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 (top 3% of genes corpus-wide)
• Clinical variants (ClinVar): 482 total — 50 pathogenic, 58 likely-pathogenic (top 7% of genes corpus-wide)
• GTEx eGene: eQTL in 5 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 32
• Drug target: yes — 2 curated mechanism-of-action drugs; 3 molecules with ChEMBL bioactivity
• Approved drugs (ChEMBL mechanism of action): 1 — Mitapivat
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.90 (unconstrained)
• 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: 4 — 4 protein_coding

MANE Select: ENST00000342741

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 5: 1

ENST00000342741, ENST00000392414, ENST00000434082, ENST00001145513

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.

Highest expression (Bgee): liver, lobe of liver, duodenum, adult mammalian kidney, bone marrow.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PKLR is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 5 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

5 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	4.7e-38	-0.70	1:155305936:C:T
Brain Hypothalamus	eqtl	3.1e-03	+0.27	1:154309746:C:T
Brain Cortex	eqtl	2.7e-02	-0.96	1:154677537:C:A
Skin Not Sun Exposed Suprapubic	eqtl	3.2e-02	+0.12	1:155345824:C:T
Colon Sigmoid	eqtl	3.6e-02	-0.26	1:154335154:C:T

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

showing 100 of 106 tissues 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
blood	UBERON:0000178	46.57	gold quality
cerebral cortex	UBERON:0000956	46.15	gold quality
skin of leg	UBERON:0001511	45.73	gold quality
right frontal lobe	UBERON:0002810	45.68	gold quality
rectum	UBERON:0001052	45.58	gold quality
placenta	UBERON:0001987	45.48	gold quality
cortical plate	UBERON:0005343	44.43	gold quality
brain	UBERON:0000955	44.00	gold quality
primary visual cortex	UBERON:0002436	43.68	silver quality
colon	UBERON:0001155	43.19	gold quality
sural nerve	UBERON:0015488	42.84	gold quality
lower esophagus mucosa	UBERON:0035834	41.90	silver quality
mucosa of stomach	UBERON:0001199	41.77	silver quality
testis	UBERON:0000473	41.01	gold quality
vermiform appendix	UBERON:0001154	40.99	gold quality
left testis	UBERON:0004533	40.80	gold quality
right testis	UBERON:0004534	40.18	gold quality
ventricular zone	UBERON:0003053	39.94	gold quality
stromal cell of endometrium	CL:0002255	39.92	gold quality
adrenal tissue	UBERON:0018303	39.05	gold quality
nucleus accumbens	UBERON:0001882	38.97	silver quality
multicellular organism	UBERON:0000468	38.94	gold quality
hindlimb stylopod muscle	UBERON:0004252	38.77	gold quality
substantia nigra	UBERON:0002038	38.65	gold quality
tibial nerve	UBERON:0001323	37.95	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	37.49	silver quality
urinary bladder	UBERON:0001255	37.07	gold quality
smooth muscle tissue	UBERON:0001135	36.57	silver quality
gall bladder	UBERON:0002110	36.37	gold quality
monocyte	CL:0000576	36.19	gold quality
caudate nucleus	UBERON:0001873	36.15	silver quality
leukocyte	CL:0000738	35.41	gold quality
Ammon’s horn	UBERON:0001954	34.66	silver quality
muscle layer of sigmoid colon	UBERON:0035805	34.57	silver quality
C1 segment of cervical spinal cord	UBERON:0006469	34.48	silver quality
spleen	UBERON:0002106	34.40	gold quality
esophagus mucosa	UBERON:0002469	34.16	silver quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
tonsil	UBERON:0002372	33.10	gold quality
lymph node	UBERON:0000029	32.81	gold quality
esophagus	UBERON:0001043	32.60	silver quality
stomach	UBERON:0000945	32.56	silver quality
adrenal gland	UBERON:0002369	32.55	silver quality
right uterine tube	UBERON:0001302	32.44	gold quality
calcaneal tendon	UBERON:0003701	32.41	gold quality
body of pancreas	UBERON:0001150	32.25	gold quality
myometrium	UBERON:0001296	31.70	gold quality
heart left ventricle	UBERON:0002084	31.57	gold quality
heart	UBERON:0000948	31.44	gold quality
right adrenal gland	UBERON:0001233	31.40	silver quality
right atrium auricular region	UBERON:0006631	31.37	gold quality
body of stomach	UBERON:0001161	31.18	gold quality
thoracic mammary gland	UBERON:0005200	31.07	gold quality
right lung	UBERON:0002167	31.04	gold quality
subcutaneous adipose tissue	UBERON:0002190	30.93	gold quality
lower esophagus	UBERON:0013473	30.84	silver quality
lower esophagus muscularis layer	UBERON:0035833	30.83	silver quality
left adrenal gland cortex	UBERON:0035825	30.78	gold quality
right ovary	UBERON:0002118	30.57	gold quality
endometrium	UBERON:0001295	30.39	silver quality
body of uterus	UBERON:0009853	30.11	gold quality
prostate gland	UBERON:0002367	29.71	gold quality
ectocervix	UBERON:0012249	29.42	silver quality
esophagogastric junction muscularis propria	UBERON:0035841	29.28	gold quality
saliva-secreting gland	UBERON:0001044	28.77	gold quality
ovary	UBERON:0000992	28.63	gold quality
left lobe of thyroid gland	UBERON:0001120	28.25	gold quality
descending thoracic aorta	UBERON:0002345	27.48	gold quality
left ovary	UBERON:0002119	27.41	gold quality
minor salivary gland	UBERON:0001830	27.18	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

HPA expression

RNA tissue specificity: Tissue enhanced

43 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	86.5	high
Kidney	tissue	23.5	high
Bone marrow	tissue	18.4	medium
Duodenum	tissue	10.6	medium
Small intestine	tissue	6.8	medium
Olfactory bulb	tissue	2.5
Pons	tissue	2.4
Thalamus	tissue	2.4
Substantia nigra	tissue	2.3
Ventral forebrain	tissue	2.1
Midbrain	tissue	2.0
Hypothalamus	tissue	2.0
Superior colliculi	tissue	2.0
Hippocampal formation	tissue	1.9
Periaqueductal gray	tissue	1.9
Septum	tissue	1.9
Cerebellum	tissue	1.8	not detected
Cerebral cortex	tissue	1.6	not detected
Amygdala	tissue	1.6
Medulla oblongata	tissue	1.6
Insular cortex	tissue	1.6
Prefrontal cortex	tissue	1.5
Motor cortex	tissue	1.5
Basal ganglia	tissue	1.5	not detected
Putamen	tissue	1.5
Retrosplenial and cingulate cortex	tissue	1.5
Retrosplenial cortex	tissue	1.5
Corpus callosum	tissue	1.4
Temporal cortex	tissue	1.4
Entorhinal cortex	tissue	1.3
Spinal cord	tissue	1.2
Somatosensory cortex	tissue	1.2
Occipital cortex	tissue	1.2
Locus coeruleus	tissue	0.5
Caudate putamen	tissue	0.5
Testis	tissue	0.4	not detected
Postcentral gyrus	tissue	0.4
Colon	tissue	0.3	low
Skin 1	tissue	0.2	not detected
Rectum	tissue	0.2	not detected
Nucleus accumbens	tissue	0.2
Choroid plexus	tissue	0.1
Epididymis	tissue	0.0	low

Brain sub-regions (HPA Brain Atlas): detected in 184; highest nTPM — Ventral hippocampus (1.9), Vermis (1.7), Cerebellar cortex (1.6), Flocculonodular lobe (1.6), Subiculum (1.6).

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)

Targeting PKLR by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 95 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 2.64e-09, LOEUF 0.901, missense Z 1.61 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000342741 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
1:155,290,575–155,293,526	183 / 250.2	0.73	no
1:155,293,527–155,301,395	519 / 537.1	0.97	no

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

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pklr	ENSDARG00000042010
mus_musculus	Pklr	ENSMUSG00000041237
rattus_norvegicus	Pklr	ENSRNOG00000020420
drosophila_melanogaster	CG2964	FBGN0031462
drosophila_melanogaster	PyK	FBGN0267385
caenorhabditis_elegans	pyk-1	WBGENE00009126
caenorhabditis_elegans		WBGENE00014001

Paralogs (1): PKM (ENSG00000067225)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97604) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 28 distinct phenotype terms.

Mouse phenotype (MP)	Records
hemolytic anemia	3
reticulocytosis	3
enlarged spleen	2
anemia	2
abnormal erythrocyte morphology	2
decreased hemoglobin content	2
decreased susceptibility to parasitic infection	2
decreased hematocrit	1
abnormal erythropoiesis	1
increased mean corpuscular volume	1
decreased erythrocyte cell number	1
increased erythroid progenitor cell number	1
abnormal metabolism	1
decreased saturated fatty acids level	1
increased circulating bilirubin level	1
abnormal enzyme/coenzyme activity	1
hemosiderosis	1
abnormal common myeloid progenitor cell morphology	1
increased nucleated erythrocyte cell number	1
increased susceptibility to bacterial infection induced morbidity/mortality	1
abnormal sphingomyelin level	1
increased erythrocyte clearance	1
decreased susceptibility to parasitic infection induced morbidity/mortality	1
increased erythroblast number	1
enhanced erythropoiesis	1

+3 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Oryza sativa Indica Group	B8BJ39	100.0%	Diamond
Escherichia coli K-12	P0AD61	100.0%	Diamond
Escherichia coli O157:H7	P0AD62	100.0%	Diamond
Mycobacterium tuberculosis CDC1551	P9WKE4	100.0%	Diamond
Mycobacterium tuberculosis H37Rv	P9WKE5	100.0%	Diamond
Staphylococcus aureus subsp. aureus USA300	Q2FG40	100.0%	Diamond
Staphylococcus aureus subsp. aureus NCTC 8325	Q2FXM9	100.0%	Diamond
Oryza sativa Japonica Group	Q2QXR8	100.0%	Diamond
Staphylococcus aureus subsp. aureus COL	Q5HF76	100.0%	Diamond
Staphylococcus epidermidis RP62A	Q5HNK7	100.0%	Diamond
Staphylococcus aureus subsp. aureus MSSA476	Q6G8M9	100.0%	Diamond
Staphylococcus aureus subsp. aureus MW2	Q7A0N4	100.0%	Diamond
Staphylococcus aureus subsp. aureus N315	Q7A559	100.0%	Diamond
Staphylococcus epidermidis ATCC 12228	Q8CS69	100.0%	Diamond
Staphylococcus aureus subsp. aureus Mu50	Q99TG5	100.0%	Diamond
Salmonella enterica subsp. enterica serovar Typhimurium str. LT2	P77983	99.8%	Diamond
Staphylococcus aureus RF122	Q2YTE3	99.8%	Diamond
Salmonella enterica subsp. enterica serovar Typhi	Q8Z6K2	99.8%	Diamond
Staphylococcus aureus subsp. aureus MRSA252	Q6GG09	99.7%	Diamond
Chlamydia trachomatis L2/434/Bu	B0B7Q0	99.6%	Diamond
Chlamydia trachomatis D/UW-3/CX	P0CE21	99.6%	Diamond
Trypanosoma brucei brucei	P30615	99.0%	Diamond
Felis catus	P11979	97.0%	Diamond
Pongo abelii	Q5NVN0	97.0%	Diamond
Oryctolagus cuniculus	P11974	96.6%	Diamond
Chlamydia muridarum str. Nigg	Q9PK61	95.0%	Diamond
Saccharomyces cerevisiae S288C	P00549	93.2%	Diamond
Corynebacterium glutamicum ATCC 13032	Q46078	93.2%	Diamond
Nakaseomyces glabratus CBS 138	Q6FIS9	93.2%	Diamond
Corynebacterium efficiens YS-314	Q8FP04	93.2%	Diamond
Canis lupus familiaris	Q29536	92.5%	Diamond
Mycobacterium intracellulare	P94939	91.5%	Diamond
Naumovozyma castellii	Q875Z9	91.2%	Diamond
Kluyveromyces lactis NRRL Y-1140	Q875M9	91.0%	Diamond
Lachancea kluyveri NRRL Y-12651	Q875S4	91.0%	Diamond
Aspergillus nidulans FGSC A4	P22360	90.5%	Diamond
Aspergillus niger	Q12669	90.5%	Diamond
Staphylococcus haemolyticus JCSC1435	Q4L739	90.1%	Diamond
Xenopus laevis	Q92122	90.1%	Diamond
Solanum tuberosum	P22200	89.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ENTREP3	protein-coding	10712
CLK2	protein-coding	1196
GBA1	protein-coding	2629
HCN3	protein-coding	57657
SCAMP3	protein-coding	10067
FDPS	protein-coding	2224
RUSC1-AS1	ncRNA	284618
RUSC1	protein-coding	23623
ASH1L	protein-coding	55870
MIR555	ncRNA	693140

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): F8W6W2, P30613

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. Also produces the side product 2-phospholactate which can inhibit fructose-2,6-bisphosphate production. 2-phospholactate can be dephosphorylated by PGP which prevents the inhibition of fructose-2,6-bisphosphate production and allows glycolysis to occur.

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)

• pyruvate + ATP = phosphoenolpyruvate + ADP + H(+) (RHEA:18157)
• (S)-lactate + ATP = (2S)-2-phospholactate + ADP + H(+) (RHEA:86567)

UniProt features (195 total): sequence variant 108, helix 28, strand 25, binding site 18, turn 6, modified residue 5, sequence conflict 2, chain 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

showing 30 of 67 structures by resolution:

PDB	Title	Method	Resolution (Å)
9RDF	Liver Pyruvate kinase in complex with a phthalazine-based fluorescent probe IV	X-RAY DIFFRACTION	1.62
7FS3	Structure of liver pyruvate kinase in complex with allosteric modulator 15	X-RAY DIFFRACTION	1.66
5SC9	Structure of liver pyruvate kinase in complex with anthraquinone derivative 29	X-RAY DIFFRACTION	1.69
7QDN	Structure of human liver pyruvate kinase from which the B domain has been deleted	X-RAY DIFFRACTION	1.7
5SCK	Structure of liver pyruvate kinase in complex with anthraquinone derivative 42	X-RAY DIFFRACTION	1.72
7FS9	Structure of liver pyruvate kinase in complex with allosteric modulator 22	X-RAY DIFFRACTION	1.72
7FRW	Structure of liver pyruvate kinase in complex with allosteric modulator 4	X-RAY DIFFRACTION	1.74
7FSD	Structure of liver pyruvate kinase in complex with allosteric modulator 44	X-RAY DIFFRACTION	1.77
5SC8	Structure of liver pyruvate kinase in complex with anthraquinone derivative 17	X-RAY DIFFRACTION	1.77
4IP7	Structure of the S12D variant of human liver pyruvate kinase in complex with citrate and …	X-RAY DIFFRACTION	1.8
5SCB	Structure of liver pyruvate kinase in complex with anthraquinone derivative 28	X-RAY DIFFRACTION	1.8
7FRX	Structure of liver pyruvate kinase in complex with allosteric modulator 5	X-RAY DIFFRACTION	1.85
7FSC	Structure of liver pyruvate kinase in complex with allosteric modulator 42	X-RAY DIFFRACTION	1.85
7FS1	Structure of liver pyruvate kinase in complex with allosteric modulator 11	X-RAY DIFFRACTION	1.86
5SCC	Structure of liver pyruvate kinase in complex with anthraquinone derivative 57	X-RAY DIFFRACTION	1.89
7FSA	Structure of liver pyruvate kinase in complex with allosteric modulator 24	X-RAY DIFFRACTION	1.91
5SCA	Structure of liver pyruvate kinase in complex with anthraquinone derivative 36	X-RAY DIFFRACTION	1.92
5SCG	Structure of liver pyruvate kinase in complex with anthraquinone derivative 101	X-RAY DIFFRACTION	1.94
5SDT	Structure of liver pyruvate kinase in complex with anthraquinone derivative 15	X-RAY DIFFRACTION	1.94
4IMA	The structure of C436M-hLPYK in complex with Citrate/Mn/ATP/Fru-1,6-BP	X-RAY DIFFRACTION	1.95
7FRY	Structure of liver pyruvate kinase in complex with allosteric modulator 6	X-RAY DIFFRACTION	1.96
7QZU	Structure of liver pyruvate kinase in complex with anthraquinone derivative 47	X-RAY DIFFRACTION	1.96
7FRV	Structure of liver pyruvate kinase in complex with allosteric modulator 3	X-RAY DIFFRACTION	2
5SCD	Structure of liver pyruvate kinase in complex with anthraquinone derivative 58	X-RAY DIFFRACTION	2.04
9R3O	Structure of liver pyruvate kinase in complex with fluorescent probe 4a	X-RAY DIFFRACTION	2.04
9R3M	Structure of liver pyruvate kinase in complex with fluorescent probe 8a	X-RAY DIFFRACTION	2.06
7FRZ	Structure of liver pyruvate kinase in complex with allosteric modulator 7	X-RAY DIFFRACTION	2.08
5SCH	Structure of liver pyruvate kinase in complex with anthraquinone derivative 100	X-RAY DIFFRACTION	2.09
7FS8	Structure of liver pyruvate kinase in complex with allosteric modulator 21	X-RAY DIFFRACTION	2.1
8XFD	Crystal structure of pyruvate kinase tetramer in complex with allosteric activator …	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of carbohydrate metabolism

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH enhanced · IF approved

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)

Position	Role
313	transition state stabilizer

Ligand- & substrate-binding residues (18)

Position	Role
116	substrate
315	Mn(2+)
338	substrate
339	Mn(2+)
339	substrate
371	substrate
475–480	beta-D-fructose 1,6-bisphosphate
525	beta-D-fructose 1,6-bisphosphate
532	beta-D-fructose 1,6-bisphosphate
559–564	beta-D-fructose 1,6-bisphosphate
118–121	ATP
118	K(+)
120	K(+)
156	K(+)
157	K(+)
163	ATP
250	ATP
313	substrate

Post-translational modifications (5)

Type	Positions
Phosphoserine	2, 19, 26, 43, 292

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 5; 1 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

5 pathways:

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

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 (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

5 top-level categories:

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

46 GO namespaces:

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 (phosphorylating, [NAD(P)+] ) 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
anion 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
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 24 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
extracellular exosome	CC	high-throughput assay

Protein interactions and networks

IntAct

Human interaction partners of PKLR in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

6 partners by confidence:

Partner	Interaction type	MIscore	Records
CPNE7	physical association	0.560	3
PKM	physical association	0.400	1
SAV1	physical association	0.370	1
CIMAP1A	association	0.350	1
LRRC3B	association	0.350	1
CLEC4G	physical association	0.000	1

BioGRID (65 interactions; top human partners by supporting records): NT5DC1 (Affinity Capture-MS; 2 records), PTBP1 (Affinity Capture-RNA; 2 records), ARHGEF6 (Affinity Capture-Western), BRCA2 (Negative Genetic), BUB1B (Affinity Capture-MS), CLEC4G (Two-hybrid), CLIP1 (Affinity Capture-MS), CPNE7 (Two-hybrid), CSK (Negative Genetic), CUL4A (Affinity Capture-MS), CYP4B1 (Affinity Capture-MS), DKK2 (Affinity Capture-MS), DVL2 (Affinity Capture-MS), EEF1A2 (Co-fractionation), EFNA3 (Affinity Capture-MS)

SIGNOR signaling

2 signaling interactions:

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

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ PKRL homotetramer	1	PKLR

Disease & clinical

Genetic variants

Variant evidence for PKLR: 482 ClinVar records (108 pathogenic / likely pathogenic); 40 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	50
Likely pathogenic	58
Uncertain significance	238
Likely benign	49
Benign	8

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 108 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1511	NM_000298.6(PKLR):c.1529G>A (p.Arg510Gln)	Pathogenic	criteria provided, multiple submitters, no conflicts	26
1510	NM_000298.6(PKLR):c.1436G>A (p.Arg479His)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
280113	NM_000298.6(PKLR):c.721G>T (p.Glu241Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
1163645	NM_000298.6(PKLR):c.826del (p.Val276fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
618827	NM_000298.6(PKLR):c.994G>A (p.Gly332Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
1456959	NM_000298.6(PKLR):c.1091G>A (p.Gly364Asp)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
2202852	NM_000298.6(PKLR):c.1462C>T (p.Arg488Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
1162853	NM_000298.6(PKLR):c.1528C>T (p.Arg510Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
2063906	NM_000298.6(PKLR):c.1484C>T (p.Ala495Val)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
811711	NM_000298.6(PKLR):c.101-1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1369122	NM_000298.6(PKLR):c.1091dup (p.Lys365fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1705384	NM_000298.6(PKLR):c.808C>T (p.Arg270Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2437882	NM_000298.6(PKLR):c.1542dup (p.Leu516fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
3648316	NM_000298.6(PKLR):c.628_629del (p.Val210fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
4746887	NM_000298.6(PKLR):c.1116+2T>G	Pathogenic	criteria provided, multiple submitters, no conflicts	2

Per-variant reference — Sugi Variant

Explore PKLR’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 38 predictions of 752):

Position(s)	Effect	Δscore	Sites
1:155291754–155291755	donor_loss	1.0000	5
1:155293175–155293176	donor_loss	1.0000	5
1:155293345	acceptor_loss	1.0000	3
1:155293436–155293437	donor_loss	1.0000	6
1:155293591–155293592	acceptor_loss	1.0000	4
1:155294480–155294481	donor_loss	1.0000	2
1:155294753–155294754	acceptor_loss	1.0000	5
1:155295303	acceptor_gain	1.0000
1:155295303–155295304	acceptor_loss	1.0000	5
1:155295435–155295436	donor_loss	1.0000	2

AlphaMissense

1,461 missense substitutions predicted likely pathogenic (of 3,687 scored), across 379 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M403	9	0.935	0.995
M377	9	0.906	0.988
M373	9	0.893	0.995
M334	9	0.862	0.994
D390	8	0.995	0.998
D156	8	0.994	0.996
D339	8	0.990	0.998
F287	8	0.974	0.999
H121	8	0.971	0.996
D221	8	0.965	0.993
D400	8	0.965	0.994
D397	8	0.962	0.991
N118	8	0.959	0.998
D268	8	0.958	0.986
D281	8	0.941	0.988
D271	8	0.931	0.968
H127	8	0.928	0.994
F284	8	0.915	0.984
F350	8	0.907	0.985
F119	8	0.891	0.966

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Liver Hepatocellular Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	7.04e-07

Disease associations

OMIM: gene MIM:609712 | disease phenotypes: MIM:266200, MIM:102900, MIM:125853

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
pyruvate kinase deficiency of red cells	Definitive	Autosomal recessive	5
pyruvate kinase hyperactivity	Limited	Autosomal dominant

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
pyruvate kinase deficiency of red cells	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (4 panels, 4 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

4 panels:

Panel	Rating
Cytopenias and congenital anaemias	green
Fetal anomalies	green
Fetal hydrops	green
Rare anaemia	green

Mondo (4): pyruvate kinase deficiency of red cells (MONDO:0009950), pyruvate kinase hyperactivity (MONDO:0007067), type 2 diabetes mellitus (MONDO:0005148), congenital anemia (MONDO:0000577)

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

HPO phenotypes

32 phenotypes (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	Elevated 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	Decreased circulating haptoglobin concentration
HP:0025109	Reduced red cell pyruvate kinase level
HP:0030271	Reduced erythrocyte 2,3-diphosphoglycerate concentration

GWAS associations

showing 30 of 40 associations:

Study	Trait	p-value
GCST90002406_189	Reticulocyte fraction of red cells	2e-64
GCST90002386_408	High light scatter reticulocyte percentage of red cells	2e-58
GCST90002405_33	Reticulocyte count	1e-52
GCST90002385_31	High light scatter reticulocyte count	8e-51
GCST007294_150	Body fat distribution (trunk fat ratio)	8e-35
GCST007295_72	Body fat distribution (leg fat ratio)	1e-28
GCST004619_103	Reticulocyte fraction of red cells	1e-23
GCST007294_159	Body fat distribution (trunk fat ratio)	6e-21
GCST004622_119	Reticulocyte count	1e-20
GCST90002384_478	Hemoglobin	1e-19
GCST001791_11	Urate levels	6e-19
GCST90002383_155	Hematocrit	4e-18
GCST007295_112	Body fat distribution (leg fat ratio)	7e-17
GCST010700_5	Cortical thickness (MOSTest)	8e-17
GCST90002387_143	Immature fraction of reticulocytes	4e-16
GCST007294_25	Body fat distribution (trunk fat ratio)	1e-15
GCST001277_4	Liver enzyme levels (gamma-glutamyl transferase)	2e-15
GCST004619_215	Reticulocyte fraction of red cells	2e-14
GCST004612_45	High light scatter reticulocyte percentage of red cells	3e-14
GCST010703_205	Brain morphology (MOSTest)	4e-14
GCST007295_17	Body fat distribution (leg fat ratio)	3e-13
GCST004611_136	High light scatter reticulocyte count	8e-13
GCST90002384_477	Hemoglobin	2e-12
GCST90002406_188	Reticulocyte fraction of red cells	1e-11
GCST004622_118	Reticulocyte count	2e-11
GCST90002383_154	Hematocrit	2e-11
GCST004612_44	High light scatter reticulocyte percentage of red cells	4e-11
GCST90002403_538	Red blood cell count	4e-11
GCST010696_10	Cortical thickness (min-P)	2e-10
GCST010697_21	Cortical surface area (min-P)	3e-10

EFO canonical traits (from GWAS)

9 canonical traits:

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 disease descriptors:

Descriptor	Name	Tree numbers
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
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)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the PKLR protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

2 curated-mechanism drugs:

Drug	Modality	Max phase
MITAPIVAT	Small molecule	4
ETAVOPIVAT	Small molecule	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 60,823 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

3 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL4299940	MITAPIVAT	4	251
CHEMBL265502	SURAMIN	3	37,133
CHEMBL6246	ELLAGIC ACID	2	23,439

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variants

1 variants:

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

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

Binding affinities (BindingDB)

49 measured of 49 human assays (92 total across all organisms); most potent 49 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-((1H-pyrazol-4-yl)sulfonyl)-2-((1-cyclopropyl-1H-pyrazol-3-yl)methyl) phthalazin-1(2H)-one	EC50	10.3 nM	US-20250051313: PHTHALAZINE DERIVATIVES AS PYRUVATE KINASE MODULATORS
CHEMBL6133200	EC50	28 nM
Mitapivat	EC50	32.1 nM	US-20250051313: PHTHALAZINE DERIVATIVES AS PYRUVATE KINASE MODULATORS
CHEMBL5429790	IC50	120 nM
CHEMBL5204170	IC50	150 nM
CHEMBL5209097	IC50	160 nM
CHEMBL5556210	IC50	180 nM
5,8-Dihydroxy-2-(1-hydroxy-4-methyl-pent-3-enyl)-[1,4]naphthoquinone	IC50	190 nM
Sodium; 3,4-dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-sulfonate	IC50	200 nM
CHEMBL5176753	IC50	200 nM
CHEMBL5208105	IC50	200 nM
CHEMBL6078153	EC50	290 nM
CHEMBL5176181	IC50	290 nM
CHEMBL5532261	EC50	290 nM
CHEMBL5181251	IC50	300 nM
CHEMBL4754666	IC50	410 nM
CHEMBL5204537	IC50	550 nM
CHEMBL5188496	IC50	700 nM
CHEMBL5183208	IC50	900 nM
CHEMBL5186564	IC50	1200 nM
CHEMBL5206382	IC50	1300 nM
CHEMBL5195754	IC50	1300 nM
CHEMBL5427010	EC50	1390 nM
CHEMBL5186706	IC50	1400 nM
CHEMBL5181273	IC50	1400 nM
CHEMBL5200212	IC50	1700 nM
CHEMBL5198643	IC50	1900 nM
CHEMBL5177546	IC50	2500 nM
CHEMBL5170574	IC50	3400 nM
CHEMBL6103083	EC50	3500 nM
CHEMBL4127005	IC50	3800 nM
CHEMBL5169856	IC50	3800 nM
CHEMBL5172724	IC50	4100 nM
CHEMBL5170819	IC50	4800 nM
CHEMBL6078101	EC50	5300 nM
CHEMBL5172682	IC50	5800 nM
CHEMBL6078230	EC50	6000 nM
CHEMBL6082868	EC50	6400 nM
CHEMBL5193313	IC50	7300 nM
CHEMBL5209293	IC50	7500 nM
CHEMBL6102650	EC50	7700 nM
CHEMBL4128703	IC50	8200 nM
CHEMBL3339205	IC50	18200 nM
CHEMBL5188932	IC50	19000 nM
CHEMBL6078104	EC50	58000 nM
CHEMBL6091803	EC50	100000 nM
CHEMBL6091947	EC50	100000 nM
CHEMBL6102262	EC50	100000 nM
CHEMBL6103330	EC50	100000 nM

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

46 with measured affinity, of 748 total; 43 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
1-[[2-(4-chloro-3-fluorophenyl)-5-methyl-1,2,4-triazol-3-yl]methyl]-3-[(2-quinolin-7-yl-1,2,4-triazol-3-yl)methyl]urea	2202822: Activation of PKR (unknown origin)	ec50	0.0280	uM
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
1,3-bis[[1-(3,4-dimethylphenyl)tetrazol-5-yl]methyl]urea	2202822: Activation of PKR (unknown origin)	ec50	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-[[1-(3,4-dimethylphenyl)tetrazol-5-yl]methyl]-3-thiophen-2-ylurea	2202824: Activation of PKR (unknown origin) by differential scanning fluorimetry analysis	ec50	3.5000	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
6-bromo-N-(thiophen-2-ylmethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide	2202824: Activation of PKR (unknown origin) by differential scanning fluorimetry analysis	ec50	5.3000	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
N-[(2,3-dimethoxyphenyl)methyl]-5-(4-ethoxyphenyl)-1-(2-methoxyethyl)imidazol-2-amine	2202824: Activation of PKR (unknown origin) by differential scanning fluorimetry analysis	ec50	6.0000	uM
4-[4-methyl-2-(4-methylpiperazin-1-yl)pyrimidin-5-yl]-2-[3-(trifluoromethyl)anilino]-1H-pyrimidin-6-one	2202824: Activation of PKR (unknown origin) by differential scanning fluorimetry analysis	ec50	6.4000	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-benzyl-9-hydroxy-2-methylpyrido[1,2-a]pyrimidin-4-one	2202824: Activation of PKR (unknown origin) by differential scanning fluorimetry analysis	ec50	7.7000	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	affects cotreatment, decreases expression	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	affects cotreatment, decreases expression	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)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT05777993	Phase 4	ENROLLING_BY_INVITATION	A Study to Provide Access to Mitapivat for Participants Who Previously Participated in an Agios-Sponsored Mitapivat Study
NCT00006163	Phase 4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	Phase 4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	Phase 4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	Phase 4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	Phase 4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	Phase 4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	Phase 4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	Phase 4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	Phase 4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	Phase 4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	Phase 4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	Phase 4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	Phase 4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	Phase 4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	Phase 4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	Phase 4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	Phase 4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	Phase 4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	Phase 4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	Phase 4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	Phase 4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	Phase 4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	Phase 4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	Phase 4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	Phase 4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	Phase 4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	Phase 4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	Phase 4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	Phase 4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	Phase 4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	Phase 4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	Phase 4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	Phase 4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	Phase 4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	Phase 4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	Phase 4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	Phase 4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	Phase 4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	Phase 4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	Phase 4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus
NCT00241605	Phase 4	COMPLETED	AVANDAMET Versus Metformin For Type 2 Diabetes Mellitus
NCT00254085	Phase 4	UNKNOWN	Substitution of First Phase Insulin Response in Patient With Type 2 Diabetes.
NCT00258804	Phase 4	COMPLETED	Insulin Glargine During and After the Period of Fasting in Ramadan
NCT00262548	Phase 4	COMPLETED	C-Reactive Protein (CRP) in Obese Diabetic Women
NCT00264589	Phase 4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00264901	Phase 4	COMPLETED	Comparison of Self Adjustment Versus Standard of Care Treatment in Subjects With Type 2 Diabetes
NCT00265746	Phase 4	WITHDRAWN	Prevention of Diabetes Mellitus Development in Women Who Had Already Experienced A Gestational Diabetes
NCT00268645	Phase 4	COMPLETED	Insulin Glargine in Type 2 Diabetes
NCT00272077	Phase 4	COMPLETED	Insulin Glargine in Type 2 Diabetes Mellitus
NCT00272831	Phase 4	COMPLETED	The Use of Cilostazol in Patients With Diabetic Nephropathy
NCT00274274	Phase 4	COMPLETED	Efficacy and Safety of a Fixed or a Flexible Supplementary Insulin Therapy in Type 2 Diabetes
NCT00279201	Phase 4	COMPLETED	The DURABLE Trial: Evaluating the Durability of Starter Insulin Regimens in Patients With Type 2 Diabetes (IOOV)
NCT00282360	Phase 4	COMPLETED	Effect of Metabolic Therapy in Patients With Chronic Ischemic Heart Disease
NCT00282451	Phase 4	COMPLETED	Effect of Biphasic Insulin Compared to Biphasic Insulin Combined With Insulin Aspart, With or Without Metformin in Type 2 Diabetes
NCT00283049	Phase 4	TERMINATED	Insulin Glargine Injection Treatment in Place of Thiazolidinedione (TZD), Sulfonylurea, or Metformin in Triple Agent Therapy for Type 2 Diabetes Mellitus (T2DM) Adult Subjects With Unsatisfactory Control
NCT00283777	Phase 4	COMPLETED	Chromium and Insulin Action
NCT00290394	Phase 4	COMPLETED	Ambulatory Blood Pressure Reduction After Rosiglitazone Treatment In Normotensive Type 2 Diabetic Patients
NCT00296296	Phase 4	COMPLETED	Immunosuppression Impact on the Metabolic Control of Kidney Transplant With Pre-Existing Type 2 Diabetes (DM)
NCT00300911	Phase 4	COMPLETED	Effects of Rosiglitazone on Plasma BNP Levels and Left Ventricular Dysfunction

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PKLR across ~30M SureChEMBL compounds — explore on Sugi Predict.