322
CHEMBL15023	TRIFLUPERIDOL	4	2,646
CHEMBL1503	OMEPRAZOLE	4	52,284
CHEMBL15870	INDOPROFEN	4	22,854
CHEMBL1590	PSEUDOEPHEDRINE	4	25,626
CHEMBL159226	MOXISYLYTE	4	1,514
CHEMBL18	ETHOXZOLAMIDE	4	3,042
CHEMBL189171	ACEMETACIN	4	17,027
CHEMBL2146124	CEFUROXIME SODIUM	4	56
CHEMBL267936	MECAMYLAMINE	4	5,623
CHEMBL276832	HYDRALAZINE	4	23,794
CHEMBL3187985	APOMORPHINE HYDROCHLORIDE	4	5,278
CHEMBL361506	PENTAMIDINE ISETHIONATE	4	4,055
CHEMBL405110	METHYLENE BLUE ANHYDROUS	4
CHEMBL413	SIROLIMUS	4
CHEMBL421701	DITHIAZANINE IODIDE	4
CHEMBL4299940	MITAPIVAT	4
CHEMBL5	NALIDIXIC ACID	4
CHEMBL53	APOMORPHINE	4
CHEMBL58	MITOXANTRONE	4
CHEMBL585	TRIAMTERENE	4
CHEMBL590	MENADIONE	4
CHEMBL744	RILUZOLE	4

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Pyruvate kinases (EC 2.7.1.40)

Most potent curated ligand interactions (5 total), top 5:

Ligand	Action	Affinity	Parameter
compound 16 [PMID: 31977207]	Activation	7.82	pEC50
mitapivat	Activation	7.0	pEC50
compound 24 [PMID: 36723914]	Inhibition	6.91	pIC50
compound 1 [PMID: 31465224]	Inhibition	6.6	pIC50
compound 3k [PMID: 28688274]	Inhibition	5.53	pIC50

Binding affinities (BindingDB)

13 measured of 15 human assays (16 total across all organisms); most potent 13 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL5399474	IC50	122 nM
CHEMBL5404355	IC50	139 nM
CHEMBL5413275	IC50	230 nM
CHEMBL5440683	IC50	285 nM
CHEMBL5400237	IC50	326 nM
CHEMBL5412106	IC50	671 nM
CHEMBL5410552	IC50	999 nM
(2E)-1-butyl-2-[(E)-3-(1-butyl-5,6-dichloro-3-pentylbenzimidazol-3-ium-2-yl)prop-2-enylidene]-5,6-dichloro-3-pentylbenzimidazole	IC50	10000 nM	US-8877791: Inhibitors of pyruvate kinase and methods of treating disease
5-(methylthio)thiophene-2-carboxylic acid	IC50	10000 nM	US-8877791: Inhibitors of pyruvate kinase and methods of treating disease
2-[(5Z)-5-[[4-(2-iodobenzoyl)oxyphenyl]methylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]acetic acid	IC50	20000 nM	US-8877791: Inhibitors of pyruvate kinase and methods of treating disease
8-methyl-2-[1-(propan-2-ylamino)ethenyl]thieno[3,2-c]chromen-4-one	IC50	70000 nM	US-8877791: Inhibitors of pyruvate kinase and methods of treating disease
1-[4-(2,5-dimethylpyrrol-1-yl)phenyl]sulfanylpropan-2-one	IC50	90000 nM	US-8877791: Inhibitors of pyruvate kinase and methods of treating disease
4-(1H-1,2,4-triazol-5-yl)-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione	IC50	90000 nM	US-8877791: Inhibitors of pyruvate kinase and methods of treating disease

ChEMBL bioactivities

4514 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.26	IC50	0.055	nM	PHENYLALANINE
9.29	EC50	0.51	nM	MYRICETIN
9.22	EC50	0.6	nM	CHEMBL5590652
9.04	Kd	0.915	nM	CHEMBL5569778
8.96	Potency	1.1	nM	CHEMBL1435175
8.87	EC50	1.34	nM	ISOQUERCETIN
8.86	Kd	1.378	nM	CHEMBL6120726
8.80	Potency	1.6	nM	CHEMBL1418590
8.77	IC50	1.7	nM	CHEMBL5573729
8.74	Potency	1.8	nM	CHEMBL1091458
8.74	Potency	1.8	nM	CHEMBL1092471
8.66	Potency	2.2	nM	CHEMBL1091831
8.60	Potency	2.5	nM	CHEMBL2448607
8.49	AC50	3.2	nM	CHEMBL4071498
8.49	Potency	3.2	nM	CHEMBL1303801
8.49	Potency	3.2	nM	CHEMBL293749
8.49	Potency	3.2	nM	CHEMBL1397797
8.49	Potency	3.2	nM	CHEMBL1086565
8.35	IC50	4.5	nM	CHEMBL5563349
8.30	Potency	5	nM	CHEMBL1455935
8.30	Potency	5	nM	ESOXYBUTYNIN
8.30	Potency	5	nM	D-GLUTAMATE
8.30	Potency	5	nM	TRIFLUPERIDOL
8.25	Potency	5.6	nM	CHEMBL1469921
8.25	Potency	5.6	nM	CHEMBL1581079
8.25	Potency	5.6	nM	CHEMBL1581017
8.22	EC50	6	nM	MICHELIOLIDE
8.22	AC50	6	nM	CHEMBL5286069
8.20	Potency	6.3	nM	CHEMBL1527980
8.20	Potency	6.3	nM	CHEMBL1336339
8.20	Potency	6.3	nM	CHEMBL1367311
8.20	Potency	6.3	nM	CHEMBL1460632
8.20	Potency	6.3	nM	CHEMBL1377716
8.20	Potency	6.3	nM	CHEMBL1612225
8.20	Potency	6.3	nM	CHEMBL56543
8.20	Potency	6.3	nM	CHEMBL48278
8.20	Potency	6.3	nM	CHEMBL1317463
8.20	Potency	6.3	nM	RITANSERIN
8.20	Potency	6.3	nM	PIRENPERONE
8.20	Potency	6.3	nM	CHEMBL22778
8.20	Potency	6.3	nM	CHEMBL1360157
8.20	Potency	6.3	nM	CHEMBL1093096
8.15	EC50	7.126	nM	CHEMBL5274026
8.15	Potency	7.1	nM	CHEMBL1316971
8.15	Potency	7.1	nM	CHEMBL1334593
8.15	Potency	7.1	nM	CHEMBL1479572
8.15	Potency	7.1	nM	CHEMBL1084899
8.15	Potency	7.1	nM	CHEMBL1091503
8.15	Potency	7.1	nM	CHEMBL1085647
8.10	Potency	7.9	nM	CHEMBL1597654

PubChem BioAssay actives

245 with measured affinity, of 1562 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
phenylalanine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0001	uM
3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)chromen-4-one	1881918: Activation of recombinant PKM2 (unknown origin) Phe26, Tyr390, Glu397, Asp354, Leu353 residues	ec50	0.0005	uM
2-[7-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]quinoxaline	2115036: Activation of PKM2 (unknown origin) by LDH enzyme coupled assay	ec50	0.0006	uM
4-imidazo[1,2-a]pyridin-3-yl-N-(2-methoxyphenyl)-1,3-thiazol-2-amine	2090582: Binding affinity to human PKM2 expressed in Escherichia coli assessed as dissociation constant by SPR analysis	kd	0.0009	uM
2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxychromen-4-one	1881919: Activation of recombinant PKM2 (unknown origin) Glu397, Lys3I I, Asp354, Leu353, Tyr390, His391 residues	ec50	0.0013	uM
4-imidazo[1,2-a]pyridin-3-yl-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0017	uM
N-(3,5-dimethylphenyl)-4-imidazo[1,2-a]pyrimidin-3-yl-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0045	uM
(3aS,9R,9aS,9bS)-9-hydroxy-6,9-dimethyl-3-methylidene-4,5,7,8,9a,9b-hexahydro-3aH-azuleno[4,5-b]furan-2-one	1375096: Activation of recombinant human PKM2 expressed in Escherichia coli BL21 at 4 uM incubated for 50 mins measured over 40 mins	ec50	0.0060	uM
N-[(2-amino-6-fluorophenyl)methyl]-N-[2-(1,1-dioxothian-4-yl)ethyl]-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide	1920260: Activation of PKM2 (unknown origin) in presence of sorafenib	ec50	0.0071	uM
4-imidazo[1,2-a]pyrimidin-3-yl-N-(4-nitrophenyl)-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0088	uM
3-[(4-imidazo[1,2-a]pyrimidin-3-yl-1,3-thiazol-2-yl)amino]benzoic acid	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0121	uM
4-imidazo[1,2-a]pyrimidin-3-yl-N-(2-methoxyphenyl)-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0156	uM
(3R)-1-benzyl-N-[4-(1,3,2-dithiarsolan-2-yl)phenyl]-N-[(1-ethylpiperidin-4-yl)methyl]pyrrolidine-3-carboxamide	2027374: Binding affinity to wild type FLAG-tagged PKM2 in human PA-1 cells measured for 72 hrs	ic50	0.0160	uM
4-imidazo[1,2-a]pyrimidin-3-yl-N-(2,4,6-trichlorophenyl)-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0180	uM
2-[(4-imidazo[1,2-a]pyridin-3-yl-1,3-thiazol-2-yl)amino]phenol	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0180	uM
Mitapivat	2090604: Activation of PKM2 (unknown origin)	ec50	0.0200	uM
6-chloro-N-(3-methoxyphenyl)-3-oxo-4H-1,4-benzoxazine-7-sulfonamide	749715: Activation of PKM2 in human Huh7 cells assessed as production of pyruvate and ATP by fluorescence assay	ec50	0.0220	uM
[(2R,3S,4S,5R)-2,3,4-trihydroxy-5-(phosphonooxymethyl)oxolan-2-yl]methyl dihydrogen phosphate	1881862: Activation of PKM2 (unknown origin)	ec50	0.0230	uM
1-imidazo[1,2-a]pyrimidin-3-yl-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethanone	2094212: Inhibition of recombinant PKM2 (unknown origin)	ic50	0.0270	uM
3-[[4-(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)-1,4-diazepan-1-yl]sulfonyl]aniline	2090604: Activation of PKM2 (unknown origin)	ec50	0.0300	uM
4-imidazo[1,2-a]pyridin-3-yl-N-phenyl-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0330	uM
4-imidazo[1,2-a]pyrimidin-3-yl-N-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0359	uM
10-[(2-fluorophenyl)methyl]-4,7-dimethyl-3-thia-7,10,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),4,11-tetraen-9-one	1881880: Activation of PKM2 (unknown origin) Phe26, Tyr390, Glu397, Leu353 residues	ec50	0.0380	uM
N-(3-fluorophenyl)-4-imidazo[1,2-a]pyridin-3-yl-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0450	uM
[(3aS,9R,9aS,9bS)-6,9-dimethyl-3-methylidene-2-oxo-4,5,7,8,9a,9b-hexahydro-3aH-azuleno[8,7-b]furan-9-yl] 4-[1-[2-[2-[2-[2-[5-[(3aR,4R,6aS)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]butanoate	1375098: Irreversible binding affinity to recombinant human PKM2 expressed in Escherichia coli BL21	ki	0.0500	uM
1-imidazo[1,2-a]pyrimidin-3-yl-2-(4-phenylpiperazin-1-yl)ethanone	2094212: Inhibition of recombinant PKM2 (unknown origin)	ic50	0.0500	uM
Sirolimus	1920242: Inhibition of PKM2 (unknown origin)	ic50	0.0500	uM
4-(5,6-dihydroimidazo[1,2-a]pyrimidin-3-yl)-N-phenyl-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0540	uM
pyridin-3-ylmethyl 1-[4-(quinolin-8-ylsulfonylamino)benzoyl]piperidine-4-carbodithioate	1881887: Activation of PKM2 (unknown origin) Leu353, Tyr390, Phe26, Glu397, Lys311, Asp354 residues	ec50	0.0560	uM
1-imidazo[1,2-a]pyrimidin-3-yl-2-[4-(4-methylphenyl)piperazin-1-yl]ethanone	2094212: Inhibition of recombinant PKM2 (unknown origin)	ic50	0.0600	uM
N-(3-chloro-4-methylphenyl)-7-[[(2S)-1-hydroxypropan-2-yl]amino]-2-oxo-3,4-dihydro-1H-quinoline-6-sulfonamide	639784: Activation of human PKM2 assessed as ATP product formation after 1 hr by luminescent pyruvate kinase-luciferase coupled assay	ec50	0.0600	uM
2-[(4-imidazo[1,2-a]pyrimidin-3-yl-1,3-thiazol-2-yl)amino]phenol	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0609	uM
N-(2,5-difluorophenyl)-4-imidazo[1,2-a]pyrimidin-3-yl-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0667	uM
4-imidazo[1,2-a]pyrimidin-3-yl-N-prop-2-enyl-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.0678	uM
6-chloro-N-(3,4-dimethylphenyl)-2-oxo-3,4-dihydro-1H-quinoline-7-sulfonamide	639784: Activation of human PKM2 assessed as ATP product formation after 1 hr by luminescent pyruvate kinase-luciferase coupled assay	ec50	0.0700	uM
2-(benzimidazol-1-ylmethyl)-6-methylpyrido[1,2-a]pyrimidin-4-one	749715: Activation of PKM2 in human Huh7 cells assessed as production of pyruvate and ATP by fluorescence assay	ec50	0.0700	uM
10-[(3-methoxyphenyl)methyl]-7-methyl-4-methylsulfinyl-3-thia-7,10,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),4,11-tetraen-9-one	639784: Activation of human PKM2 assessed as ATP product formation after 1 hr by luminescent pyruvate kinase-luciferase coupled assay	ec50	0.0730	uM
N-(3-chloro-4-methylphenyl)-7-methyl-2-oxo-3,4-dihydro-1H-quinoline-6-sulfonamide	1881881: Activation of PKM2 (unknown origin) Glu397, Phe26, Tyr390, Leu353 residues	ec50	0.0900	uM
10-[(3-aminophenyl)methyl]-7-methyl-4-methylsulfinyl-3-thia-7,10,11-triazatricyclo[6.4.0.02,6]dodeca-1(8),2(6),4,11-tetraen-9-one	2090604: Activation of PKM2 (unknown origin)	ec50	0.0900	uM
6-chloro-N-(3-chloro-4-methylphenyl)-2-oxo-3,4-dihydro-1H-quinoline-7-sulfonamide	639784: Activation of human PKM2 assessed as ATP product formation after 1 hr by luminescent pyruvate kinase-luciferase coupled assay	ec50	0.0900	uM
N-(3-chloro-4-fluorophenyl)-7-fluoro-2-oxo-3,4-dihydro-1H-quinoline-6-sulfonamide	639784: Activation of human PKM2 assessed as ATP product formation after 1 hr by luminescent pyruvate kinase-luciferase coupled assay	ec50	0.0900	uM
N-[4-[4-[dideuterio-(3,5-difluorophenyl)methyl]piperazine-1-carbonyl]phenyl]quinoline-8-sulfonamide	1881862: Activation of PKM2 (unknown origin)	ec50	0.1000	uM
N-[4-(3-benzyl-3-hydroxyazetidine-1-carbonyl)phenyl]quinoline-8-sulfonamide	1881862: Activation of PKM2 (unknown origin)	ec50	0.1000	uM
N-(3-chloro-4-methylphenyl)-2-oxo-3,4-dihydro-1H-quinoline-6-sulfonamide	639784: Activation of human PKM2 assessed as ATP product formation after 1 hr by luminescent pyruvate kinase-luciferase coupled assay	ec50	0.1000	uM
4-(2,3-dihydro-1,4-benzodioxin-5-ylsulfonyl)-7-(4-methoxyphenyl)sulfonyl-2,1,3-benzothiadiazole	1881862: Activation of PKM2 (unknown origin)	ec50	0.1000	uM
N-[4-[4-(2,3-difluorophenyl)-4-hydroxypiperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide	1881862: Activation of PKM2 (unknown origin)	ec50	0.1000	uM
N-(4-fluorophenyl)-4-imidazo[1,2-a]pyridin-3-yl-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.1154	uM
N-(4-fluorophenyl)-4-imidazo[1,2-a]pyrimidin-3-yl-1,3-thiazol-2-amine	2090562: Inhibition of recombinant human PKM2 expressed in Escherichia coli preincubated for 30 mins followed by beta-NADH addition and measured over 20 mins by LDH-coupled enzyme assay	ic50	0.1169	uM
[4-[[(3R)-1-benzylpyrrolidine-3-carbonyl]-[(1-ethylpiperidin-4-yl)methyl]amino]phenyl]arsonous acid	2027354: Inhibition of human PKM2 assessed as ATP production incubated for 10 mins by Celltiter-glo luminescent analysis	ic50	0.1220	uM
N-(3-chloro-4-fluorophenyl)-7-[[(2S)-1-hydroxypropan-2-yl]amino]-2-oxo-3,4-dihydro-1H-quinoline-6-sulfonamide	639784: Activation of human PKM2 assessed as ATP product formation after 1 hr by luminescent pyruvate kinase-luciferase coupled assay	ec50	0.1300	uM

CTD chemical–gene interactions

186 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	affects reaction, decreases reaction, increases abundance, increases expression, increases reaction (+2 more)	7
bisphenol A	affects expression, decreases expression, increases expression, affects cotreatment	6
Valproic Acid	affects cotreatment, increases expression	6
sodium arsenite	increases expression, affects reaction, decreases expression, affects expression, affects binding (+2 more)	5
Acetylcysteine	affects localization, decreases expression, decreases reaction, increases expression	5
Cyclosporine	increases expression, increases secretion, decreases expression	5
Arsenic Trioxide	affects cotreatment, affects reaction, decreases reaction, decreases expression, increases reaction (+1 more)	4
Air Pollutants	affects cotreatment, increases abundance, increases expression, decreases expression	4
Cadmium	affects reaction, decreases reaction, increases abundance, increases expression, increases reaction (+1 more)	4
Glucose	increases uptake, decreases reaction, increases phosphorylation, increases reaction, affects reaction (+3 more)	4
Quercetin	decreases expression, decreases reaction, increases expression	4
Tretinoin	affects cotreatment, increases expression, decreases expression	4
trichostatin A	affects cotreatment, increases expression	3
3-methyladenine	decreases reaction, increases abundance, increases expression	3
Oxygen	affects reaction, affects cotreatment, increases expression, affects expression	3
Potassium Dichromate	decreases reaction, increases expression, increases reaction	3
Silicon Dioxide	increases expression, affects expression, increases secretion, decreases reaction	3
Smoke	decreases expression, increases abundance, increases expression	3
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
Tunicamycin	affects reaction, increases expression, decreases expression	3
Sirolimus	decreases reaction, increases expression, increases abundance, decreases activity, decreases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
4’-methoxy-1-naphthylfenoterol	decreases expression	2
bisphenol F	increases expression, affects cotreatment	2
arsenite	increases expression, affects binding, decreases reaction	2
3,4,5,3’,4’-pentachlorobiphenyl	decreases activity, increases expression, decreases reaction, increases reaction, decreases expression (+1 more)	2
artenimol	affects binding, decreases reaction, increases cleavage, increases expression, increases secretion	2
2,3’,4,4’,5-pentachlorobiphenyl	increases expression, decreases reaction, affects reaction, affects localization, decreases activity	2
4-phenylbutyric acid	decreases reaction, increases expression	2
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	affects localization, decreases reaction, increases expression, increases phosphorylation	2

ChEMBL screening assays

356 unique, capped per target: 334 binding, 20 functional, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1111818	Binding	Activation of PKM2 assessed as reduction of Km for phosphoenolpyruvate relative to untreated control	Evaluation of substituted N,N’-diarylsulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase. — J Med Chem
CHEMBL1613843	Functional	PUBCHEM_BIOASSAY: Secondary assay for Inhibitors of Human Pyruvate Kinase M2 isoform. (Class of assay: confirmatory) [Related pubchem assays: 1634, 1631 ]	PubChem BioAssay data set
CHEMBL4119691	ADMET	Inhibition of recombinant human N-terminal His-tagged PKM1 expressed in Escherichia coli BL21 preincubated for 15 mins followed by PEP/NADH addition measured at 30 secs interval for 3 to 6 mins by fluorescent PK-LDH assay	Discovery of novel naphthoquinone derivatives as inhibitors of the tumor cell specific M2 isoform of pyruvate kinase. — Eur J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7XM	Ubigene A-549 PKM KO	Cancer cell line	Male
CVCL_E0KZ	Ubigene HeLa PKM KO	Cancer cell line	Female
CVCL_E0YN	Ubigene MDA-MB-231 PKM KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.