ENPP3

Summary

ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase 3, HGNC:3358) is a protein-coding gene on chromosome 6q23.2, encoding Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (O14638). Hydrolase that metabolizes extracellular nucleotides, including ATP, GTP, UTP and CTP.

The protein encoded by this gene belongs to a series of ectoenzymes that are involved in hydrolysis of extracellular nucleotides. These ectoenzymes possess ATPase and ATP pyrophosphatase activities and are type II transmembrane proteins. Expression of the related rat mRNA has been found in a subset of immature glial cells and in the alimentary tract. The corresponding rat protein has been detected in the pancreas, small intestine, colon, and liver. The human mRNA is expressed in glioma cells, prostate, and uterus. Expression of the human protein has been detected in uterus, basophils, and mast cells. Two transcript variants, one protein coding and the other non-protein coding, have been found for this gene.

Source: NCBI Gene 5169 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 163 total — 2 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005021

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3358
Approved symbol	ENPP3
Name	ectonucleotide pyrophosphatase/phosphodiesterase 3
Location	6q23.2
Locus type	gene with protein product
Status	Approved
Aliases	PD-IBETA, gp130RB13-6, B10, CD203c
Ensembl gene	ENSG00000154269
Ensembl biotype	protein_coding
OMIM	602182
Entrez	5169

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000357639, ENST00000358229, ENST00000414305, ENST00000423831, ENST00000427707, ENST00000470930, ENST00000494023, ENST00000946666, ENST00000946667, ENST00000946668, ENST00000946669

RefSeq mRNA: 1 — MANE Select: NM_005021 NM_005021

CCDS: CCDS5148

Canonical transcript exons

ENST00000357639 — 25 exons

Exon	Start	End
ENSE00001234509	131746786	131747410
ENSE00003561522	131738031	131738163
ENSE00003681550	131740224	131740380
ENSE00003890380	131733588	131733723
ENSE00003891740	131737355	131737432
ENSE00004283261	131675080	131675189
ENSE00004283262	131724040	131724091
ENSE00004283263	131683054	131683162
ENSE00004283264	131671248	131671327
ENSE00004283265	131637302	131637462
ENSE00004283267	131650027	131650149
ENSE00004283268	131720292	131720379
ENSE00004283270	131693497	131693624
ENSE00004283271	131676736	131676801
ENSE00004283272	131685876	131685907
ENSE00004283273	131674162	131674281
ENSE00004283274	131677868	131677940
ENSE00004283275	131722227	131722405
ENSE00004283276	131641455	131641530
ENSE00004283277	131658323	131658420
ENSE00004283278	131652542	131652667
ENSE00004283279	131726046	131726200
ENSE00004283280	131652831	131652891
ENSE00004283281	131718672	131718738
ENSE00004283282	131685364	131685495

Expression profiles

Bgee: expression breadth ubiquitous, 181 present calls, max score 96.39.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 8.1163 / max 6979.3550, expressed in 171 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69791	8.0307	160
69794	0.0856	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	96.39	gold quality
ileal mucosa	UBERON:0000331	96.38	gold quality
seminal vesicle	UBERON:0000998	91.49	gold quality
adrenal tissue	UBERON:0018303	90.46	gold quality
duodenum	UBERON:0002114	86.05	gold quality
mucosa of paranasal sinus	UBERON:0005030	85.06	gold quality
bronchial epithelial cell	CL:0002328	83.88	gold quality
bronchus	UBERON:0002185	82.87	gold quality
endometrium	UBERON:0001295	82.75	gold quality
buccal mucosa cell	CL:0002336	82.56	silver quality
tibialis anterior	UBERON:0001385	82.22	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	81.93	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.39	gold quality
rectum	UBERON:0001052	80.00	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.99	gold quality
kidney epithelium	UBERON:0004819	79.55	silver quality
right adrenal gland	UBERON:0001233	79.26	gold quality
mucosa of transverse colon	UBERON:0004991	79.11	gold quality
colonic mucosa	UBERON:0000317	79.05	gold quality
right adrenal gland cortex	UBERON:0035827	78.62	gold quality
pancreatic ductal cell	CL:0002079	78.60	silver quality
adrenal gland	UBERON:0002369	77.28	gold quality
left adrenal gland	UBERON:0001234	77.22	gold quality
cardiac muscle of right atrium	UBERON:0003379	77.11	gold quality
mucosa of sigmoid colon	UBERON:0004993	76.93	gold quality
left adrenal gland cortex	UBERON:0035825	76.93	gold quality
saliva-secreting gland	UBERON:0001044	76.67	gold quality
parotid gland	UBERON:0001831	76.50	gold quality
left ventricle myocardium	UBERON:0006566	76.41	gold quality
adrenal cortex	UBERON:0001235	76.20	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	5.11
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA

miRNA regulators (miRDB)

54 targeting ENPP3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-135A-5P	99.36	71.85	1601
HSA-MIR-135B-5P	99.36	71.63	1613
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-4477B	99.23	70.49	1733

Literature-anchored findings (GeneRIF, showing 23)

• E-NPP3 is associated with carcinogenesis of human colon cancer and that serum E-NPP3 might be a tumor marker of colon carcinoma (PMID:14533006)
• E-NPP3 is involved in the infiltration of neoplastic bile duct carcinoma (PMID:15072822)
• Our data demonstrate that leptin promotes platelet activation, provides a mechanistic basis for the prothrombotic effect of this hormone, and identifies a potentially novel therapeutic avenue to limit obesity-associated cardiovascular disease. (PMID:15886225)
• In conclusion, using well-defined experimental conditions, the measurement of CD203c up-regulation on basophils in response to specific allergens is as reliable as CD63-BAT for the in vitro diagnosis of patients with IgE-mediated allergy. (PMID:17275019)
• Data show that low and high dilutions of histamine inhibit CD203c up-regulation in anti-IgE stimulated basophils. (PMID:19418203)
• Influence of hyperosmotic conditions on basophil CD203c upregulation in patients with food-dependent exercise-induced anaphylaxis. (PMID:20047266)
• Asthma exacerbation was accompanied by increased expression of CD203c on basophils that decreased significantly during remission (PMID:20159259)
• Subjects with nut allergy show an increase of basophil CD203c levels at baseline and following rapid ex vivo stimulation with nut allergen (PMID:20975283)
• The early signaling requirements for the CD11b/CD203c compartment expression and CD63 degranulation provide support for the hypothesis that CD11b and CD203c reside in a similar compartment. (PMID:22722613)
• Expression of CD203c on basophils as a marker of immunoglobulin E-mediated (L)-asparaginase allergy. (PMID:23581640)
• ENPP3 is a regulator of N-acetylglucosaminyltransferase GnT-IX (GnT-Vb) (PMID:23960081)
• Anaphylactic transfusion reaction in homozygous haptoglobin deficiency detected by CD203c expression on basophils. (PMID:24497482)
• Both NPP1 and NPP3 ectoenzymes are expressed in N2a cells, their levels dramatically changing when cells differentiate into a neuronal-like phenotype (PMID:24947519)
• Basophil CD203c surface expression reliably discriminated cystic fibrosis with allergic bronchopulmonary aspergillosis from cystic fibrosis with Aspergillus colonization and cystic fibrosis over time. (PMID:26585435)
• ENPP3 was expressed in endometrial epithelial cells and its expression levels changed during the menstrual cycle, peaking in the mid-secretory phase, corresponding to the time of embryo implantation. ENPP3 may play an important role in embryo implantation and may be a unique biomarker of endometrial receptivity. (PMID:29614240)
• We showed the ability of the immunological marker CD203c to predict the clinical efficacy of sublingual immunotherapy on rhinitis subjects allergic to Parietaria. (PMID:29702283)
• Studies determined the crystal structure of ectonucleotide pyrophosphatase/phosphodiesterase 3 (NPP3) as well as its complex with an ATP analog. (PMID:29717535)
• ENPP3 was detected at high levels in archived tumor samples in agreement with preclinical data (PMID:29848572)
• Updates on the surface antigens of basophils: CD16 on basophils of patients with respiratory or insect venom allergy and the rejection of CD203c and CD63 externalization decoupling by bisindolylmaleimides. (PMID:30288810)
• Activated steady status and distinctive FcepsilonRI-mediated responsiveness in basophils of atopic dermatitis. (PMID:33674191)
• Serum CD203c+ Extracellular Vesicle Serves as a Novel Diagnostic and Prognostic Biomarker for Succinylated Gelatin Induced Perioperative Hypersensitive Reaction. (PMID:34650557)
• Identification of CD203c as a New Basophil-Specific Flow-Marker in Ph[+] Chronic Myeloid Leukemia. (PMID:36611797)
• Hypomethylation of the ENPP3 promoter region contributes to the occurrence and development of ovarian endometriosis via the AKT/mTOR/4EBP1 signaling pathway. (PMID:38149831)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Enpp3	ENSMUSG00000019989
rattus_norvegicus	Enpp3	ENSRNOG00000013791
caenorhabditis_elegans		WBGENE00007753
caenorhabditis_elegans		WBGENE00007755
caenorhabditis_elegans		WBGENE00015283

Paralogs (6): ENPP4 (ENSG00000001561), ENPP5 (ENSG00000112796), ENPP2 (ENSG00000136960), ENPP6 (ENSG00000164303), ENPP7 (ENSG00000182156), ENPP1 (ENSG00000197594)

Protein

Protein identifiers

Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 — O14638 (reviewed: O14638)

Alternative names: Alkaline phosphodiesterase I, Dinucleoside polyphosphatase, Nucleotide diphosphatase, Nucleotide pyrophosphatase, Phosphodiesterase I beta, Phosphodiesterase I/nucleotide pyrophosphatase 3

All UniProt accessions (4): O14638, E7ETI7, E9PDB4, F8W6H5

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolase that metabolizes extracellular nucleotides, including ATP, GTP, UTP and CTP. Also hydrolyzes extracellular 2’,3’-cGAMP (cyclic GMP-AMP), a second messenger that activates TMEM173/STING and triggers type-I interferon production, and is therefore involved in the regulation of innate immune response. 2’,3’-cGAMP appears to be further processed to GMP, AMP and inorganic phosphate. Limits mast cells and basophils response during inflammation and during the chronic phases of allergic responses by eliminating extracellular ATP, a signaling molecule activating these cells in an autocrine manner. Metabolizes extracellular ATP in the lumen of the small intestine, and thereby prevents ATP-induced apoptosis of intestinal plasmacytoid dendritic cells. Has a broad specificity and can also hydrolyze UDP-GlcNAc into UMP and GlcNAc-1-phosphate and potentially several other intracellular nucleotide sugars, including UDP-GalNAc, CMP-NeuAc, GDP-Fuc, and UDP-GlcA. Thereby, could modulate glycan biosynthesis and protein glycosylation. Can hydrolyze extracellular dinucleoside polyphosphates, including the vasoactive adenosine polyphosphates as well. In addition, displays an alkaline phosphodiesterase activity in vitro.

Subunit / interactions. Monomer and homodimer.

Subcellular location. Cell membrane. Apical cell membrane. Secreted.

Tissue specificity. Detected on bile ducts in liver, and in blood serum (at protein level). Detected in prostate and uterus. Detected on basophils, but not neutrophils.

Post-translational modifications. N-glycosylated. N-glycosylation is necessary for normal transport to the cell membrane, but is not the apical targeting signal.

Cofactor. Binds 2 zinc ions per subunit.

Induction. Up-regulated by stimulation by allergen or by cross-linking with IgE. The IgE-mediated activation is enhanced by tetradecanoyl phorbol acetate (TPA), a stimulator of the PKC pathway, and inhibited by the P13 kinase inhibitors, LY294002 and wortmannin. Up-regulated in invasive bile duct cancers.

Similarity. Belongs to the nucleotide pyrophosphatase/phosphodiesterase family.

RefSeq proteins (1): NP_005012* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001212	Somatomedin_B_dom	Domain
IPR001604	Endo_G_ENPP1-like_dom	Domain
IPR002591	Phosphodiest/P_Trfase	Family
IPR017850	Alkaline_phosphatase_core_sf	Homologous_superfamily
IPR020821	ENPP1-3/EXOG-like_nuc-like	Domain
IPR036024	Somatomedin_B-like_dom_sf	Homologous_superfamily
IPR044925	His-Me_finger_sf	Homologous_superfamily
IPR044929	DNA/RNA_non-sp_Endonuclease_sf	Homologous_superfamily

Pfam: PF01033, PF01663

Enzyme classification (BRENDA):

• EC 3.6.1.9 — nucleotide diphosphatase (BRENDA: 33 organisms, 282 substrates, 447 inhibitors, 181 Km, 58 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.0062–78	14
NAD+	0.004–31.2	12
FAD	0.005–1.8	10
UDP-GLUCOSE	0.62–50	8
NADH	0.042–20	7
THYMIDINE 5’-MONOPHOSPHATE P-NITROPHENYL ESTER	0.066–20	7
UTP	0.0566–33	7
4-NITROPHENYL-5’-THYMIDINE MONOPHOSPHATE	0.0618–0.222	5
4-NITROPHENYL-5’-TMP	0.027–0.1185	4
AP3A	0.0051–0.0495	4
ADENOSINE 5’-PHOSPHOSULFATE	0.5–3	3
ADP	0.18–4.3	3
ADP-GLUCOSE	0.7–0.8	3
ADP-RIBOSE	0.5–18.9	3
BIS(4-NITROPHENYL)PHOSPHATE	2.1–3	3

Catalyzed reactions (Rhea), 12 shown:

• P(1),P(3)-bis(5’-adenosyl) triphosphate + H2O = AMP + ADP + 2 H(+) (RHEA:13893)
• ATP + H2O = AMP + diphosphate + H(+) (RHEA:14245)
• P(1),P(4)-bis(5’-guanosyl) tetraphosphate + H2O = GMP + GTP + 2 H(+) (RHEA:22484)
• a ribonucleoside 5’-triphosphate + H2O = a ribonucleoside 5’-phosphate + diphosphate + H(+) (RHEA:23996)
• GMP + H2O = guanosine + phosphate (RHEA:27714)
• CTP + H2O = CMP + diphosphate + H(+) (RHEA:27762)
• AMP + H2O = adenosine + phosphate (RHEA:29375)
• GTP + H2O = GMP + diphosphate + H(+) (RHEA:29391)
• UTP + H2O = UMP + diphosphate + H(+) (RHEA:29395)
• UDP-N-acetyl-alpha-D-glucosamine + H2O = N-acetyl-alpha-D-glucosamine 1-phosphate + UMP + 2 H(+) (RHEA:29547)
• P(1),P(4)-bis(5’-adenosyl) tetraphosphate + H2O = AMP + ATP + 2 H(+) (RHEA:32039)
• P(1),P(5)-bis(5’-adenosyl) pentaphosphate + H2O = adenosine 5’-tetraphosphate + AMP + 2 H(+) (RHEA:32051)

UniProt features (146 total): helix 43, strand 33, binding site 16, disulfide bond 16, glycosylation site 10, turn 9, mutagenesis site 5, sequence variant 3, topological domain 2, domain 2, region of interest 2, chain 1, transmembrane region 1, sequence conflict 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6C02	X-RAY DIFFRACTION	1.94
6C01	X-RAY DIFFRACTION	2.3
9NIR	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14638-F1	95.50	0.93

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): 205 (nucleophile)

Ligand- & substrate-binding residues (16): 167; 204; 205; 226; 275; 289; 325; 329; 372; 373; 483; 752 …

Disulfide bonds (16): 54–71, 58–89, 69–82, 75–81, 98–115, 103–133, 113–126, 119–125, 144–190, 152–364, 380–478, 429–818, 562–623, 575–679, 577–664, 787–797

Glycosylation sites (10): 236, 279, 290, 426, 533, 582, 594, 687, 699, 789

Mutagenesis-validated functional residues (5):

Position	Phenotype
179	causes the formation of covalently linked homodimers in solution; when associated with c-336.
204	strongly decreases affinity for nucleotides and slows their hydrolysis.
227	no effect on affinity for nucleotides and enzyme activity.
275	no effect on substrate specificity. increases affinity for nucleotides and slows their hydrolysis.
336	causes the formation of covalently linked homodimers in solution; when associated with c-179.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-199220	Vitamin B5 (pantothenate) metabolism

MSigDB gene sets: 285 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_INFLAMMATORY_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOMF_NUCLEASE_ACTIVITY, GOBP_REGULATION_OF_MAST_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOCC_CELL_SURFACE, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_MAST_CELL_ACTIVATION

GO Biological Process (10): basophil activation involved in immune response (GO:0002276), pyrimidine nucleotide metabolic process (GO:0006220), phosphate-containing compound metabolic process (GO:0006796), nucleoside triphosphate catabolic process (GO:0009143), negative regulation of mast cell activation involved in immune response (GO:0033007), ATP metabolic process (GO:0046034), negative regulation of inflammatory response (GO:0050728), phosphate ion homeostasis (GO:0055062), negative regulation of mast cell proliferation (GO:0070667), negative regulation of cGAS/STING signaling pathway (GO:0160049)

GO Molecular Function (15): nucleic acid binding (GO:0003676), bis(5’-nucleosyl)-tetraphosphatase (asymmetrical) activity (GO:0004081), phosphodiesterase I activity (GO:0004528), calcium ion binding (GO:0005509), zinc ion binding (GO:0008270), bis(5’-adenosyl)-pentaphosphatase activity (GO:0034432), GTP diphosphatase activity (GO:0036219), UTP diphosphatase activity (GO:0036221), nucleoside triphosphate diphosphatase activity (GO:0047429), ATP diphosphatase activity (GO:0047693), bis(5’-adenosyl)-triphosphatase activity (GO:0047710), cyclic-GMP-AMP hydrolase activity (GO:0106177), pyrophosphatase activity (GO:0016462), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (8): plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), apical plasma membrane (GO:0016324), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), extracellular region (GO:0005576), cell surface (GO:0009986), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
pyrophosphatase activity	3
nucleoside triphosphate diphosphatase activity	3
hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides	2
myeloid cell activation involved in immune response	1
leukocyte activation involved in immune response	1
immune response	1
basophil activation	1
nucleotide metabolic process	1
pyrimidine-containing compound metabolic process	1
metabolic process	1
nucleoside triphosphate metabolic process	1
nucleoside phosphate catabolic process	1
mast cell activation involved in immune response	1
negative regulation of immune effector process	1
negative regulation of mast cell activation	1
negative regulation of immune response	1
purine ribonucleotide metabolic process	1
purine ribonucleoside triphosphate metabolic process	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
inorganic ion homeostasis	1
mast cell proliferation	1
negative regulation of leukocyte proliferation	1
regulation of mast cell proliferation	1
negative regulation of cytoplasmic pattern recognition receptor signaling pathway	1
cGAS/STING signaling pathway	1
binding	1
bis(5’-nucleosyl)-tetraphosphatase activity	1
exonuclease activity	1
phosphoric diester hydrolase activity	1
metal ion binding	1
transition metal ion binding	1
catalytic activity	1
cation binding	1
membrane	1
cell periphery	1
plasma membrane	1

Protein interactions and networks

STRING

1140 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENPP3	GDPD1	Q8N9F7	924
ENPP3	GDPD3	Q7L5L3	921
ENPP3	CD63	P08962	772
ENPP3	ENTPD3	O75355	704
ENPP3	VTN	P01141	668
ENPP3	IL3RA	P26951	582
ENPP3	PTGDR2	Q9Y5Y4	577
ENPP3	FCER1A	P12319	506
ENPP3	ENTPD2	Q9Y5L3	499
ENPP3	ENTPD8	Q5MY95	499
ENPP3	ALPL	P05186	495
ENPP3	CCR3	P51677	480
ENPP3	PDCL	Q13371	479
ENPP3	ENTPD1	P49961	470
ENPP3	IL3	P08700	448

IntAct

5 interactions, top by confidence:

A	B	Type	Score
Dlg4	ENPP3	psi-mi:“MI:0407”(direct interaction)	0.440
ENPP3	DHRS2	psi-mi:“MI:0915”(physical association)	0.400
ENPP3	DAPK3	psi-mi:“MI:0915”(physical association)	0.400
ENPP3	CSE1L	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): DHRS2 (Proximity Label-MS), DAPK3 (Proximity Label-MS), EIF2B4 (Affinity Capture-MS), SAAL1 (Affinity Capture-MS), CSE1L (Affinity Capture-MS), ENPP3 (Reconstituted Complex), ENPP3 (Affinity Capture-MS)

ESM2 similar proteins: A0A2D0TC04, A1A4K5, A2VDP5, A8K7I4, J3SBP3, J3SEZ3, O14638, P06802, P0DQQ4, P15396, P18563, P18564, P22413, P54793, P97259, P97675, Q08834, Q09328, Q13822, Q14CN2, Q1RPR6, Q29444, Q2TU62, Q32KH8, Q3SZI1, Q4FZV0, Q5FYA8, Q5GF25, Q5R5M5, Q64610, Q6AYF4, Q6DDW2, Q6DYE8, Q6NXH2, Q6PT52, Q6Q473, Q863C4, Q8BTJ4, Q8K1B9, Q8K2I4

Diamond homologs: A0A2D0TC04, A1A4K5, A2VDP5, J3SBP3, J3SEZ3, O14638, O94323, P06802, P0DQQ4, P15396, P22413, P84039, P97675, Q0VA77, Q13822, Q3TIW9, Q566N0, Q5EZ72, Q5R5M5, Q5RAC0, Q64610, Q6AX80, Q6DYE8, Q6UWV6, Q8BTJ4, Q924C3, Q9EQG7, Q9R1E6, Q9UJA9, Q9Y6X5, W8E7D1, P90754, A1YYW7, B0BND0, F1N5C8, P90755, Q58D68, Q5BKW7, Q5RB45, Q6DDP3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	135
Likely benign	9
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1699970	NC_000006.12:g.131688637_132215008del	Pathogenic
57486	GRCh38/hg38 6q21-23.2(chr6:108944899-132067720)x1	Pathogenic

SpliceAI

4444 predictions. Top by Δscore:

Variant	Effect	Δscore
6:131628617:C:G	donor_gain	1.0000
6:131637458:GCATT:G	donor_gain	1.0000
6:131637459:CATT:C	donor_gain	1.0000
6:131637463:G:GG	donor_gain	1.0000
6:131650150:G:GG	donor_gain	1.0000
6:131650152:A:G	donor_gain	1.0000
6:131650161:GAGAA:G	donor_gain	1.0000
6:131650163:GAA:G	donor_gain	1.0000
6:131650165:A:AG	donor_gain	1.0000
6:131650165:A:G	donor_gain	1.0000
6:131674309:G:GT	donor_gain	1.0000
6:131674395:GGC:G	donor_gain	1.0000
6:131675220:C:G	donor_gain	1.0000
6:131676734:A:AG	acceptor_gain	1.0000
6:131676735:G:GA	acceptor_gain	1.0000
6:131676735:GA:G	acceptor_gain	1.0000
6:131676735:GAA:G	acceptor_gain	1.0000
6:131676735:GAAGT:G	acceptor_gain	1.0000
6:131677866:A:AG	acceptor_gain	1.0000
6:131677867:G:GG	acceptor_gain	1.0000
6:131677937:CAGAG:C	donor_loss	1.0000
6:131677939:GA:G	donor_gain	1.0000
6:131677939:GAGT:G	donor_loss	1.0000
6:131677940:AGTA:A	donor_loss	1.0000
6:131677941:G:A	donor_loss	1.0000
6:131677941:G:GG	donor_gain	1.0000
6:131677942:T:G	donor_loss	1.0000
6:131683053:GGT:G	acceptor_gain	1.0000
6:131683053:GGTA:G	acceptor_gain	1.0000
6:131683160:ATGG:A	donor_loss	1.0000

AlphaMissense

5827 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:131675083:T:A	W256R	0.998
6:131675083:T:C	W256R	0.998
6:131658358:A:T	D167V	0.995
6:131726174:T:A	W643R	0.995
6:131726174:T:C	W643R	0.995
6:131737399:A:C	S712R	0.995
6:131737401:C:A	S712R	0.995
6:131737401:C:G	S712R	0.995
6:131658361:G:A	G168E	0.994
6:131674228:T:C	F237L	0.994
6:131674230:T:A	F237L	0.994
6:131674230:T:G	F237L	0.994
6:131675128:T:A	W271R	0.994
6:131675128:T:C	W271R	0.994
6:131718708:T:A	H483Q	0.994
6:131718708:T:G	H483Q	0.994
6:131658357:G:C	D167H	0.993
6:131658359:T:A	D167E	0.993
6:131658359:T:G	D167E	0.993
6:131671309:T:A	N208K	0.993
6:131671309:T:G	N208K	0.993
6:131674163:G:T	G215V	0.993
6:131674197:T:A	N226K	0.993
6:131674197:T:G	N226K	0.993
6:131675085:G:C	W256C	0.993
6:131675085:G:T	W256C	0.993
6:131683157:A:T	D372V	0.993
6:131685457:G:C	R405P	0.993
6:131671301:T:C	F206L	0.992
6:131671303:C:A	F206L	0.992

dbSNP variants (sampled 300 via entrez): RS1000009033 (6:131664405 G>C), RS1000066504 (6:131730411 A>T), RS1000079512 (6:131723714 G>A), RS1000083992 (6:131663957 C>T), RS1000227180 (6:131695881 A>C,G), RS1000254895 (6:131670257 T>C), RS1000276383 (6:131706458 G>A,T), RS1000280924 (6:131651502 G>A), RS1000315908 (6:131676239 C>T), RS1000330620 (6:131743009 G>T), RS1000337787 (6:131687664 T>C), RS1000391310 (6:131693139 C>T), RS1000425823 (6:131639218 T>C), RS1000444118 (6:131735826 A>G), RS1000524044 (6:131637640 C>T)

Disease associations

OMIM: gene MIM:602182 | disease phenotypes: MIM:208000

GenCC curated gene-disease

Mondo (1): arterial calcification, generalized, of infancy, 1 (MONDO:0008817)

Orphanet (1): Generalized arterial calcification of infancy (Orphanet:51608)

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001738_7	Response to fenofibrate (adiponectin levels)	5.000000e-06
GCST002623_1	L-arginine levels	4.000000e-19
GCST004104_2	Body mass index (change over time) in lung cancer	2.000000e-06
GCST005981_3	Phosphorus levels	1.000000e-08
GCST009100_3	Resistant hypertension	1.000000e-06
GCST009596_2	Osteoarthritis of the hand	4.000000e-07
GCST010118_140	Type 2 diabetes	2.000000e-11
GCST90011900_58	Serum alkaline phosphatase levels	1.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006524	L-arginine measurement
EFO:0005937	longitudinal BMI measurement
EFO:0004861	phosphorus measurement
EFO:1002006	treatment-resistant hypertension
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5580 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 36,848 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL265502	SURAMIN	3	36,848

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

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5194668	KI	1700 nM

ChEMBL bioactivities

102 potent at pChembl≥5 of 136 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.05	IC50	0.09	nM	CHEMBL5566114
7.40	Ki	40	nM	SURAMIN
7.27	Ki	53.7	nM	CHEMBL2336905
6.93	Ki	117	nM	CHEMBL1485038
6.82	IC50	150	nM	CHEMBL4753995
6.77	IC50	170	nM	CHEMBL4791706
6.68	IC50	210	nM	CHEMBL4859945
6.67	IC50	214	nM	CHEMBL4573280
6.64	IC50	230	nM	CHEMBL4280275
6.64	IC50	230	nM	CHEMBL4540180
6.59	IC50	254	nM	CHEMBL4585698
6.59	IC50	255	nM	CHEMBL4451311
6.50	IC50	320	nM	CHEMBL4285649
6.46	IC50	350	nM	CHEMBL298036
6.44	IC50	360	nM	CHEMBL4162261
6.43	IC50	369	nM	CHEMBL3797764
6.41	IC50	390	nM	CHEMBL4159530
6.39	IC50	410	nM	CHEMBL4280333
6.32	Ki	480	nM	CHEMBL5172114
6.31	IC50	490	nM	CHEMBL4561757
6.29	IC50	510	nM	CHEMBL4283786
6.26	IC50	550	nM	CHEMBL4848343
6.24	Ki	570	nM	CHEMBL5208063
6.23	IC50	590	nM	CHEMBL4850521
6.20	IC50	630	nM	CHEMBL243638
6.15	IC50	710	nM	CHEMBL4473374
6.15	Ki	710	nM	REACTIVE BLUE 2
6.13	IC50	740	nM	CHEMBL5432925
6.09	IC50	807	nM	CHEMBL4476115
6.07	IC50	856	nM	CHEMBL3798550
6.06	IC50	880	nM	CHEMBL4859229
6.05	IC50	890	nM	SURAMIN
6.05	IC50	900	nM	SURAMIN
6.04	Ki	920	nM	CHEMBL4284270
6.02	Ki	950	nM	CHEMBL4277262
5.99	IC50	1014	nM	CHEMBL4538105
5.97	IC50	1079	nM	CHEMBL4465256
5.96	Ki	1110	nM	CHEMBL1485038
5.94	IC50	1140	nM	CHEMBL4172933
5.94	IC50	1150	nM	CHEMBL390695
5.93	IC50	1170	nM	CHEMBL4875454
5.92	IC50	1203	nM	CHEMBL4467551
5.91	IC50	1220	nM	CHEMBL4287085
5.91	IC50	1240	nM	CHEMBL4589775
5.90	IC50	1270	nM	SURAMIN
5.90	IC50	1260	nM	CHEMBL4279910
5.90	IC50	1260	nM	CHEMBL4291645
5.89	IC50	1273	nM	CHEMBL5411127
5.88	IC50	1310	nM	CHEMBL4758988
5.88	IC50	1310	nM	CHEMBL4874559

PubChem BioAssay actives

102 with measured affinity, of 346 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(1S,5R)-3-(7-oxo-8H-pyrido[2,3-d]pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl]ethylphosphonic acid	2080853: Inhibition of human ENPP3 using p-Nph-5’-TMP incubated for 40 mins by absorbance based analysis	ic50	0.0001	uM
8-[4-methyl-3-[(5Z)-5-[(Z)-[5-[[2-methyl-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	1881410: Inhibition of recombinant human NPP3 expressed in CHO cells using ATP as substrate measured after 20 mins by mini-capillary electrophoresis	ki	0.0400	uM
2-methyl-5-[4-(4-sulfamoylanilino)phthalazin-1-yl]benzenesulfonamide	1881398: Inhibition of recombinant human soluble NPP3 expressed in Sf9 insect cells using ATP as substrate measured after 4 hrs by capillary electrophoresis	ki	0.0537	uM
4-[(4-methylphthalazin-1-yl)amino]benzenesulfonamide	1881397: Inhibition of recombinant human soluble NPP3 expressed in Sf9 insect cells using p-Nph-5’-TMP as substrate measured after 30 mins	ki	0.1170	uM
2-methyl-4-(4-naphthalen-1-ylphenyl)-1,3-oxazole	1705060: Inhibition of human recombinant NPP3 expressed in COS-7 cell membrane at 100 uM using p-nitrophenyl thymidine monophosphate substrate incubated for 35 mins by spectrophotometric analysis	ic50	0.1500	uM
4-[4-(4-methoxyphenyl)phenyl]-2-methyl-1,3-oxazole	1705060: Inhibition of human recombinant NPP3 expressed in COS-7 cell membrane at 100 uM using p-nitrophenyl thymidine monophosphate substrate incubated for 35 mins by spectrophotometric analysis	ic50	0.1700	uM
1-[3-[3-(3-chloro-4-hydroxyphenyl)-4-pyridin-4-ylpyrazol-1-yl]phenyl]-3-phenylthiourea	1758438: Inhibition of NPP3 (unknown origin) transfected in COS7 cells using pNP-TMP as substrate incubated for 35 mins by spectrophotometric method	ic50	0.2100	uM
[4-(cyclooctanecarbonylamino)phenyl] 4-(trifluoromethyl)benzenesulfonate	1544906: Inhibition of human NPP3 expressed in African green monkey COS7 cell membranes pre-incubated for 10 mins before pNP-TMP substrate addition and further incubated for 15 mins by colorimetric method	ic50	0.2140	uM
(4-chloro-3,5-dimethylpyrazol-1-yl)-(4-methylphenyl)methanone	1406006: Inhibition of human NPP3 expressed in COS7 cells using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 5 to 10 mins followed by substrate addition measured after 35 mins	ic50	0.2300	uM
[4-[3-[4-(2-piperidin-1-ylethoxy)benzoyl]-6-[4-(trifluoromethyl)phenyl]sulfonyloxy-1-benzothiophen-2-yl]phenyl] 4-(trifluoromethyl)benzenesulfonate	1516776: Inhibition of human NPP3 expressed in COS-7 cell membranes assessed as reduction in p-nitrophenol production using pNP-TMP as substrate preincubated with enzyme for 15 mins followed by substrate addition and measured after 35 mins	ic50	0.2300	uM
[4-(cyclohexanecarbonylamino)phenyl] 4-fluorobenzenesulfonate	1544906: Inhibition of human NPP3 expressed in African green monkey COS7 cell membranes pre-incubated for 10 mins before pNP-TMP substrate addition and further incubated for 15 mins by colorimetric method	ic50	0.2540	uM
[4-(cycloheptanecarbonylamino)phenyl] 4-methylbenzenesulfonate	1544906: Inhibition of human NPP3 expressed in African green monkey COS7 cell membranes pre-incubated for 10 mins before pNP-TMP substrate addition and further incubated for 15 mins by colorimetric method	ic50	0.2550	uM
(4-chloro-3,5-dimethylpyrazol-1-yl)-(2-methylphenyl)methanone	1406006: Inhibition of human NPP3 expressed in COS7 cells using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 5 to 10 mins followed by substrate addition measured after 35 mins	ic50	0.3200	uM
(3,5-dimethylpyrazol-1-yl)-pyridin-4-ylmethanone	1406006: Inhibition of human NPP3 expressed in COS7 cells using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 5 to 10 mins followed by substrate addition measured after 35 mins	ic50	0.3500	uM
3-bromo-4-chloro-8-(2,5-dimethoxyphenyl)-2-(trifluoromethyl)quinoline	1499685: Inhibition of human full length NPP3 expressed in African green monkey COS7 cell membrane fraction using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 10 mins followed by substrate addition measured after 30 mins	ic50	0.3600	uM
[4-(cyclohexanecarbonylamino)phenyl] ethanesulfonate	1544906: Inhibition of human NPP3 expressed in African green monkey COS7 cell membranes pre-incubated for 10 mins before pNP-TMP substrate addition and further incubated for 15 mins by colorimetric method	ic50	0.3690	uM
3,8-dibromo-4-chloro-2-(trifluoromethyl)quinoline	1499685: Inhibition of human full length NPP3 expressed in African green monkey COS7 cell membrane fraction using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 10 mins followed by substrate addition measured after 30 mins	ic50	0.3900	uM
2-(4-aminobenzoyl)-5-methyl-1H-pyrazol-3-one	1406006: Inhibition of human NPP3 expressed in COS7 cells using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 5 to 10 mins followed by substrate addition measured after 35 mins	ic50	0.4100	uM
6-(5-cyanoindol-1-yl)indolo[2,1-a]isoquinoline-10-carbonitrile	1881412: Inhibition of human NPP3 expressed in COS-7 cells using p-Nph-5’-TMP as substrate preincubated for 10 mins followed by substrate addition and measured after 30 mins by spectrophotometric method	ki	0.4800	uM
[4-[6-cyclohexylsulfonyloxy-3-[4-(2-piperidin-1-ylethoxy)benzoyl]-1-benzothiophen-2-yl]phenyl] cyclohexanesulfonate	1516776: Inhibition of human NPP3 expressed in COS-7 cell membranes assessed as reduction in p-nitrophenol production using pNP-TMP as substrate preincubated with enzyme for 15 mins followed by substrate addition and measured after 35 mins	ic50	0.4900	uM
(4-aminophenyl)-[3,5-dimethyl-4-(4-methylphenoxy)pyrazol-1-yl]methanone	1406006: Inhibition of human NPP3 expressed in COS7 cells using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 5 to 10 mins followed by substrate addition measured after 35 mins	ic50	0.5100	uM
N-(benzenesulfonyl)-4-(dimethylamino)pyrrolo[2,3-b]pyridine-1-carboxamide	1758440: Inhibition of human NPP3 transfected in COS7 cells using pNP-TMP as substrate incubated for 35 mins	ic50	0.5500	uM
5-[(1,3-diphenylpyrazol-4-yl)methylidene]-1,3-diethyl-2-sulfanylidene-1,3-diazinane-4,6-dione	1881411: Inhibition of human NPP3 expressed in COS-7 cells using p-Nph-5’-TMP as substrate preincubated for 10 mins followed by substrate addition and measured after 30 mins	ki	0.5700	uM
5-bromo-N-(4-methylphenyl)sulfonylpyrrolo[2,3-b]pyridine-1-carboxamide	1758440: Inhibition of human NPP3 transfected in COS7 cells using pNP-TMP as substrate incubated for 35 mins	ic50	0.5900	uM
(4-chloro-3,5-dimethylpyrazol-1-yl)-(4-chlorophenyl)methanone	1406006: Inhibition of human NPP3 expressed in COS7 cells using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 5 to 10 mins followed by substrate addition measured after 35 mins	ic50	0.6300	uM
[4-[6-(4-tert-butylphenyl)sulfonyloxy-3-[4-(2-piperidin-1-ylethoxy)benzoyl]-1-benzothiophen-2-yl]phenyl] 4-tert-butylbenzenesulfonate	1516776: Inhibition of human NPP3 expressed in COS-7 cell membranes assessed as reduction in p-nitrophenol production using pNP-TMP as substrate preincubated with enzyme for 15 mins followed by substrate addition and measured after 35 mins	ic50	0.7100	uM
1-amino-4-[4-[[4-chloro-6-(3-sulfoanilino)-1,3,5-triazin-2-yl]amino]-3-sulfoanilino]-9,10-dioxoanthracene-2-sulfonic acid	1881398: Inhibition of recombinant human soluble NPP3 expressed in Sf9 insect cells using ATP as substrate measured after 4 hrs by capillary electrophoresis	ki	0.7100	uM
[4-(adamantane-1-carbonylamino)phenyl] 4-fluorobenzenesulfonate	1980060: Inhibition of human NPP3 expressed in COS-7 cells using pNP-TMP as substrate preincubated for 10 mins followed by substrate addition and measured after 35 mins by microplate reader analysis	ic50	0.7400	uM
[4-(cyclohexanecarbonylamino)phenyl] 4-tert-butylbenzenesulfonate	1544906: Inhibition of human NPP3 expressed in African green monkey COS7 cell membranes pre-incubated for 10 mins before pNP-TMP substrate addition and further incubated for 15 mins by colorimetric method	ic50	0.8070	uM
[4-(cyclopentanecarbonylamino)phenyl] 4-methylbenzenesulfonate	1544906: Inhibition of human NPP3 expressed in African green monkey COS7 cell membranes pre-incubated for 10 mins before pNP-TMP substrate addition and further incubated for 15 mins by colorimetric method	ic50	0.8560	uM
N-(4-chlorophenyl)sulfonylpyrrolo[2,3-b]pyridine-1-carboxamide	1758440: Inhibition of human NPP3 transfected in COS7 cells using pNP-TMP as substrate incubated for 35 mins	ic50	0.8800	uM
2-(3,5-dimethylphenyl)-6-fluoro-7-methyl-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one	1881413: Inhibition of human NPP3 expressed in COS-7 cells using p-Nph-5’-TMP as substrate preincubated for 10 mins followed by substrate addition and measured after 30 mins by malachite green reagent based spectrophotometric method	ki	0.9200	uM
[(2R)-2-[(1R)-1-(6-aminopurin-9-yl)-2-oxoethoxy]-3-oxopropyl] phosphono hydrogen phosphate	1881409: Inhibition of recombinant human NPP3 expressed in HEK293 cells using p-Nph-5’-TMP as substrate measured after 60 mins by mini-capillary electrophoresis	ki	0.9500	uM
[4-(cyclopentanecarbonylamino)phenyl] 4-fluorobenzenesulfonate	1544906: Inhibition of human NPP3 expressed in African green monkey COS7 cell membranes pre-incubated for 10 mins before pNP-TMP substrate addition and further incubated for 15 mins by colorimetric method	ic50	1.0140	uM
[4-(cyclohexanecarbonylamino)phenyl] benzenesulfonate	1544906: Inhibition of human NPP3 expressed in African green monkey COS7 cell membranes pre-incubated for 10 mins before pNP-TMP substrate addition and further incubated for 15 mins by colorimetric method	ic50	1.0790	uM
3-bromo-4-chloro-8-(4-methoxyphenyl)-2-(trifluoromethyl)quinoline	1499685: Inhibition of human full length NPP3 expressed in African green monkey COS7 cell membrane fraction using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 10 mins followed by substrate addition measured after 30 mins	ic50	1.1400	uM
(4-chlorophenyl)-(3,5-dimethylpyrazol-1-yl)methanone	1406006: Inhibition of human NPP3 expressed in COS7 cells using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 5 to 10 mins followed by substrate addition measured after 35 mins	ic50	1.1500	uM
N-(3-nitrophenyl)sulfonylpyrrolo[2,3-b]pyridine-1-carboxamide	1758440: Inhibition of human NPP3 transfected in COS7 cells using pNP-TMP as substrate incubated for 35 mins	ic50	1.1700	uM
[4-[(4-chlorobenzoyl)amino]phenyl] 2,4,6-tri(propan-2-yl)benzenesulfonate	1544906: Inhibition of human NPP3 expressed in African green monkey COS7 cell membranes pre-incubated for 10 mins before pNP-TMP substrate addition and further incubated for 15 mins by colorimetric method	ic50	1.2030	uM
(4-aminophenyl)-(4-chloro-3,5-dimethylpyrazol-1-yl)methanone	1406006: Inhibition of human NPP3 expressed in COS7 cells using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 5 to 10 mins followed by substrate addition measured after 35 mins	ic50	1.2200	uM
[4-[6-(4-methoxyphenyl)sulfonyloxy-3-[4-(2-piperidin-1-ylethoxy)benzoyl]-1-benzothiophen-2-yl]phenyl] 4-methoxybenzenesulfonate	1516776: Inhibition of human NPP3 expressed in COS-7 cell membranes assessed as reduction in p-nitrophenol production using pNP-TMP as substrate preincubated with enzyme for 15 mins followed by substrate addition and measured after 35 mins	ic50	1.2400	uM
3,5-dimethyl-4-naphthalen-2-yloxy-1H-pyrazole	1406006: Inhibition of human NPP3 expressed in COS7 cells using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 5 to 10 mins followed by substrate addition measured after 35 mins	ic50	1.2600	uM
5-methyl-2-(4-methylbenzoyl)-1H-pyrazol-3-one	1406006: Inhibition of human NPP3 expressed in COS7 cells using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 5 to 10 mins followed by substrate addition measured after 35 mins	ic50	1.2600	uM
7-methoxy-4-[4-[(sulfamoylamino)methyl]phenyl]quinoline	2131202: Inhibition of recombinant human ENPP3 using p-Nph-5’-TMP as substrate by absorbance based analysis	ic50	1.2730	uM
4-chloro-N-naphthalen-2-ylsulfonylpyrrolo[2,3-b]pyridine-1-carboxamide	1758440: Inhibition of human NPP3 transfected in COS7 cells using pNP-TMP as substrate incubated for 35 mins	ic50	1.3100	uM
2-methyl-4-[4-(4-phenylmethoxyphenyl)phenyl]-1,3-oxazole	1705060: Inhibition of human recombinant NPP3 expressed in COS-7 cell membrane at 100 uM using p-nitrophenyl thymidine monophosphate substrate incubated for 35 mins by spectrophotometric analysis	ic50	1.3100	uM
[4-(cyclohexanecarbonylamino)phenyl] methanesulfonate	1544906: Inhibition of human NPP3 expressed in African green monkey COS7 cell membranes pre-incubated for 10 mins before pNP-TMP substrate addition and further incubated for 15 mins by colorimetric method	ic50	1.3540	uM
[4-[6-ethylsulfonyloxy-3-[4-(2-piperidin-1-ylethoxy)benzoyl]-1-benzothiophen-2-yl]phenyl] ethanesulfonate	1516776: Inhibition of human NPP3 expressed in COS-7 cell membranes assessed as reduction in p-nitrophenol production using pNP-TMP as substrate preincubated with enzyme for 15 mins followed by substrate addition and measured after 35 mins	ic50	1.5100	uM
[4-[(4-chlorobenzoyl)amino]phenyl] 4-tert-butylbenzenesulfonate	1544906: Inhibition of human NPP3 expressed in African green monkey COS7 cell membranes pre-incubated for 10 mins before pNP-TMP substrate addition and further incubated for 15 mins by colorimetric method	ic50	1.5250	uM
(4-chloro-3,5-dimethylpyrazol-1-yl)-(3-methylphenyl)methanone	1406006: Inhibition of human NPP3 expressed in COS7 cells using p-nitrophenyl-5’-thymidine monophosphate as substrate preincubated for 5 to 10 mins followed by substrate addition measured after 35 mins	ic50	1.5300	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, decreases expression, decreases methylation, increases methylation	4
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Cyclosporine	decreases expression	3
Quercetin	affects reaction, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
perfluorooctanoic acid	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
abrine	decreases expression	1
Dasatinib	increases expression, decreases expression, decreases reaction	1
Acetaminophen	decreases expression	1
Allergens	increases expression, decreases reaction	1
Azathioprine	decreases expression	1
N-Formylmethionine Leucyl-Phenylalanine	increases expression, affects reaction	1
N-Nitrosopyrrolidine	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

58 unique, capped per target: 51 binding, 7 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004222	Binding	Activity of human NPP3 expressed in human 293T cells assessed as drug hydrolysis at 100 uM after 20 mins by reverse-phase HPLC relative to p-nitrophenyl-thymidine-5-monophosphate	Identification of hydrolytically stable and selective P2Y(1) receptor agonists. — Eur J Med Chem
CHEMBL2090464	ADMET	Hydrolytic stability of the compound assessed as human NPP3-mediated hydrolysis after 3 hrs by HPLC analysis	UDP made a highly promising stable, potent, and selective P2Y6-receptor agonist upon introduction of a boranophosphate moiety. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E6Q7	Genomeditech CHO-K1 H_ENPP3	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07473973	PHASE3	RECRUITING	ENERGY 2: Evaluation of the Efficacy and Safety of INZ-701 in Infants With ENPP1 Deficiency
NCT06739980	PHASE2	WITHDRAWN	The ENABLE Study: Safety and Efficacy Study of INZ-701 in Patients With ENPP1 Deficiency