PKLR

Summary

PKLR (pyruvate kinase L/R, HGNC:9020) is a protein-coding gene on chromosome 1q22, encoding Pyruvate kinase PKLR (P30613). Pyruvate kinase that catalyzes the conversion of phosphoenolpyruvate to pyruvate with the synthesis of ATP, and which plays a key role in glycolysis.

The protein encoded by this gene is a pyruvate kinase that catalyzes the transphosphorylation of phohsphoenolpyruvate into pyruvate and ATP, which is the rate-limiting step of glycolysis. Defects in this enzyme, due to gene mutations or genetic variations, are the common cause of chronic hereditary nonspherocytic hemolytic anemia (CNSHA or HNSHA). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5313 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pyruvate kinase deficiency of red cells (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 40
• Clinical variants (ClinVar): 457 total — 48 pathogenic, 53 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000298

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9020
Approved symbol	PKLR
Name	pyruvate kinase L/R
Location	1q22
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000143627
Ensembl biotype	protein_coding
OMIM	609712
Entrez	5313

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000342741, ENST00000392414, ENST00000434082

RefSeq mRNA: 2 — MANE Select: NM_000298 NM_000298, NM_181871

CCDS: CCDS1109, CCDS44240

Canonical transcript exons

ENST00000342741 — 11 exons

Exon	Start	End
ENSE00000961246	155295116	155295302
ENSE00000961247	155294482	155294752
ENSE00000961248	155294235	155294385
ENSE00000961249	155293438	155293590
ENSE00000961250	155293177	155293343
ENSE00000961251	155291756	155291937
ENSE00001791302	155300098	155300280
ENSE00001835019	155289293	155290678
ENSE00002299405	155301296	155301438
ENSE00003512685	155295665	155295756
ENSE00003658804	155295437	155295568

Expression profiles

Bgee: expression breadth broad, 69 present calls, max score 92.51.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.7215 / max 146.0499, expressed in 96 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14960	1.8783	70
14959	0.5573	62
14957	0.2314	27
14958	0.0544	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
liver	UBERON:0002107	92.51	gold quality
right lobe of liver	UBERON:0001114	92.03	gold quality
duodenum	UBERON:0002114	83.90	gold quality
adult mammalian kidney	UBERON:0000082	82.61	gold quality
bone marrow	UBERON:0002371	77.64	gold quality
kidney	UBERON:0002113	75.83	gold quality
bone marrow cell	CL:0002092	71.05	gold quality
small intestine	UBERON:0002108	66.89	gold quality
small intestine Peyer’s patch	UBERON:0003454	66.04	gold quality
cortex of kidney	UBERON:0001225	61.89	gold quality
cerebellum	UBERON:0002037	59.19	gold quality
cerebellar cortex	UBERON:0002129	59.08	gold quality
cerebellar hemisphere	UBERON:0002245	58.97	gold quality
right hemisphere of cerebellum	UBERON:0014890	57.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	55.65	silver quality
metanephros cortex	UBERON:0010533	54.43	gold quality
ganglionic eminence	UBERON:0004023	53.53	gold quality
mucosa of transverse colon	UBERON:0004991	52.77	gold quality
hypothalamus	UBERON:0001898	52.35	gold quality
superior frontal gyrus	UBERON:0002661	51.01	gold quality
prefrontal cortex	UBERON:0000451	50.75	gold quality
intestine	UBERON:0000160	49.84	gold quality
colonic epithelium	UBERON:0000397	49.74	gold quality
frontal cortex	UBERON:0001870	48.90	gold quality
transverse colon	UBERON:0001157	48.31	gold quality
skin of abdomen	UBERON:0001416	48.26	gold quality
anterior cingulate cortex	UBERON:0009835	48.11	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	47.68	gold quality
Brodmann (1909) area 9	UBERON:0013540	47.02	gold quality
zone of skin	UBERON:0000014	46.85	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-7407	yes	137.08
E-CURD-112	yes	39.84
E-CURD-122	yes	19.78
E-MTAB-10042	yes	14.29
E-MTAB-9388	yes	8.13
E-ANND-3	yes	5.18

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, FOXO1, GATA1, HHEX, HNF1A, HNF4A, LHX8, MAX, MLX, MLXIPL, MYC, NFIA, NR1H4, NR2F1, NR2F2, PPARA, SREBF1, TCF3, TFE3, USF1, USF2, ZNF236

miRNA regulators (miRDB)

95 targeting PKLR, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3202	99.66	67.70	2737

Literature-anchored findings (GeneRIF, showing 40)

• congenital insensitivity to pain with anhidrosis (CIPA): novel mutations of the TRKA (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutant TRKA and PKLR genes in a family with CIPA and pyruvate kinase deficiency (PMID:11668614)
• Erythrocyte pyruvate kinase was modified with bromopyruvate and the kinetic behavior of the modified enzyme was investigated as model for the mutant enzyme associated with nonspherocytic hemolytic anemia. (PMID:11916152)
• first crystal structure of recombinant erythrocyte pyruvate kinase and the biochemical characterization of eight mutants found in nonspherocytic hemolytic anemia patients (PMID:11960989)
• PKLR- GBA region shows almost complete linkage disequilibrium over 70 kb in a set of worldwide populations. (PMID:12107439)
• Liver pyruvate kinase polymorphisms are associated with type 2 diabetes in northern European Caucasians. (PMID:12196482)
• regulatory element is a necessary transcriptional regulatory element in the erythroid-specific promoter of the human pyruvate kinase gene (PMID:15727904)
• The current work exploits a ’natural screen’- the 122 point mutations identified in the human gene encoding the erythrocyte PYK isozyme and associated with nonspherocytic hemolytic anemia. (PMID:16540430)
• genotype-phenotype association in pyruvate kinase deficiency [review] (PMID:17360088)
• Northern Ireland has uncovered 4 new cases of pyruvate kinase deficiency. Molecular investigation revealed a total of six different mutations (PMID:17574881)
• 14 different mutations in the coding sequence of the R-PK gene in 74 Iranian individuals with low enzyme activity were identified; the most common were the G1168A and G1529A mutations at exon 11 occurring in 54% of the cases (PMID:17977029)
• pyruvate kinase deficiency provides protection against infection and replication of P. falciparum in human erythrocytes, raising the possibility that mutant pyruvate kinase alleles may confer a protective advantage against malaria in human populations (PMID:18420493)
• Pyruvate kinase deficiency protects against malaria in humans (PMID:18460648)
• The investigators identified a patient with pyruvate kinase deficiency caused by a mutation in the PK-LR gene. (PMID:18683378)
• identified the -148C>T mutation in the erythroidspecific promoter of PKLR in 3 unrelated patients with low PK activity (PMID:18698090)
• pyruvate kinase gene mutations are associated with anemia in pyruvate kinase deficient patients. (PMID:18726918)
• This is the first study to correlate the clinical profile with the molecular defects causing PK deficiency from India where 10 novel mutations that produce non-spherocytic haemolytic anaemia were identified. (PMID:18759866)
• Data report novel alterations of enzymescinvolved in glucose metabolism, including pyruvate kinase, that may be associated with the pathophysiology of insulin resistance and of renal damage in patients with type 1 diabetes mellitus with nephropathy. (PMID:18840520)
• Results provided a rationale for the observed enzyme deficiency and contribute to both a better understanding of the genotype-to-phenotype correlation in PK deficiency as well as the enzyme’s structure and function. (PMID:19085939)
• We failed to provide evidence of an association between PKLR rs3020781 and type 2 diabetes, overweight, obesity or related quantitative metabolic phenotypes in large-scale studies of Danes (PMID:19111066)
• Results are consistent with a mechanism by which phosphorylation at L-PYK Ser12 interrupts an activating interaction of N-terminal residues (including those at positions 7-10) with the main body of the protein, as a means of inhibiting substrate affinity (PMID:19320443)
• Decreased pyruvate kinase M2 expression to oxaliplatin resistance in patients with colorectal cancer. (PMID:19372549)
• Expression of pAkt, GLUT1 and TKTL1 were higher in breast cancer and DCIS than in normal tissue. Surprisingly, M2PK expression was highest in normal breast tissue. (PMID:19655166)
• These data suggest that reduced erythrocyte ATP levels may contribute to the malaria protection displayed by pyruvate kinase deficient erythrocytes in vitro. (PMID:19743919)
• Studies indicate that switching from pyruvate kinase spliced isoform PKM1 to PKM2 promotes aerobic glycolysis and provides a selective advantage for tumor formation, and the alternative splicing is controlled by hnRNP family members. (PMID:20978194)
• The results reveal an acetylation regulation of pyruvate kinase and the link between lysine acetylation and chaperone-mediated autophagy. (PMID:21700219)
• We identified the pyruvate kinase liver/red cell enzyme gene mutation of 8 children previously diagnosed with pyruvate kinase deficiency who were living in a remote town in the western United States (PMID:21784452)
• Rich genetic diversity was detected in PKLR, including 59 single-nucleotide polymorphisms and several loss-of-function variants (frequency 1.5%). (PMID:21833022)
• These results suggest that SARS coronavirus could reduce pyruvate kinase activity via its nucleocapsid protein, and this may in turn cause disease. (PMID:22222284)
• A global geographical co-distribution between malaria and high frequency of PK deficiency seems to occur suggesting that malaria may be a selective force raising the frequency of this 277Lys variant. (PMID:23082140)
• investigation of structure-function relationship of the N-terminus of liver pyruvate kinase and its regulation by oxidation/oxidative coupling and post-translational phosphorylation (PMID:23270483)
• Herpes simplex virus type 1 virion-derived US11 inhibits type 1 interferon-induced protein kinase R phosphorylation. (PMID:23773021)
• Hemolytic anemia associated with a novel heterozygous mutation 1183A in the pyruvate kinase gene has been found in two unrelated Jordanian patients. (PMID:24330591)
• A new type of inherited PK hyperactivity having solely increased expression of a kinetically normal PK-R had no mutations or copy number variants. An upregulatory mutation at an unlinked site is proposed. (PMID:24375447)
• 11 patients from 10 unrelated pyruvate kinse deficiency families had 9 different disease-causing PKLR mutations, including 2 new ones: the point mutation c.878A>T (p.Asp293Val) and the frameshift deletion c.1553delG (p.(Arg518Leufs*12). (PMID:24533562)
• Case Report: unknown mutation in the pyruvate kinase gene (PKLR) identified from a neonate with severe jaundice. (PMID:24969675)
• Partial pyruvate kinase deficiency aggravates the phenotypic expression of band 3 deficiency in a family with hereditary spherocytosis. (PMID:25388786)
• This study determined which interactions in the fructose 1,6-bisphosphate binding site of human liver pyruvate kinase contribute to allostery. (PMID:25629396)
• Pyruvate kinase variants modulate malaria phenotypes in a Thai population. (PMID:26658699)
• Two Novel Missense Mutations and a 5bp Deletion in the Erythroid-Specific Promoter of the PKLR Gene in Two Unrelated Patients With Pyruvate Kinase Deficient Transfusion-Dependent Chronic Nonspherocytic Hemolytic Anemia. (PMID:26728349)
• PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis. (PMID:26784545)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	pklr	ENSDARG00000042010
mus_musculus	Pklr	ENSMUSG00000041237
rattus_norvegicus	Pklr	ENSRNOG00000020420
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): PKM (ENSG00000067225)

Protein

Protein identifiers

Pyruvate kinase PKLR — P30613 (reviewed: P30613)

Alternative names: Pyruvate kinase 1, Pyruvate kinase isozymes L/R, R-type/L-type pyruvate kinase, Red cell/liver pyruvate kinase

All UniProt accessions (2): P30613, F8W6W2

UniProt curated annotations — full annotation on UniProt →

Function. Pyruvate kinase that catalyzes the conversion of phosphoenolpyruvate to pyruvate with the synthesis of ATP, and which plays a key role in glycolysis.

Subunit / interactions. Homotetramer.

Disease relevance. Pyruvate kinase hyperactivity (PKHYP) [MIM:102900] Autosomal dominant phenotype characterized by increase of red blood cell ATP. The disease is caused by variants affecting the gene represented in this entry. Anemia, congenital, non-spherocytic hemolytic, 2 (CNSHA2) [MIM:266200] An autosomal recessive disorder characterized by a variable degree of chronic hemolysis and decreased red cell pyruvate kinase activity. Clinical manifestations range from fatal anemia at birth to a fully compensated hemolysis without apparent anemia. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Allosterically activated by fructose 1,6-bisphosphate.

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 and M2. 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.

Similarity. Belongs to the pyruvate kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P30613-1	R-type, PKR	yes
P30613-2	L-type, PKL

RefSeq proteins (2): NP_000289, NP_870986 (=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), 1 shown:

• pyruvate + ATP = phosphoenolpyruvate + ADP + H(+) (RHEA:18157)

UniProt features (192 total): sequence variant 108, helix 26, strand 24, binding site 18, turn 6, modified residue 5, sequence conflict 2, chain 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

58 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9RDF	X-RAY DIFFRACTION	1.62
7FS3	X-RAY DIFFRACTION	1.66
5SC9	X-RAY DIFFRACTION	1.69
7QDN	X-RAY DIFFRACTION	1.7
5SCK	X-RAY DIFFRACTION	1.72
7FS9	X-RAY DIFFRACTION	1.72
7FRW	X-RAY DIFFRACTION	1.74
7FSD	X-RAY DIFFRACTION	1.77
5SC8	X-RAY DIFFRACTION	1.77
4IP7	X-RAY DIFFRACTION	1.8
5SCB	X-RAY DIFFRACTION	1.8
7FRX	X-RAY DIFFRACTION	1.85
7FSC	X-RAY DIFFRACTION	1.85
7FS1	X-RAY DIFFRACTION	1.86
5SCC	X-RAY DIFFRACTION	1.89
7FSA	X-RAY DIFFRACTION	1.91
5SCA	X-RAY DIFFRACTION	1.92
5SCG	X-RAY DIFFRACTION	1.94
5SDT	X-RAY DIFFRACTION	1.94
4IMA	X-RAY DIFFRACTION	1.95
7FRY	X-RAY DIFFRACTION	1.96
7QZU	X-RAY DIFFRACTION	1.96
7FRV	X-RAY DIFFRACTION	2
5SCD	X-RAY DIFFRACTION	2.04
9R3O	X-RAY DIFFRACTION	2.04
9R3M	X-RAY DIFFRACTION	2.06
7FRZ	X-RAY DIFFRACTION	2.08
5SCH	X-RAY DIFFRACTION	2.09
7FS8	X-RAY DIFFRACTION	2.1
8XFD	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30613-F1	90.75	0.85

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 (1): 313 (transition state stabilizer)

Ligand- & substrate-binding residues (18): 116; 315; 338; 339; 339; 371; 475–480; 525; 532; 559–564; 118–121; 118 …

Post-translational modifications (5): 2, 19, 26, 43, 292

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-163765	ChREBP activates metabolic gene expression
R-HSA-210745	Regulation of gene expression in beta cells
R-HSA-70171	Glycolysis
R-HSA-70268	Pyruvate metabolism
R-HSA-9692914	SARS-CoV-1-host interactions

MSigDB gene sets: 247 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, PID_HNF3B_PATHWAY, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, KEGG_GLYCOLYSIS_GLUCONEOGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, COUP_01, GOBP_RESPONSE_TO_METAL_ION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY

GO Biological Process (10): response to hypoxia (GO:0001666), glycolytic process (GO:0006096), response to nutrient (GO:0007584), response to glucose (GO:0009749), response to metal ion (GO:0010038), cellular response to insulin stimulus (GO:0032869), response to ATP (GO:0033198), pyruvate biosynthetic process (GO:0042866), response to cAMP (GO:0051591), cellular response to epinephrine stimulus (GO:0071872)

GO Molecular Function (11): magnesium ion binding (GO:0000287), pyruvate kinase activity (GO:0004743), ATP binding (GO:0005524), kinase activity (GO:0016301), potassium ion binding (GO:0030955), monosaccharide binding (GO:0048029), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062), pyruvate kinase complex (GO:1902912)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Integration of energy metabolism	1
Regulation of beta-cell development	1
Glucose metabolism	1
Aerobic respiration and respiratory electron transport	1
SARS-CoV-1 Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
pyruvate metabolic process	2
response to chemical	2
response to purine-containing compound	2
response to organophosphorus	2
response to oxygen-containing compound	2
cellular anatomical structure	2
response to stress	1
response to decreased oxygen levels	1
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	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
response to nutrient levels	1
response to hexose	1
response to insulin	1
cellular response to peptide hormone stimulus	1
monocarboxylic acid biosynthetic process	1
cellular response to chemical stimulus	1
response to epinephrine	1
metal ion binding	1
glycolytic process	1
phosphotransferase activity, alcohol group as acceptor	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transferase activity, transferring phosphorus-containing groups	1
alkali metal ion binding	1
carbohydrate binding	1
small molecule binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

30 interactions, top by confidence:

A	B	Type	Score
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
PKLR	CPNE7	psi-mi:“MI:0915”(physical association)	0.560
SRD5A2	CLPTM1	psi-mi:“MI:0914”(association)	0.500
PKLR	PKM	psi-mi:“MI:0915”(physical association)	0.400
SAV1	PKLR	psi-mi:“MI:0915”(physical association)	0.370
OTUD5	TP53	psi-mi:“MI:0914”(association)	0.350
USP3	EIF3F	psi-mi:“MI:0914”(association)	0.350
USPL1	ANXA1	psi-mi:“MI:0914”(association)	0.350
	CLIC1	psi-mi:“MI:0914”(association)	0.350
BUB1B	AP5Z1	psi-mi:“MI:0914”(association)	0.350
SRPK3	SNRPGP15	psi-mi:“MI:0914”(association)	0.350
CLIP1	RGPD3	psi-mi:“MI:0914”(association)	0.350
PI15		psi-mi:“MI:0914”(association)	0.350
ISX	GAPDHS	psi-mi:“MI:0914”(association)	0.350
TMEM69	ACOX3	psi-mi:“MI:0914”(association)	0.350
DKK2	LRP5	psi-mi:“MI:0914”(association)	0.350
UBE2J2	ALOX12B	psi-mi:“MI:0914”(association)	0.350
PCGF3	MBL2	psi-mi:“MI:0914”(association)	0.350
RASL11A	MBL2	psi-mi:“MI:0914”(association)	0.350
SPIN4	MBL2	psi-mi:“MI:0914”(association)	0.350
SBDS	IGFBP4	psi-mi:“MI:0914”(association)	0.350
LRRC3B	PKLR	psi-mi:“MI:0914”(association)	0.350
CIMAP1A	PKLR	psi-mi:“MI:0914”(association)	0.350
FCER1A	PRSS2	psi-mi:“MI:0914”(association)	0.350
ANXA1	DHX15	psi-mi:“MI:0914”(association)	0.350
SBDS	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
PKLR	CLEC4G	psi-mi:“MI:0915”(physical association)	0.000
CPNE7	PKLR	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (64): PKLR (Affinity Capture-MS), PKLR (Co-fractionation), PKLR (Co-fractionation), PKLR (Affinity Capture-MS), PKLR (Affinity Capture-MS), PKLR (Affinity Capture-MS), PKLR (Negative Genetic), PKLR (Negative Genetic), PKLR (Negative Genetic), PKLR (Negative Genetic), PKLR (Negative Genetic), PKLR (Affinity Capture-MS), PKLR (Synthetic Lethality), CPNE7 (Two-hybrid), PKLR (Affinity Capture-MS)

ESM2 similar proteins: A0A1X9QHJ0, A4XTM7, A5PK65, B9FFD2, O24210, O32183, O34882, O35215, O44786, O75891, O86237, P12928, P22989, P30046, P30613, P53657, P55434, P80254, P81529, P84172, P90835, P91850, P94502, Q05354, Q0APT7, Q0VFN1, Q18785, Q1GTY6, Q28J83, Q29536, Q2G6R7, Q2IZ07, Q2NAA7, Q2W6A0, Q3MHY6, Q5NQB9, Q5ZMG0, Q640C5, Q68FI3, Q7G764

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

2 interactions.

A	Effect	B	Mechanism
PKLR	“down-regulates quantity”	phosphonatoenolpyruvate	“chemical modification”
PKLR	“up-regulates quantity”	pyruvate	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	48
Likely pathogenic	53
Uncertain significance	237
Likely benign	42
Benign	8

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1162853	NM_000298.6(PKLR):c.1528C>T (p.Arg510Ter)	Pathogenic
1163645	NM_000298.6(PKLR):c.826del (p.Val276fs)	Pathogenic
1330671	NM_000298.6(PKLR):c.376-1G>A	Pathogenic
1369122	NM_000298.6(PKLR):c.1091dup (p.Lys365fs)	Pathogenic
1456959	NM_000298.6(PKLR):c.1091G>A (p.Gly364Asp)	Pathogenic
1505	PKLR, 1-BP DEL	Pathogenic
1509	NM_000298.6(PKLR):c.1261C>A (p.Gln421Lys)	Pathogenic
1510	NM_000298.6(PKLR):c.1436G>A (p.Arg479His)	Pathogenic
1511	NM_000298.6(PKLR):c.1529G>A (p.Arg510Gln)	Pathogenic
1514	NM_000298.6(PKLR):c.389C>A (p.Ser130Tyr)	Pathogenic
1515	NC_000001.11:g.155301478C>G	Pathogenic
1516	NM_000298.6(PKLR):c.1318G>T (p.Glu440Ter)	Pathogenic
1687397	NM_000298.6(PKLR):c.1015del (p.Asp339fs)	Pathogenic
1705384	NM_000298.6(PKLR):c.808C>T (p.Arg270Ter)	Pathogenic
2063906	NM_000298.6(PKLR):c.1484C>T (p.Ala495Val)	Pathogenic
2202852	NM_000298.6(PKLR):c.1462C>T (p.Arg488Ter)	Pathogenic
2422833	NC_000001.10:g.(?155271067)(155271280_?)del	Pathogenic
2422834	NC_000001.10:g.(?155261527)(155261748_?)del	Pathogenic
2437853	NM_000298.6(PKLR):c.1299C>A (p.Tyr433Ter)	Pathogenic
2437857	NM_000298.6(PKLR):c.695-2A>T	Pathogenic
2437871	NM_000298.6(PKLR):c.1573del (p.Trp525fs)	Pathogenic
2437882	NM_000298.6(PKLR):c.1542dup (p.Leu516fs)	Pathogenic
2437886	NM_000298.6(PKLR):c.1618+2T>C	Pathogenic
2437890	NM_000298.6(PKLR):c.965+2T>C	Pathogenic
2690489	NM_000298.6(PKLR):c.1676_1683del (p.Arg559fs)	Pathogenic
280113	NM_000298.6(PKLR):c.721G>T (p.Glu241Ter)	Pathogenic
2981212	NM_000298.6(PKLR):c.644dup (p.Arg216fs)	Pathogenic
3235888	NM_000298.6(PKLR):c.695-1G>A	Pathogenic
3247880	NC_000001.10:g.(?155260363)(155265567_?)del	Pathogenic
3341365	NM_000298.6(PKLR):c.603G>A (p.Trp201Ter)	Pathogenic

SpliceAI

1506 predictions. Top by Δscore:

Variant	Effect	Δscore
1:155291750:GCTCA:G	donor_loss	1.0000
1:155291751:CTCA:C	donor_loss	1.0000
1:155291753:CAC:C	donor_loss	1.0000
1:155291754:ACC:A	donor_loss	1.0000
1:155291755:C:CA	donor_loss	1.0000
1:155291755:CCA:C	donor_gain	1.0000
1:155293171:CCTCA:C	donor_loss	1.0000
1:155293172:CTCA:C	donor_loss	1.0000
1:155293173:TCAC:T	donor_loss	1.0000
1:155293174:CACCG:C	donor_loss	1.0000
1:155293175:A:AG	donor_loss	1.0000
1:155293175:ACCGG:A	donor_gain	1.0000
1:155293176:C:A	donor_loss	1.0000
1:155293176:CCGGC:C	donor_gain	1.0000
1:155293340:CAAT:C	acceptor_gain	1.0000
1:155293342:ATCTG:A	acceptor_loss	1.0000
1:155293343:TC:T	acceptor_loss	1.0000
1:155293344:C:CC	acceptor_gain	1.0000
1:155293344:CT:C	acceptor_loss	1.0000
1:155293345:T:C	acceptor_loss	1.0000
1:155293432:TCCTA:T	donor_loss	1.0000
1:155293433:CCTA:C	donor_loss	1.0000
1:155293435:TA:T	donor_loss	1.0000
1:155293436:A:AC	donor_gain	1.0000
1:155293437:C:CC	donor_gain	1.0000
1:155293437:CCG:C	donor_gain	1.0000
1:155293460:T:TA	donor_gain	1.0000
1:155293588:CAT:C	acceptor_gain	1.0000
1:155293589:ATC:A	acceptor_loss	1.0000
1:155293590:TCT:T	acceptor_loss	1.0000

AlphaMissense

3687 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:155293331:C:G	A428P	0.999
1:155294338:C:T	G338E	0.999
1:155294586:A:C	F287L	0.999
1:155294586:A:T	F287L	0.999
1:155294588:A:G	F287L	0.999
1:155293527:C:G	A394P	0.998
1:155293532:G:T	A392D	0.998
1:155293535:A:T	V391D	0.998
1:155293539:C:G	D390H	0.998
1:155293540:G:C	S389R	0.998
1:155293540:G:T	S389R	0.998
1:155293542:T:G	S389R	0.998
1:155294271:G:C	C360W	0.998
1:155294332:A:G	L340P	0.998
1:155294335:T:C	D339G	0.998
1:155294339:C:A	G338W	0.998
1:155294339:C:G	G338R	0.998
1:155294339:C:T	G338R	0.998
1:155294361:G:C	S330R	0.998
1:155294361:G:T	S330R	0.998
1:155294363:T:G	S330R	0.998
1:155294509:T:A	K313I	0.998
1:155294511:G:C	S312R	0.998
1:155294511:G:T	S312R	0.998
1:155294513:T:G	S312R	0.998
1:155295483:G:T	A154D	0.998
1:155295686:G:C	N118K	0.998
1:155295686:G:T	N118K	0.998
1:155295756:C:T	G95E	0.998
1:155293229:C:G	A462P	0.997

dbSNP variants (sampled 300 via entrez): RS1000012586 (1:155305868 C>T), RS1000191346 (1:155302542 T>G), RS1000430487 (1:155292937 C>A), RS1000592917 (1:155300815 A>G), RS1000623938 (1:155301042 A>G), RS1001040398 (1:155307411 T>A,C), RS1001339888 (1:155297327 A>G), RS1001415574 (1:155304483 A>G), RS1001469823 (1:155307720 T>G), RS1001603532 (1:155309188 C>A,T), RS1001620482 (1:155296227 G>A), RS1001957539 (1:155294966 A>G), RS1001990214 (1:155296172 A>G), RS1002015202 (1:155302501 T>G), RS1002171247 (1:155308180 C>G)

Disease associations

OMIM: gene MIM:609712 | disease phenotypes: MIM:102900, MIM:266200

GenCC curated gene-disease

Disease	Classification	Inheritance
pyruvate kinase deficiency of red cells	Definitive	Autosomal recessive
pyruvate kinase hyperactivity	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
pyruvate kinase deficiency of red cells	Definitive	AR

Mondo (4): pyruvate kinase hyperactivity (MONDO:0007067), pyruvate kinase deficiency of red cells (MONDO:0009950), congenital anemia (MONDO:0000577), hemolytic anemia (MONDO:0003664)

Orphanet (1): Hemolytic anemia due to red cell pyruvate kinase deficiency (Orphanet:766)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000952	Jaundice
HP:0000980	Pallor
HP:0001081	Cholelithiasis
HP:0001082	Cholecystitis
HP:0001511	Intrauterine growth retardation
HP:0001744	Splenomegaly
HP:0001789	Hydrops fetalis
HP:0001790	Nonimmune hydrops fetalis
HP:0001877	Abnormal erythrocyte morphology
HP:0001901	Polycythemia
HP:0001903	Anemia
HP:0001923	Reticulocytosis
HP:0002240	Hepatomegaly
HP:0003281	Increased circulating ferritin concentration
HP:0003452	Increased circulating iron concentration
HP:0003577	Congenital onset
HP:0004447	Poikilocytosis
HP:0004804	Congenital hemolytic anemia
HP:0004870	Chronic hemolytic anemia
HP:0005502	Increased red cell osmotic fragility
HP:0006579	Prolonged neonatal jaundice
HP:0008282	Unconjugated hyperbilirubinemia
HP:0011273	Anisocytosis
HP:0011463	Childhood onset
HP:0012132	Erythroid hyperplasia
HP:0012463	Elevated transferrin saturation
HP:0020062	Decreased hemoglobin concentration
HP:0020181	Reduced haptoglobin level

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST001277_10	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-15
GCST001791_35	Urate levels	6.000000e-19
GCST004131_70	Inflammatory bowel disease	6.000000e-08
GCST004132_44	Crohn’s disease	2.000000e-07
GCST004611_112	High light scatter reticulocyte count	1.000000e-09
GCST004611_113	High light scatter reticulocyte count	8.000000e-13
GCST004612_151	High light scatter reticulocyte percentage of red cells	4.000000e-11
GCST004612_152	High light scatter reticulocyte percentage of red cells	3.000000e-14
GCST004619_218	Reticulocyte fraction of red cells	2.000000e-14
GCST004619_75	Reticulocyte fraction of red cells	1.000000e-23
GCST004622_108	Reticulocyte count	2.000000e-11
GCST004622_109	Reticulocyte count	1.000000e-20
GCST005231_43	Major depressive disorder	2.000000e-07
GCST007294_124	Body fat distribution (trunk fat ratio)	8.000000e-35
GCST007294_3	Body fat distribution (trunk fat ratio)	6.000000e-21
GCST007294_50	Body fat distribution (trunk fat ratio)	1.000000e-15
GCST007295_17	Body fat distribution (leg fat ratio)	3.000000e-13
GCST007295_37	Body fat distribution (leg fat ratio)	7.000000e-17
GCST007295_72	Body fat distribution (leg fat ratio)	1.000000e-28
GCST009467_1	Hemoglobin levels	1.000000e-06
GCST010696_19	Cortical thickness (min-P)	2.000000e-10
GCST010697_10	Cortical surface area (min-P)	3.000000e-10
GCST010698_59	Subcortical volume (min-P)	9.000000e-10
GCST010699_20	Brain morphology (min-P)	7.000000e-10
GCST010700_5	Cortical thickness (MOSTest)	8.000000e-17
GCST010701_66	Cortical surface area (MOSTest)	1.000000e-09
GCST010702_43	Subcortical volume (MOSTest)	3.000000e-10
GCST010703_253	Brain morphology (MOSTest)	4.000000e-14
GCST90002383_336	Hematocrit	2.000000e-11
GCST90002383_337	Hematocrit	4.000000e-18

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004531	urate measurement
EFO:0007986	reticulocyte count
EFO:0004341	body fat distribution
EFO:0004509	hemoglobin measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004348	hematocrit
EFO:0004305	erythrocyte count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000743	Anemia, Hemolytic	C15.378.050.141
C566310	Adenosine Triphosphate, Elevated, Of Erythrocytes (supp.)
C564858	Pyruvate Kinase Deficiency of Red Cells (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1075126 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 60,232 (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
CHEMBL4299940	MITAPIVAT	4	236
CHEMBL265502	SURAMIN	3	36,848
CHEMBL6246	ELLAGIC ACID	2	23,148

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2297480	FDPS, PKLR	3	2.00	3	zoledronate;Bisphosphonates;atorvastatin
rs118204085	PKLR		0.00	0

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 (1 total), top 1:

Ligand	Action	Affinity	Parameter
etavopivat	Positive	6.95	pEC50

ChEMBL bioactivities

801 potent at pChembl≥5 of 888 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	Potency	1	nM	CHEMBL1323190
8.89	Potency	1.3	nM	CHEMBL1084058
8.80	Potency	1.6	nM	CHEMBL1085412
8.80	Potency	1.6	nM	CHEMBL1082796
8.74	Potency	1.8	nM	CHEMBL1093091
8.70	Potency	2	nM	CHEMBL1551624
8.70	Potency	2	nM	CHEMBL1085873
8.66	Potency	2.2	nM	CHEMBL1085411
8.66	Potency	2.2	nM	CHEMBL1092121
8.66	Potency	2.2	nM	CHEMBL1083728
8.66	Potency	2.2	nM	CHEMBL1093688
8.60	Potency	2.5	nM	CHEMBL1086320
8.49	Potency	3.2	nM	CHEMBL1093688
8.49	Potency	3.2	nM	CHEMBL1093096
8.46	Potency	3.5	nM	CHEMBL1083165
8.46	Potency	3.5	nM	CHEMBL1089364
8.35	Potency	4.5	nM	CHEMBL1093093
8.25	Potency	5.6	nM	CHEMBL1089366
8.20	Potency	6.3	nM	CHEMBL1315562
8.15	Potency	7.1	nM	CHEMBL1323190
8.15	Potency	7.1	nM	CHEMBL1082796
8.05	Potency	8.9	nM	CHEMBL1088762
8.00	Potency	10	nM	CHEMBL1088747
8.00	Potency	10	nM	CHEMBL1085410
7.90	Potency	12.6	nM	CHEMBL1090711
7.90	Potency	12.6	nM	CHEMBL1091078
7.85	Potency	14.1	nM	CHEMBL1083728
7.80	Potency	15.8	nM	CHEMBL1085410
7.80	Potency	15.8	nM	CHEMBL1090753
7.80	Potency	15.8	nM	CHEMBL1084625
7.75	Potency	17.8	nM	CHEMBL1089059
7.70	Potency	20	nM	CHEMBL1091057
7.65	Potency	22.4	nM	CHEMBL1551624
7.65	Potency	22.4	nM	CHEMBL1091078
7.65	Potency	22.4	nM	CHEMBL1091458
7.65	Potency	22.4	nM	CHEMBL1089603
7.60	Potency	25.1	nM	CHEMBL1086539
7.60	Potency	25.1	nM	CHEMBL1092462
7.55	IC50	28	nM	CHEMBL6338
7.55	EC50	28	nM	CHEMBL6133200
7.55	Potency	28.2	nM	CHEMBL1082454
7.54	AC50	29	nM	MITAPIVAT
7.50	IC50	32	nM	ELLAGIC ACID
7.50	Potency	31.6	nM	CHEMBL1091795
7.45	Potency	35.5	nM	CHEMBL1092297
7.45	Potency	35.5	nM	CHEMBL1092480
7.35	Potency	44.7	nM	CHEMBL1090774
7.35	Potency	44.7	nM	CHEMBL1591871
7.35	Potency	44.7	nM	CHEMBL1093996
7.30	Potency	50.1	nM	CHEMBL1084625

PubChem BioAssay actives

37 with measured affinity, of 720 total; 36 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
3,4,8,9-tetrahydroxybenzo[c]chromen-6-one	2075044: Inhibition of full length N-terminal His-tagged human PKL (2 to 543 residues) expressed in Escherichia coli by kinase Glo luminescence based plate reader assay	ic50	0.0280	uM
6,7,13,14-tetrahydroxy-2,9-dioxatetracyclo[6.6.2.04,16.011,15]hexadeca-1(15),4,6,8(16),11,13-hexaene-3,10-dione	2075044: Inhibition of full length N-terminal His-tagged human PKL (2 to 543 residues) expressed in Escherichia coli by kinase Glo luminescence based plate reader assay	ic50	0.0320	uM
6,6-dioxobenzo[c][1,2]benzoxathiine-1,2,3,8,9-pentol	2075044: Inhibition of full length N-terminal His-tagged human PKL (2 to 543 residues) expressed in Escherichia coli by kinase Glo luminescence based plate reader assay	ic50	0.0700	uM
N,2-bis(3,4-dihydroxyphenyl)-4,5-dihydroxybenzenesulfonamide	1983224: Inhibition of purified human PLK (unknown origin) assessed as ATP production by Kinase-Glo Max luminescence assay	ic50	0.1200	uM
1,2-dihydroxy-3-piperazin-1-ylsulfonylanthracene-9,10-dione	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	0.1500	uM
1-(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylpiperidine-3-carboxylic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	0.1600	uM
2-[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylamino]acetic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	0.2000	uM
2-[2-[4-(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylpiperazin-1-yl]-2-oxoethyl]-2-hydroxybutanedioic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	0.2000	uM
sodium 3,4-dihydroxy-9,10-dioxoanthracene-2-sulfonate	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	0.2000	uM
2-(carboxymethyl)-5-[[[4-(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylpiperazine-1-carbonyl]amino]methyl]benzoic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	0.2900	uM
methyl 2-[(1,1-dioxo-1,2-benzothiazol-3-yl)sulfanyl]benzoate	2076428: Allosteric activation at human liver pyruvate kinase	ec50	0.2900	uM
2-(carboxymethyl)-5-[[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylamino]methyl]benzoic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	0.3000	uM
3,8,9-trihydroxybenzo[c]chromen-6-one	2075044: Inhibition of full length N-terminal His-tagged human PKL (2 to 543 residues) expressed in Escherichia coli by kinase Glo luminescence based plate reader assay	ic50	0.4100	uM
(2S)-2-[[4-(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylpiperazine-1-carbonyl]amino]pentanedioic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	0.5500	uM
2-[[2-[[2-[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylamino]acetyl]amino]acetyl]amino]acetic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	0.7000	uM
(2S)-2-[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylamino]-3-hydroxypropanoic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	0.9000	uM
8-[[4-methyl-3-[[3-[[3-[[2-methyl-5-[(4,6,8-trisulfonaphthalen-1-yl)carbamoyl]phenyl]carbamoyl]phenyl]carbamoylamino]benzoyl]amino]benzoyl]amino]naphthalene-1,3,5-trisulfonic acid	1920250: Binding affinity to PKL (unknown origin)	ki	1.1000	uM
(2S)-2-[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylamino]-3-methoxypropanoic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	1.2000	uM
2-(carboxymethyl)-5-[[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)amino]methyl]benzoic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	1.3000	uM
(2S)-2-[[1-(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylpiperidine-3-carbonyl]amino]pentanedioic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	1.3000	uM
4-[4-(3-aminophenyl)sulfonylpiperazin-1-yl]sulfonylbenzene-1,2-diol	1983223: Activation of purified human PLK (unknown origin) assessed as ATP production by Kinase-Glo Max luminescence assay	ec50	1.3900	uM
sodium 3,4-dihydroxy-9,10-dioxoanthracene-2-carboxylate	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	1.4000	uM
2-[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylamino]-4-methylsulfanylbutanoic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	1.4000	uM
2-(carboxymethyl)-5-[[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)carbamoylamino]methyl]benzoic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	1.7000	uM
(2S)-2-[[1-(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylpiperidine-3-carbonyl]amino]butanedioic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	1.9000	uM
2-[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)amino]butanedioic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	2.5000	uM
[1,4-dioxo-3-(piperidine-1-carbothioylsulfanylmethyl)naphthalen-2-yl]methyl piperidine-1-carbodithioate	1412803: Inhibition of recombinant human N-terminal His-tagged PKL expressed in Escherichia coli preincubated for 25 mins in presence of PEP/FBP followed by ADP/NADH addition measured after 25 mins by PK-LDH assay	ic50	2.9000	uM
sodium 3-hydroxy-9,10-dioxoanthracene-2-sulfonate	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	3.4000	uM
(1,4-dioxonaphthalen-2-yl)methyl 4-phenylpiperazine-1-carbodithioate	1491466: Inhibition of recombinant human N-terminal His-tagged PKL expressed in Escherichia coli preincubated for 15 mins followed by PEP/NADH addition measured at 30 secs interval for 3 to 6 mins by fluorescent PK-LDH assay	ic50	3.8000	uM
2-[4-[[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)amino]methyl]phenyl]acetic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	3.8000	uM
2-[[2-[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylamino]acetyl]amino]acetic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	4.1000	uM
1-(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylpiperidine-4-carboxylic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	4.8000	uM
3-[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylamino]propanoic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	5.8000	uM
sodium 4-hydroxy-9,10-dioxoanthracene-2-sulfonate	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	7.3000	uM
4-[(3,4-dihydroxy-9,10-dioxoanthracen-2-yl)sulfonylamino]butanoic acid	1879867: Inhibition of PKL (unknown origin) for 30 mins by Kinase-Glo Max reagent based luminescence assay	ic50	7.5000	uM
(3-methyl-1,4-dioxonaphthalen-2-yl)methyl piperidine-1-carbodithioate	1491466: Inhibition of recombinant human N-terminal His-tagged PKL expressed in Escherichia coli preincubated for 15 mins followed by PEP/NADH addition measured at 30 secs interval for 3 to 6 mins by fluorescent PK-LDH assay	ic50	8.2000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects cotreatment, decreases expression, decreases methylation	4
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects expression	4
sodium arsenite	decreases expression, increases expression	3
Acetaminophen	decreases expression	3
Aflatoxin B1	affects expression, decreases expression	3
Endosulfan	affects cotreatment, decreases expression	2
Valproic Acid	decreases expression, increases methylation	2
Cyclosporine	decreases expression	2
Palmitic Acid	affects cotreatment, affects expression, decreases expression	2
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
benzo(b)fluoranthene	affects cotreatment, decreases expression	1
bisphenol A	decreases expression	1
deoxynivalenol	decreases expression	1
perfluorooctanoic acid	decreases expression	1
benz(a)anthracene	decreases expression, affects cotreatment	1
chrysene	affects cotreatment, decreases expression	1
stearic acid	decreases expression	1
benazol P	affects expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
bisphenol S	increases expression	1
jinfukang	increases expression	1
bisphenol AF	increases expression	1
Rosiglitazone	decreases expression	1
Resveratrol	decreases expression, affects cotreatment	1
Troglitazone	decreases expression	1
Bosentan	affects expression	1

ChEMBL screening assays

82 unique, capped per target: 69 binding, 12 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1108910	Binding	Activation of PKR assessed as pyruvate formation by fluorescent pyruvate kinase-lactate dehydrogenase coupled assay relative to control	Evaluation of substituted N,N’-diarylsulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase. — J Med Chem
CHEMBL1613911	Functional	PUBCHEM_BIOASSAY: Secondary LDH Assay for Activators of Human Reticulocyte Pyruvate Kinase: for Probe SAR. (Class of assay: confirmatory) [Related pubchem assays: 2095, 1631 ]	PubChem BioAssay data set
CHEMBL4119693	ADMET	Inhibition of recombinant human N-terminal His-tagged PKL expressed in Escherichia coli 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

5 cell lines: 3 cancer cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D1PU	Abcam K-562 PKLR KO	Cancer cell line	Female
CVCL_D2LF	Abcam Raji PKLR KO	Cancer cell line	Male
CVCL_WQ30	Abcam Jurkat PKLR KO	Cancer cell line	Male
CVCL_XJ90	PKD2.78	Induced pluripotent stem cell	Male
CVCL_XJ91	PKD3.54	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05777993	PHASE4	ENROLLING_BY_INVITATION	A Study to Provide Continued Access to Mitapivat for Participants Who Previously Completed an Agios-Sponsored Mitapivat Study
NCT03548220	PHASE3	COMPLETED	A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
NCT03559699	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD)
NCT03853798	PHASE3	COMPLETED	Extension Study of AG-348 in Adult Participants With Pyruvate Kinase Deficiency Previously Enrolled in AG-348-006 or AG348-C-007
NCT00001729	PHASE3	COMPLETED	Combination Drug Therapy for Patients With Hepatitis C
NCT02476916	PHASE2	COMPLETED	A Study of AG-348 in Adult Participants With Pyruvate Kinase (PK) Deficiency
NCT06422351	PHASE2	SUSPENDED	Clinical Trial to Evaluate the Efficacy of Gene Therapy for Pyruvate Kinase Deficiency
NCT00110617	PHASE2	COMPLETED	Study of Deferasirox Relative to Subcutaneous Deferoxamine in Sickle Cell Disease Patients
NCT01579110	PHASE2	UNKNOWN	Efficacy and Safety of Levamisole Combined With Standard Prednisolone in Warm Antibody Autoimmune Hemolytic Anemia.
NCT01642979	PHASE2	UNKNOWN	Safety and Efficacy of Levamisole Combined With Cyclosporine A in Patients With Classic Paroxysmal Nocturnal Hemoglobinuria
NCT01760096	PHASE2	UNKNOWN	Safety and Efficacy of Levamisole Combined With Cyclosporine A in Patients With Subclinical Paroxysmal Nocturnal Hemoglobinuria and PNH in the Setting of Another Bone Marrow Failure Syndromes(PNH-2013)
NCT04105166	PHASE1	COMPLETED	Gene Therapy for Pyruvate Kinase Deficiency (PKD)
NCT07612345	PHASE1	NOT_YET_RECRUITING	High-Dose Vitamin C in G6PDA and Pyruvate Kinase Deficiency: A Safety Study
NCT05004259	PHASE1	COMPLETED	The Safety of Repurposing Daratumumab for Relapsed or Refractory Autoimmune Antibody Mediated Hemolytic Anemia
NCT06684041	PHASE1	COMPLETED	A Safety, Tolerability, Pharmacokinetic/Pharmacodynamic Study, and QT Interval Study of HRS-5965 Capsules in Healthy Subjects
NCT07040787	PHASE1	COMPLETED	Investigation of Drug-drug Interaction of HRS-5965 With Clopidogrel and Clarithromycin in Healthy Subjects
NCT02053480	Not specified	COMPLETED	Pyruvate Kinase Deficiency Natural History Study
NCT03481738	Not specified	ACTIVE_NOT_RECRUITING	Pyruvate Kinase Deficiency Global Longitudinal Registry
NCT03866590	Not specified	COMPLETED	Pyruvate Kinase Deficiency Epidemiological Study (PIECE)
NCT04902833	Not specified	COMPLETED	Acquired Pyruvate Kinase Deficiency In Clonal Myeloid Neoplasms
NCT04964323	Not specified	TERMINATED	Pyruvate Kinase (PK) Deficiency Global Longitudinal Registry: Patient-Reported Outcomes (PRO)
NCT04995315	Not specified	COMPLETED	Pyruvate Kinase Deficiency Global Longitudinal Registry Substudy of Protocol AG348-C-008
NCT00658385	Not specified	COMPLETED	Assess the Feasibility and Safety of Granulocyte Colony Stimulating Factor (GCSF) Mobilization of CD34+ Hematopoietic Progenitor Cells in Patients With Betathalassemia Major
NCT03513328	PHASE1/PHASE2	COMPLETED	Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation
NCT04610866	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Long-term Mitapivat Dosing in Subjects With Stable Sickle Cell Disease: An Extension of a Phase I Pilot Study of Mitapivat
NCT00842621	Not specified	COMPLETED	Long Term Effects of Erythrocyte Lysis
NCT00971984	Not specified	COMPLETED	Demographic, Clinical and Laboratory Characteristics of Children With Alpha Thalassemia in Northern Israel
NCT02111590	Not specified	COMPLETED	Immunoglobulin Dosage and Administration Form in CIDP and MMN
NCT03006718	Not specified	COMPLETED	SCD-PROMIS: A Software Platform to Enhance Self-efficacy and Patient-provider Engagement for Patients With Sickle Cell Pain
NCT04721262	Not specified	COMPLETED	Ferumoxytol Enhanced Hyperfine Low Field Strength MRI
NCT06708728	Not specified	NOT_YET_RECRUITING	Study of Acquired Hemolytic Anemia in Adult Hospitalized Patients