ENTPD2

Summary

ENTPD2 (ectonucleoside triphosphate diphosphohydrolase 2, HGNC:3364) is a protein-coding gene on chromosome 9q34.3, encoding Ectonucleoside triphosphate diphosphohydrolase 2 (Q9Y5L3). Catalyzes the hydrolysis of nucleoside triphosphates (NTPs) and diphosphates (NDPs), with a marked preference for triphosphonucleosides over diphosphonucleosides.

The protein encoded by this gene is the type 2 enzyme of the ecto-nucleoside triphosphate diphosphohydrolase family (E-NTPDase). E-NTPDases are a family of ecto-nucleosidases that hydrolyze 5’-triphosphates. This ecto-ATPase is an integral membrane protein. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 954 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 137 total — 1 likely-pathogenic
• GTEx eGene: eQTL in 18 tissues, sQTL in 20 (q < 0.05)
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.38 (unconstrained)
• MANE Select transcript: NM_203468
• Notable: 137 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3364
Approved symbol	ENTPD2
Name	ectonucleoside triphosphate diphosphohydrolase 2
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Aliases	NTPDase-2
Ensembl gene	ENSG00000054179
Ensembl biotype	protein_coding
OMIM	602012
Entrez	954

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000355097

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 5: 1

ENST00000355097, ENST00000312665, ENST00000460614, ENST00000469106, ENST00000902978, ENST00000902979, ENST00000902980, ENST00000902981, ENST00001141141

RefSeq mRNA: 2 — MANE Select: NM_203468 NM_001246, NM_203468

CCDS: CCDS7025, CCDS7026

Canonical transcript exons

ENST00000355097 — 9 exons

Exon	Start	End
ENSE00001194447	137051211	137051370
ENSE00001244464	137049870	137049989
ENSE00001308239	137053881	137054061
ENSE00001310256	137050284	137050538
ENSE00001413449	137048941	137049075
ENSE00001880985	137048107	137048860
ENSE00003566021	137050902	137051129
ENSE00003755352	137052231	137052348
ENSE00003758755	137051510	137051660

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 91.33.

FANTOM5 (CAGE): breadth broad, TPM avg 1.6367 / max 60.4142, expressed in 436 samples.

Highest expression (Bgee): dorsal root ganglion, tibial nerve, pancreatic ductal cell, trigeminal ganglion, mucosa of transverse colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ENTPD2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 18 tissues and its splicing (sQTL) in 20 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 38 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	1.7e-19	-0.34	9:137107735:C:T
Testis	eqtl	4.2e-15	+0.54	9:137044341:G:C
Esophagus Mucosa	eqtl	3.8e-11	-0.43	9:137054790:C:CAG
Colon Transverse	sqtl	2.5e-09	+0.59	9:137050911:G:A
Cells EBV-transformed lymphocytes	eqtl	2.8e-08	+0.37	9:137052464:G:A
Esophagus Mucosa	sqtl	4.7e-08	-0.55	9:137056145:G:A
Skin Sun Exposed Lower leg	sqtl	5.5e-08	-1.20	9:137049085:G:T
Colon Sigmoid	eqtl	5.3e-06	-0.23	9:137051875:C:T
Esophagus Muscularis	sqtl	1.5e-05	-1.39	9:137049085:G:T
Testis	sqtl	1.9e-05	-1.41	9:137049085:G:T
Skin Sun Exposed Lower leg	eqtl	4.5e-05	-0.51	9:137049085:G:T
Colon Sigmoid	sqtl	6.1e-05	-1.45	9:137049085:G:T
Brain Cerebellum	sqtl	2.3e-04	-1.55	9:137049085:G:T
Colon Transverse	eqtl	2.3e-04	-0.23	9:137060775:T:C
Stomach	sqtl	5.8e-04	-0.53	9:137048660:A:G
Brain Anterior cingulate cortex BA24	sqtl	6.1e-04	+1.65	9:137049085:G:T
Skin Not Sun Exposed Suprapubic	eqtl	1.2e-03	+0.29	9:137749858:G:A
Nerve Tibial	eqtl	2.1e-03	+0.14	9:137055378:A:C
Brain Frontal Cortex BA9	eqtl	2.4e-03	-0.85	9:137347290:C:T
Muscle Skeletal	eqtl	4.3e-03	-0.14	9:137041401:C:T

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
103300	1.4730	420
103299	0.1636	93

Top tissues by expression

showing 100 of 262 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
dorsal root ganglion	UBERON:0000044	91.33	gold quality
tibial nerve	UBERON:0001323	90.25	gold quality
pancreatic ductal cell	CL:0002079	88.40	silver quality
trigeminal ganglion	UBERON:0001675	86.91	gold quality
mucosa of transverse colon	UBERON:0004991	85.49	gold quality
epithelial cell of pancreas	CL:0000083	84.91	gold quality
lower esophagus mucosa	UBERON:0035834	83.84	gold quality
vena cava	UBERON:0004087	83.08	silver quality
right uterine tube	UBERON:0001302	82.65	gold quality
amygdala	UBERON:0001876	82.38	gold quality
ventral tegmental area	UBERON:0002691	82.31	gold quality
skin of abdomen	UBERON:0001416	82.26	gold quality
hypothalamus	UBERON:0001898	81.73	gold quality
left ventricle myocardium	UBERON:0006566	81.39	gold quality
cardiac muscle of right atrium	UBERON:0003379	81.27	gold quality
sural nerve	UBERON:0015488	81.21	gold quality
nucleus accumbens	UBERON:0001882	80.72	gold quality
transverse colon	UBERON:0001157	80.54	gold quality
skin of leg	UBERON:0001511	80.16	gold quality
lateral globus pallidus	UBERON:0002476	79.46	silver quality
right frontal lobe	UBERON:0002810	79.41	gold quality
caudate nucleus	UBERON:0001873	79.34	gold quality
small intestine Peyer’s patch	UBERON:0003454	78.80	gold quality
cardia of stomach	UBERON:0001162	78.65	silver quality
dorsal plus ventral thalamus	UBERON:0001897	78.48	silver quality
subthalamic nucleus	UBERON:0001906	78.46	silver quality
zone of skin	UBERON:0000014	78.28	gold quality
Brodmann (1909) area 9	UBERON:0013540	78.01	gold quality
superior vestibular nucleus	UBERON:0007227	77.74	silver quality
inferior vagus X ganglion	UBERON:0005363	77.66	silver quality
small intestine	UBERON:0002108	77.64	gold quality
temporal lobe	UBERON:0001871	77.53	gold quality
midbrain	UBERON:0001891	77.29	gold quality
minor salivary gland	UBERON:0001830	77.18	gold quality
substantia nigra	UBERON:0002038	77.00	gold quality
nipple	UBERON:0002030	76.88	silver quality
pylorus	UBERON:0001166	76.84	silver quality
myocardium	UBERON:0002349	76.83	gold quality
fundus of stomach	UBERON:0001160	76.65	gold quality
medulla oblongata	UBERON:0001896	76.36	silver quality
saliva-secreting gland	UBERON:0001044	76.32	gold quality
right hemisphere of cerebellum	UBERON:0014890	76.32	gold quality
anterior cingulate cortex	UBERON:0009835	76.24	gold quality
muscle layer of sigmoid colon	UBERON:0035805	76.20	gold quality
body of tongue	UBERON:0011876	75.96	gold quality
body of stomach	UBERON:0001161	75.90	gold quality
mouth mucosa	UBERON:0003729	75.84	gold quality
pericardium	UBERON:0002407	75.73	gold quality
pons	UBERON:0000988	75.47	silver quality
colon	UBERON:0001155	75.29	gold quality
Ammon’s horn	UBERON:0001954	75.29	gold quality
apex of heart	UBERON:0002098	75.28	gold quality
spinal cord	UBERON:0002240	75.27	gold quality
pharyngeal mucosa	UBERON:0000355	75.20	gold quality
saphenous vein	UBERON:0007318	75.18	gold quality
thymus	UBERON:0002370	75.11	gold quality
forebrain	UBERON:0001890	75.04	gold quality
trachea	UBERON:0003126	74.96	gold quality
intestine	UBERON:0000160	74.90	gold quality
large intestine	UBERON:0000059	74.83	gold quality
cerebellar hemisphere	UBERON:0002245	74.81	gold quality
brain	UBERON:0000955	74.73	gold quality
central nervous system	UBERON:0001017	74.73	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	74.73	gold quality
cerebellar cortex	UBERON:0002129	74.70	gold quality
globus pallidus	UBERON:0001875	74.60	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	74.60	gold quality
duodenum	UBERON:0002114	74.51	gold quality
heart right ventricle	UBERON:0002080	74.36	gold quality
gall bladder	UBERON:0002110	74.36	gold quality
pituitary gland	UBERON:0000007	73.90	gold quality
frontal cortex	UBERON:0001870	73.81	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	73.79	gold quality
cerebellum	UBERON:0002037	73.71	gold quality
sigmoid colon	UBERON:0001159	73.64	gold quality
medial globus pallidus	UBERON:0002477	73.64	silver quality
neocortex	UBERON:0001950	73.63	gold quality
stomach	UBERON:0000945	73.53	gold quality
cerebral cortex	UBERON:0000956	73.43	gold quality
esophagus mucosa	UBERON:0002469	73.28	gold quality
renal medulla	UBERON:0000362	73.25	silver quality
adult mammalian kidney	UBERON:0000082	73.24	gold quality
layer of synovial tissue	UBERON:0007616	73.10	gold quality
adenohypophysis	UBERON:0002196	73.04	gold quality
cardiac ventricle	UBERON:0002082	72.97	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	72.91	gold quality
heart left ventricle	UBERON:0002084	72.89	gold quality
endocervix	UBERON:0000458	72.81	gold quality
penis	UBERON:0000989	72.72	gold quality
rectum	UBERON:0001052	72.10	gold quality
prostate gland	UBERON:0002367	72.05	gold quality
jejunum	UBERON:0002115	71.65	silver quality
esophagus	UBERON:0001043	71.55	gold quality
putamen	UBERON:0001874	71.45	gold quality
cerebellar vermis	UBERON:0004720	71.42	gold quality
mammary duct	UBERON:0001765	71.40	gold quality
epithelium of mammary gland	UBERON:0003244	71.40	gold quality
parietal lobe	UBERON:0001872	71.29	silver quality
cardiac atrium	UBERON:0002081	71.19	gold quality
prefrontal cortex	UBERON:0000451	71.13	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	14.75
E-GEOD-83139	yes	4.47
E-ANND-3	yes	4.14
E-HCAD-31	no	3.40

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Hypothalamus	tissue	24.3
Hippocampus	tissue	20.0	low
Substantia nigra	tissue	16.6
Medulla oblongata	tissue	16.2
Pons	tissue	15.2
Locus coeruleus	tissue	14.7
Periaqueductal gray	tissue	14.7
Nucleus accumbens	tissue	14.6
Caudate putamen	tissue	12.8
Spinal cord	tissue	11.9
Duodenum	tissue	11.5	high
Thalamus	tissue	11.1
Midbrain	tissue	10.9
Frontal cortex	tissue	10.7
Septum	tissue	9.3
Putamen	tissue	9.1
Ventral forebrain	tissue	9.1
Amygdala	tissue	8.7
Cerebral cortex	tissue	8.0	high
Hippocampal formation	tissue	8.0
Insular cortex	tissue	8.0
Motor cortex	tissue	7.7
Superior colliculi	tissue	7.7
Basal ganglia	tissue	7.6	medium
Prefrontal cortex	tissue	7.3
Small intestine	tissue	7.3	high
Retrosplenial cortex	tissue	7.2
Prostate	tissue	6.9	low
Retrosplenial and cingulate cortex	tissue	6.9
Entorhinal cortex	tissue	6.6
Occipital cortex	tissue	6.1
Postcentral gyrus	tissue	6.0
Somatosensory cortex	tissue	5.9
Stomach 1	tissue	5.7	medium
Colon	tissue	5.7	high
Fallopian tube	tissue	5.7	medium
Temporal cortex	tissue	5.6
Cervix	tissue	5.5	medium
Choroid plexus	tissue	5.3
Skin 1	tissue	4.3	medium
Gallbladder	tissue	4.3	medium
Breast	tissue	4.2	medium
Salivary gland	tissue	3.8	medium
Rectum	tissue	3.5	medium
Testis	tissue	3.3	medium
Vagina	tissue	3.3	low
Tongue	tissue	3.2
Pituitary gland	tissue	2.7
Kidney	tissue	2.7	medium
Cerebellum	tissue	2.6	high
Corpus callosum	tissue	2.6
Esophagus	tissue	1.9	high
Skeletal muscle	tissue	1.8	medium
Olfactory bulb	tissue	1.7
Seminal vesicle	tissue	1.5	medium
Pancreas	tissue	1.5	high
Endometrium 1	tissue	1.5	medium
Epididymis	tissue	1.5	medium
Heart muscle	tissue	1.4	medium
Smooth muscle	tissue	1.0	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Periaquaductal grey, lateral (64.5), Supraoptic nucleus (56.5), Habenula (52.6), Periaquaductal grey, dorsal (42.7), Medial dorsal thalamic nucleus (37.6).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFATC2

miRNA regulators (miRDB)

Targeting ENTPD2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 73 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-4516	99.61	67.78	3390

Functional genomics

gnomAD constraint: pLI 1.86e-18, LOEUF 1.38, missense Z -1.37 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000355097 — one region, missense o/e 1.09.

Literature-anchored findings (GeneRIF, showing 9)

• the lack of ecto-nucleotidase activity exhibited by NTPDase2 beta and -2 gamma and the C399S mutant, as well as the large reduction of activity in the N443D mutant are due to alterations in the folding/maturation of these proteins (PMID:12888562)
• NTPDase2 preferentially hydrolyzes nucleoside triphosphates. (PMID:15496502)
• down-regulation in biliary cirrhosis (PMID:15651265)
• NTPDase2 has a role in portal fibroblast regulation of bile duct epithelium proliferation (PMID:15799977)
• Mutagenesis study indicate the importance of K62 located in CR1, K182 downstream of ACR3, and R155. Mutation of Asp at the six potential glycosylation sites showed the importance of N64 in CR1 and N443 in ACR5 in protein function and expression (PMID:17489562)
• The role of cysteine 26 in the catalytic activity of NTPDase-2 and as the target of p-chloromercuriphenylsulfonate (pCMPS), a sulfhydryl reagent and NTPDase-2 inhibitor, is reported. (PMID:18656957)
• NTPDase2 and -3 are ecto-enzymes expressed in the enteric nervous system. Both enzymes confer protection against gut inflammation in experimental colitis and exhibit alterations in Crohn’s disease. These observations suggest that purinergic signalling modulated by E-NTPDases governs neuro-immune interactions that are relevant in Crohn’s disease. (PMID:28472257)
• Hypoxia upregulates ENTPD2 through HIF-1alpha in hepatocellular carcinoma and subsequently leading to the accumulation of extracellular 5’-AMP, which maintains myeloid-derived suppressor cells undifferentiated. (PMID:28894087)
• In oviducts, remarkably, ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2), with the ability to hydrolyze ATP to AMP, are expressed in ciliated epithelial cells but with different subcellular localization. (PMID:29273916)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	entpd2a.2	ENSDARG00000033953
danio_rerio	entpd2a.1	ENSDARG00000035506
danio_rerio	entpd2b	ENSDARG00000044795
mus_musculus	Entpd2	ENSMUSG00000015085
rattus_norvegicus	Entpd2	ENSRNOG00000013102

Paralogs (7): ENTPD1 (ENSG00000138185), ENTPD3 (ENSG00000168032), ENTPD5 (ENSG00000187097), ENTPD8 (ENSG00000188833), ENTPD4 (ENSG00000197217), ENTPD6 (ENSG00000197586), ENTPD7 (ENSG00000198018)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1096863) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal gustatory system physiology	1
abnormal taste sensitivity	1
abnormal nerve fiber response	1
abnormal gustatory papilla taste bud morphology	1

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
Bos taurus	A0JND9	77.0%	Diamond
Sus scrofa	Q9MYU4	75.4%	Diamond
Saccharomyces cerevisiae S288C	P32621	65.6%	Diamond
Kluyveromyces lactis NRRL Y-1140	Q9HEM6	65.1%	Diamond
Gallus gallus	P79784	58.8%	Diamond
Schizosaccharomyces pombe 972h-	Q9USP2	42.2%	Diamond
Caenorhabditis elegans	Q9XU84	37.0%	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
FUT7	protein-coding	2529
LINC02908	ncRNA	401563
NPDC1	protein-coding	56654
SAPCD2	protein-coding	89958
UAP1L1	protein-coding	91373
ABCA2	protein-coding	20
MAN1B1-DT	ncRNA	100289341
MAN1B1	protein-coding	11253
CLIC3	protein-coding	9022
PAXX	protein-coding	286257

Protein

Protein identifiers

Ectonucleoside triphosphate diphosphohydrolase 2 — Q9Y5L3 (reviewed: Q9Y5L3)

Alternative names: CD39 antigen-like 1, Ecto-ATP diphosphohydrolase 2

All UniProt accessions (1): Q9Y5L3

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the hydrolysis of nucleoside triphosphates (NTPs) and diphosphates (NDPs), with a marked preference for triphosphonucleosides over diphosphonucleosides. The enzyme sequentially removes phosphate groups in two successive steps, converting NTPs to nucleoside monophosphates (NMPs) via NDP intermediates. This activity contributes to the regulation of extracellular nucleotides levels. ATP hydrolysis is characterized by fast ADP accumulation and delayed AMP formation, reflecting limited ADP hydrolase activity. Hydrolyzes ADP and UDP only to a marginal extent, and does not hydrolyze AMP. All nucleoside 5’-diphosphates are hydrolyzed at rates lower than those of their corresponding triphosphates. Catalytically inactive. Catalytically inactive.

Subcellular location. Cell membrane Endoplasmic reticulum membrane Endoplasmic reticulum membrane.

Tissue specificity. Brain, placenta, skeletal muscle, kidney, pancreas, heart, ovary, testis, colon, small intestine, prostate and pancreas. No expression in adult thymus, spleen, lung, liver and peripheral blood leukocytes.

Activity regulation. ATP hydrolysis activity is inhibited about 70% by 0.25 mM p-chloromercuri-phenylsulfonate (pCMPS) and >90% by 0.1% Nonidet P-40 (NP-40). ATP hydrolysis activity is markedly stimulated by concanavalin A, disuccinimidyl suberate (DSS) and glutaraldehyde; The stimulatory effects are greater at 55 degrees Celsius (6-10-fold) than at 37 degrees Celsius (about 2-fold). ATPase activity is decreased by about 50% at 55 degrees Celsius. ATPase activity increases from 15 to 37 degrees Celsius but declines at higher temperatures. ATPase activity is inhibited by 0.1% NP-40 at all temperatures.

Similarity. Belongs to the GDA1/CD39 NTPase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y5L3-1	Long, alpha	yes
Q9Y5L3-2	Short, beta
Q9Y5L3-3	gamma

RefSeq proteins (2): NP_001237, NP_982293* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000407	GDA1_CD39_NTPase	Family

Pfam: PF01150

Enzyme classification (BRENDA)

• EC 3.6.1.5 — apyrase (BRENDA: 66 organisms, 384 substrates, 230 inhibitors, 158 Km, 64 kcat entries)

Substrate kinetics (BRENDA)

29 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0025–8.7	44
ADP	0.0025–5.3	42
UDP	0.0113–0.555	7
GDP	0.0114–0.357	6
UTP	0.01–0.207	5
N-[5-[4-CARBOXY-3-(3-OXO-9,9A-DIHYDRO-3H-XANTHEN	0.0133–0.105	4
DATP	0.018–0.89	3
DCTP	0.029–0.276	3
DGTP	0.028–0.16	3
IDP	0.0105–0.622	3
1,N6-ETHENO-ADP	0.073–0.114	2
1,N6-ETHENO-ATP	0.024–0.031	2
2’(3’)-O-(2,4,6-TRINITROPHENYL)ADENOSINE 5’-DIPH	0.009–0.019	2
2’(3’)-O-(2,4,6-TRINITROPHENYL)ADENOSINE 5’-TRIP	0.008–0.018	2
3’(2’)-O-(METHYLANTHRANOYL)ADENOSINE 5’-DIPHOSPH	0.014–0.017	2

Catalyzed reactions (Rhea)

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)
• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)
• ATP + 2 H2O = AMP + 2 phosphate + 2 H(+) (RHEA:20988)
• GDP + H2O = GMP + phosphate + H(+) (RHEA:22156)
• a ribonucleoside 5’-triphosphate + H2O = a ribonucleoside 5’-diphosphate + phosphate + H(+) (RHEA:23680)
• ITP + H2O = IDP + phosphate + H(+) (RHEA:28330)
• CTP + H2O = CDP + phosphate + H(+) (RHEA:29387)
• IDP + H2O = IMP + phosphate + H(+) (RHEA:35207)
• a ribonucleoside 5’-triphosphate + 2 H2O = a ribonucleoside 5’-phosphate + 2 phosphate + 2 H(+) (RHEA:36795)
• a ribonucleoside 5’-diphosphate + H2O = a ribonucleoside 5’-phosphate + phosphate + H(+) (RHEA:36799)
• ADP + H2O = AMP + phosphate + H(+) (RHEA:61436)
• UDP + H2O = UMP + phosphate + H(+) (RHEA:64876)

UniProt features (73 total): binding site 51, glycosylation site 5, disulfide bond 5, topological domain 3, transmembrane region 2, splice variant 2, mutagenesis site 2, chain 1, active site 1, sequence variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5L3-F1	93.02	0.82

Human Protein Atlas

Protein class: Metabolic proteins, Predicted membrane proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH 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
165	proton acceptor

Ligand- & substrate-binding residues (51)

Position	Role
48	GTP
48	phosphate
48	UTP
49	ADP
49	AMP
49	ATP
49	GTP
49	UTP
50	AMP
50	ATP
50	GTP
50	UTP
122	ADP
122	ATP
122	GTP
122	phosphate
122	UTP
204	ADP
204	AMP
204	ATP
204	GTP
204	phosphate
204	UTP
205	ADP
205	ATP
205	GTP
205	phosphate
205	UTP
206	ADP
206	ATP
206	phosphate
206	UTP
245	AMP
245	ATP
245	GTP
245	UTP
246	ADP
246	AMP
246	ATP
246	GTP
246	UTP
350	AMP
394	ADP
394	AMP
394	ATP
398	ADP
398	AMP
398	GTP
48	ADP
48	AMP
48	ATP

Disulfide bonds (5)

Type	Positions
Disulfide bond	75–99, 242–284, 265–310, 323–328, 377–399

Glycosylation sites (5)

Type	Positions
N-linked (glcnac…) asparagine	64, 129, 294, 378, 443

Mutagenesis-validated functional residues (2)

Position	Phenotype
399	abolishes ecto-atpase activity, accumulates intracellularly.
443	7% of wild-type atpase activity, accumulates intracellularly.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-8850843	Phosphate bond hydrolysis by NTPDase proteins	curated
R-HSA-1430728	Metabolism	—
R-HSA-15869	Metabolism of nucleotides	—
R-HSA-8956319	Nucleotide catabolism	—

MSigDB gene sets: 131 (showing top): GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, BENPORATH_ES_WITH_H3K27ME3, XU_GH1_AUTOCRINE_TARGETS_UP, GOBP_PLATELET_ACTIVATION, MODULE_45, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_WOUND_HEALING, MODULE_118, MODULE_379, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, GOBP_NUCLEOSIDE_TRIPHOSPHATE_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS, KEGG_PURINE_METABOLISM

GO Biological Process (2): nucleoside diphosphate catabolic process (GO:0009134), ribonucleoside triphosphate catabolic process (GO:0009203)

GO Molecular Function (17): GTPase activity (GO:0003924), apyrase activity (GO:0004050), GDP phosphatase activity (GO:0004382), ATP binding (GO:0005524), GTP binding (GO:0005525), ATP hydrolysis activity (GO:0016887), ribonucleoside triphosphate phosphatase activity (GO:0017111), CDP phosphatase activity (GO:0036384), ADP phosphatase activity (GO:0043262), CTPase activity (GO:0043273), UDP phosphatase activity (GO:0045134), ITPase activity (GO:0103023), IDP phosphatase activity (GO:1990003), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), nucleoside diphosphate phosphatase activity (GO:0017110)

GO Cellular Component (4): basement membrane (GO:0005604), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), extracellular exosome (GO:0070062)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Nucleotide catabolism	1
Metabolism	1
Metabolism of nucleotides	1

GO top-level categories

21 GO namespaces:

Category	Terms
nucleoside diphosphate phosphatase activity	5
ribonucleoside triphosphate phosphatase activity	4
pyrophosphatase activity	3
nucleoside phosphate catabolic process	2
purine ribonucleoside triphosphate binding	2
anion binding	2
nucleoside diphosphate metabolic process	1
adenyl ribonucleotide binding	1
guanyl ribonucleotide binding	1
ATP-dependent activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
extracellular matrix	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
extracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 23 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
ribonucleoside triphosphate catabolic process	BP	direct assay
extracellular exosome	CC	high-throughput assay
apyrase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,078 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENTPD2	DNAH8	Q96JB1	856
ENTPD2	P2RY1	P47900	843
ENTPD2	SIX3	O95343	757
ENTPD2	CHMP3	Q9Y3E7	749
ENTPD2	A0A140T963	A0A140T963	743
ENTPD2	CHMP2A	O43633	741
ENTPD2	VPS4A	Q9UN37	704
ENTPD2	MITD1	Q8WV92	661
ENTPD2	ATP6AP2	O75787	630
ENTPD2	VPS4B	O75351	626
ENTPD2	P2RY2	P41231	619
ENTPD2	PAX6	P26367	617
ENTPD2	ATP6V0D1	P12953	609
ENTPD2	MYH14	Q7Z406	606
ENTPD2	HIF1A	Q16665	582

IntAct

Human interaction partners of ENTPD2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

6 partners by confidence:

Partner	Interaction type	MIscore	Records
HTT	physical association	0.560	3
OPTN	physical association	0.560	3
HMBOX1	physical association	0.370	1
ATP2A1	association	0.350	1
CLGN	association	0.350	1
ORC4	association	0.350	1

BioGRID (96 interactions; top human partners by supporting records): ACSL3 (Affinity Capture-MS), ARF5 (Affinity Capture-MS), ARL8B (Affinity Capture-MS), ASIC1 (Affinity Capture-MS), ASIC4 (Affinity Capture-MS), ATP13A1 (Affinity Capture-MS), ATP1A3 (Affinity Capture-MS), ATP2A1 (Affinity Capture-MS), B3GALT4 (Affinity Capture-MS), B3GNT2 (Affinity Capture-MS), BRICD5 (Affinity Capture-MS), BTNL2 (Affinity Capture-MS), CD1A (Affinity Capture-MS), CD1B (Affinity Capture-MS), CD97 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for ENTPD2: 137 ClinVar records (1 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	92
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (1)

Showing all 1 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
3256927	NM_203468.3(ENTPD2):c.1170del (p.Gln391fs)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore ENTPD2’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; 28 predictions of 910):

Position(s)	Effect	Δscore	Sites
9:137048861–137048862	acceptor_loss	1.0000	4
9:137048939–137048940	donor_loss	1.0000	3
9:137048943	donor_gain	1.0000
9:137049868–137049869	donor_loss	1.0000	5
9:137049967	acceptor_gain	1.0000
9:137051661	acceptor_loss	1.0000
9:137052229–137052230	donor_loss	1.0000	4
9:137052349–137052350	acceptor_loss	1.0000	5
9:137053879–137053880	donor_loss	1.0000	3
9:137048862	acceptor_loss	0.9900

AlphaMissense

780 missense substitutions predicted likely pathogenic (of 3,181 scored), across 229 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
D201	8	0.942	0.970
D45	8	0.930	0.956
F425	8	0.889	0.974
F415	8	0.849	0.961
F345	8	0.835	0.979
F318	8	0.834	0.936
F152	8	0.827	0.955
C310	7	0.973	0.989
C265	7	0.968	0.984
W170	7	0.967	0.993
C377	7	0.967	0.989
C242	7	0.962	0.986
C399	7	0.957	0.981
W436	7	0.957	0.992
W58	7	0.954	0.991
C284	7	0.948	0.971
N174	7	0.942	0.988
C99	7	0.927	0.965
F240	7	0.913	0.973
F211	7	0.910	0.981

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

5 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.63e-05
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	2.57e-05
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	0.000379
Stomach Adenocarcinoma (TCGA)	favorable	0.000573
Lung Adenocarcinoma (TCGA)	unfavorable	0.000745

Disease associations

OMIM: gene MIM:602012 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5049 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 37,133 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL265502	SURAMIN	3	37,133

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Hydrolases & Lipases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
PSB-6426	Inhibition	5.09	pKi

Binding affinities (BindingDB)

19 measured of 32 human assays (35 total across all organisms); most potent 19 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL4743437	IC50	0.0027 nM
CHEMBL4761506	IC50	0.01 nM
2-(((2R,3S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-3-ethynyl-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-2-(4-(2-oxotetrahydropyrimidin-1 (2H)-yl)benzyl)malonic acid	IC50	0.1 nM
[(2R,3S,4R,5R)-5-[6-chloro-4-(cyclopentylamino)pyrazolo[3,4-d]pyrimidin-1-yl]-3,4-dihydroxyoxolan-2-yl]methoxymethylphosphonic acid	IC50	0.55 nM	US-11377469: CD73 inhibitors
[[(2R,3S,4R,5R)-5-[6-chloro-4-[[(1S)-1-(2-fluorophenyl)ethyl]amino]pyrazolo[5,4-b]pyridin-1-yl]-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]methylphosphonic acid	EC50	3.3 nM	US-20230295213: CD73 INHIBITORS AND PHARMACEUTICAL USES THEREOF
CHEMBL4467828	IC50	19 nM
CHEMBL4787368	IC50	5200 nM
CHEMBL3040216	IC50	11000 nM
CHEMBL597418	IC50	20000 nM
CHEMBL3314932	IC50	40000 nM
4-[2-((2S,3R,4S,5R)-5-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofurane-2-carboxamido)ethylamido-]benzylphosphonic Acid Diethyl Ester	IC50	42000 nM
4-[3-((2S,3R,4S,5R)-5-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofurane-2-carboxamido)propylamido]benzylphosphonic acid diethyl ester	KI	55200 nM
4-[(2S,3R,4S,5R)-5-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofurane-2-carboxamido]butylamidomethylphosphonic acid diethyl ester	IC50	101000 nM
2-[2-((2S,3R,4S,5R)-5-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofurane-2-carboxamido)ethylamido]ethylphosphonic acid diethyl ester	KI	116000 nM
4-[3-((2S,3R,4S,5R)-5-(6-Amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofurane-2-carboxamido)propylamido]benzylphosphonic acid diethyl ester	KI	154000 nM
4-[4-((2S,3R,4S,5R)-5-(6-Amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofurane-2-carboxamido)butylamido]benzylphosphonic acid diethyl ester	KI	161000 nM
3-[(2S,3R,4S,5R)-5-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofurane-2-carboxamido]propylamidomethylphosphonic acid diethyl ester	KI	167000 nM
4-[4-((2S,3R,4S,5R)-5-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofurane-2-carboxamido)butylamido]benzylphosphonic acid diethyl ester	KI	182000 nM
2-[(2S,3R,4S,5R)-5-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofurane-2-carboxamido]ethylamidomethylphosphonic acid diethyl ester	KI	786000 nM

ChEMBL bioactivities

3 potent at pChembl≥5 of 10 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.52	IC50	3000	nM	CHEMBL597418
5.38	IC50	4200	nM	CHEMBL4787368
5.09	Ki	8200	nM	CHEMBL469212

PubChem BioAssay actives

3 with measured affinity, of 118 total; 3 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
sodium 1-amino-9,10-dioxo-4-(phenanthren-9-ylamino)anthracene-2-sulfonate	1312288: Inhibition of recombinant human NTPDase2 expressed in CHO cells using ADP as substrate incubated for 10 mins by capillary electrophoresis method	ic50	3.0000	uM
8-[3-[(5Z)-5-[(Z)-[5-[[5-[(4,6,8-trisulfo-2H-naphthalen-1-ylidene)carbamoyl]cyclohexa-2,4-dien-1-ylidene]carbamoyl]cyclohexa-2,4-dien-1-ylidene]carbamoyl]iminocyclohexa-1,3-diene-1-carbonyl]iminocyclohexa-1,4-diene-1-carbonyl]imino-7H-naphthalene-1,3,5-trisulfonic acid	1692619: Inhibition of human NTPDase2 expressed in green monkey Cos-7 cells using ATP as substrate preincubated for 3 mins followed by substrate addition by malachite green reagent based assay	ic50	4.2000	uM
(2S,3S,4R,5R)-N-[2-[4-(diethoxyphosphorylmethyl)anilino]-2-oxoethyl]-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolane-2-carboxamide	366263: Inhibition of human NTPDase 2 expressed in HEK293 cells	ki	8.2000	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects expression, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
sotorasib	affects cotreatment, decreases expression	1
lead acetate	decreases expression	1
sulforaphane	decreases expression	1
aflatoxin B2	affects methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Calcitriol	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Coumestrol	decreases expression	1
Demecolcine	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Lipopolysaccharides	increases expression, affects cotreatment, decreases reaction	1
Methyl Methanesulfonate	increases expression	1
Thiram	decreases expression	1
Vincristine	increases expression	1
Cadmium Chloride	decreases expression	1
Particulate Matter	increases expression	1

ChEMBL screening assays

29 unique, capped per target: 24 binding, 5 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1001639	Binding	Activity of human NTPDase 2 expressed in human 293T cells assessed as drug hydrolysis at 100 uM after 20 mins relative to ATP	Identification of hydrolytically stable and selective P2Y(1) receptor agonists. — *Eur J Med Chem*
CHEMBL2390589	ADMET	Drug metabolism assessed as human nucleotide triphosphate diphosphohydrolase2-mediated compound hydrolysis at 4.24 mM after 1 hr by HPLC analysis relative to ADP	Highly efficient biocompatible neuroprotectants with dual activity as antioxidants and P2Y receptor agonists. — *J Med Chem*

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ENTPD2 across ~30M SureChEMBL compounds — explore on Sugi Predict.