ENPP5

Summary

ENPP5 (ectonucleotide pyrophosphatase/phosphodiesterase family member 5, HGNC:13717) is a protein-coding gene on chromosome 6p21.1, encoding Ectonucleotide pyrophosphatase/phosphodiesterase family member 5 (Q9UJA9). Can hydrolyze NAD but cannot hydrolyze nucleotide di- and triphosphates.

This gene encodes a type-I transmembrane glycoprotein. Studies in rat suggest the encoded protein may play a role in neuronal cell communications. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 59084 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 70 total
• MANE Select transcript: NM_001290072

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13717
Approved symbol	ENPP5
Name	ectonucleotide pyrophosphatase/phosphodiesterase family member 5
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000112796
Ensembl biotype	protein_coding
OMIM	617001
Entrez	59084

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000230565, ENST00000371383, ENST00000492313, ENST00000906433, ENST00000906434, ENST00000906435, ENST00000906436, ENST00000906437, ENST00000906438

RefSeq mRNA: 3 — MANE Select: NM_001290072 NM_001290072, NM_001290073, NM_021572

CCDS: CCDS4915

Canonical transcript exons

ENST00000371383 — 5 exons

Exon	Start	End
ENSE00000754695	46165387	46165563
ENSE00000754696	46167434	46168297
ENSE00001455105	46170053	46170114
ENSE00003347777	46159185	46161753
ENSE00003844805	46170808	46170980

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 99.56.

FANTOM5 (CAGE): breadth broad, TPM avg 4.6212 / max 213.9158, expressed in 782 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73816	3.5154	721
73815	0.8008	313
73817	0.1665	88
73814	0.0911	28
73813	0.0474	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.56	gold quality
bronchial epithelial cell	CL:0002328	97.77	gold quality
seminal vesicle	UBERON:0000998	96.98	gold quality
caput epididymis	UBERON:0004358	96.53	gold quality
bronchus	UBERON:0002185	96.51	gold quality
cauda epididymis	UBERON:0004360	95.41	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.64	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.08	gold quality
islet of Langerhans	UBERON:0000006	92.93	gold quality
endothelial cell	CL:0000115	92.61	gold quality
substantia nigra pars compacta	UBERON:0001965	92.46	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.10	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.74	gold quality
kidney epithelium	UBERON:0004819	91.48	gold quality
adenohypophysis	UBERON:0002196	88.72	gold quality
adult organism	UBERON:0007023	88.71	gold quality
pigmented layer of retina	UBERON:0001782	88.34	gold quality
retina	UBERON:0000966	88.31	gold quality
palpebral conjunctiva	UBERON:0001812	87.89	gold quality
Brodmann (1909) area 46	UBERON:0006483	87.53	gold quality
urethra	UBERON:0000057	87.51	gold quality
pituitary gland	UBERON:0000007	87.25	gold quality
prefrontal cortex	UBERON:0000451	86.96	gold quality
thyroid gland	UBERON:0002046	86.92	gold quality
right testis	UBERON:0004534	86.70	gold quality
nasal cavity mucosa	UBERON:0001826	86.65	gold quality
left lobe of thyroid gland	UBERON:0001120	86.62	gold quality
right lobe of thyroid gland	UBERON:0001119	86.13	gold quality
parotid gland	UBERON:0001831	86.04	gold quality
testis	UBERON:0000473	85.79	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

114 targeting ENPP5, 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-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-130A-3P	99.90	73.31	1861

Literature-anchored findings (GeneRIF, showing 3)

• The ENPP5 is able to cleave nicotinamide adenine dinucleotide (NAD), suggesting a potential role of this enzyme in NAD-based neurotransmission. (PMID:28898552)
• New oncogenic functions of LINE1 retroelement as a ceRNA for tumor suppressive microRNA miR-126 on ENPP5. (PMID:37352273)
• Regulation of ENPP5, a senescence-associated secretory phenotype factor, prevents skin aging. (PMID:38436793)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	enpp5	ENSDARG00000070625
mus_musculus	Enpp5	ENSMUSG00000023960
rattus_norvegicus	Enpp5	ENSRNOG00000010232
caenorhabditis_elegans		WBGENE00007753
caenorhabditis_elegans		WBGENE00007755
caenorhabditis_elegans		WBGENE00015283

Paralogs (6): ENPP4 (ENSG00000001561), ENPP2 (ENSG00000136960), ENPP3 (ENSG00000154269), ENPP6 (ENSG00000164303), ENPP7 (ENSG00000182156), ENPP1 (ENSG00000197594)

Protein

Protein identifiers

Ectonucleotide pyrophosphatase/phosphodiesterase family member 5 — Q9UJA9 (reviewed: Q9UJA9)

All UniProt accessions (1): Q9UJA9

UniProt curated annotations — full annotation on UniProt →

Function. Can hydrolyze NAD but cannot hydrolyze nucleotide di- and triphosphates. Lacks lysopholipase D activity. May play a role in neuronal cell communication.

Subcellular location. Secreted. Membrane.

Post-translational modifications. N-glycosylated.

Cofactor. Binds 2 Zn(2+) ions per subunit.

Similarity. Belongs to the nucleotide pyrophosphatase/phosphodiesterase family.

RefSeq proteins (3): NP_001277001, NP_001277002, NP_067547 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002591	Phosphodiest/P_Trfase	Family
IPR017850	Alkaline_phosphatase_core_sf	Homologous_superfamily

Pfam: PF01663

Catalyzed reactions (Rhea), 1 shown:

• NAD(+) + H2O = beta-nicotinamide D-ribonucleotide + AMP + 2 H(+) (RHEA:11800)

UniProt features (64 total): helix 18, strand 17, glycosylation site 8, binding site 7, sequence variant 5, turn 4, signal peptide 1, chain 1, transmembrane region 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5VEM	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UJA9-F1	88.56	0.77

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): 72 (nucleophile)

Ligand- & substrate-binding residues (7): 339; 36; 72; 191; 195; 238; 239

Glycosylation sites (8): 101, 158, 292, 329, 362, 369, 382, 389

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 113 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, TGCACTT_MIR519C_MIR519B_MIR519A, GCANCTGNY_MYOD_Q6, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, TCF4_Q5, GUO_HEX_TARGETS_UP, TTTGCAC_MIR19A_MIR19B, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, SENESE_HDAC3_TARGETS_DN, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, LIU_SOX4_TARGETS_UP, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ACID_ANHYDRIDES, GCACTTT_MIR175P_MIR20A_MIR106A_MIR106B_MIR20B_MIR519D, DODD_NASOPHARYNGEAL_CARCINOMA_DN, BRUINS_UVC_RESPONSE_VIA_TP53_GROUP_B

GO Biological Process (1): cell communication (GO:0007154)

GO Molecular Function (4): NAD+ diphosphatase activity (GO:0000210), zinc ion binding (GO:0008270), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): extracellular region (GO:0005576), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cellular process	1
dinucleotide phosphatase activity	1
transition metal ion binding	1
catalytic activity	1
cation binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ENPP5	CSRNP3	Q8WYN3	478
ENPP5	SPHKAP	Q2M3C7	457
ENPP5	SCGB3A2	Q96PL1	429
ENPP5	PPP1R14C	Q8TAE6	409
ENPP5	PDGFD	Q9GZP0	393
ENPP5	TRAPPC14	Q8WVR3	384
ENPP5	PLEKHA3	Q9HB20	375
ENPP5	B4GAT1	O43505	372
ENPP5	ITGA1	P56199	366
ENPP5	RCAN2	Q14206	362
ENPP5	ENTPD6	O75354	359
ENPP5	KRAS	P01116	353
ENPP5	SRRM1	Q8IYB3	353
ENPP5	NRCAM	Q92823	353
ENPP5	NTRK3	Q16288	351

IntAct

8 interactions, top by confidence:

A	B	Type	Score
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
ENPP5	CFTR	psi-mi:“MI:0915”(physical association)	0.370
CFTR	ENPP5	psi-mi:“MI:0915”(physical association)	0.370
SIGLECL1	ELAPOR2	psi-mi:“MI:0914”(association)	0.350
SKP1	RNASET2	psi-mi:“MI:0914”(association)	0.350
TIAM1	ENPP5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (9): ENPP5 (Synthetic Lethality), ENPP5 (Affinity Capture-RNA), ENPP5 (Affinity Capture-MS), ENPP5 (Affinity Capture-MS), ENPP5 (Affinity Capture-MS), ENPP5 (PCA), ENPP5 (Two-hybrid), ENPP5 (Cross-Linking-MS (XL-MS)), TRAK1 (Cross-Linking-MS (XL-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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	60
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

730 predictions. Top by Δscore:

Variant	Effect	Δscore
6:46161751:CTA:C	acceptor_gain	1.0000
6:46165379:ATAC:A	donor_loss	1.0000
6:46165380:TACT:T	donor_loss	1.0000
6:46165381:A:AC	donor_gain	1.0000
6:46165381:AC:A	donor_loss	1.0000
6:46165382:C:CC	donor_gain	1.0000
6:46165382:C:CG	donor_loss	1.0000
6:46165383:T:TG	donor_loss	1.0000
6:46165384:C:CC	donor_loss	1.0000
6:46165385:A:AC	donor_gain	1.0000
6:46165386:C:CC	donor_gain	1.0000
6:46165386:CA:C	donor_gain	1.0000
6:46165386:CACAG:C	donor_gain	1.0000
6:46165503:T:TC	acceptor_gain	1.0000
6:46167428:CCTTA:C	donor_loss	1.0000
6:46167429:CTTA:C	donor_loss	1.0000
6:46167431:TACC:T	donor_loss	1.0000
6:46167433:C:CA	donor_loss	1.0000
6:46167433:CCTT:C	donor_gain	1.0000
6:46170803:CTCA:C	donor_loss	1.0000
6:46170804:TCA:T	donor_loss	1.0000
6:46170805:CACC:C	donor_loss	1.0000
6:46170806:AC:A	donor_gain	1.0000
6:46170807:CC:C	donor_gain	1.0000
6:46161754:C:CC	acceptor_gain	0.9900
6:46165386:CACA:C	donor_gain	0.9900
6:46165406:A:AC	donor_gain	0.9900
6:46165406:ATT:A	donor_gain	0.9900
6:46165407:T:C	donor_gain	0.9900
6:46165503:T:C	acceptor_gain	0.9900

AlphaMissense

3184 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:46167848:A:G	W139R	0.997
6:46167848:A:T	W139R	0.997
6:46167552:A:C	S237R	0.996
6:46167552:A:T	S237R	0.996
6:46167554:T:G	S237R	0.996
6:46167893:A:G	W124R	0.996
6:46167893:A:T	W124R	0.996
6:46167550:T:A	D238V	0.994
6:46167553:C:A	S237I	0.994
6:46167544:C:T	G240E	0.992
6:46167547:T:G	H239P	0.992
6:46167861:A:C	S134R	0.992
6:46167861:A:T	S134R	0.992
6:46167863:T:G	S134R	0.992
6:46168153:C:T	G37E	0.992
6:46168156:T:A	D36V	0.992
6:46167544:C:A	G240V	0.991
6:46167550:T:G	D238A	0.990
6:46167551:C:G	D238H	0.990
6:46167912:C:A	W117C	0.990
6:46167912:C:G	W117C	0.990
6:46168155:A:C	D36E	0.990
6:46168155:A:T	D36E	0.990
6:46161699:G:T	A354D	0.989
6:46167549:A:C	D238E	0.989
6:46167549:A:T	D238E	0.989
6:46167610:A:G	L218P	0.989
6:46167550:T:C	D238G	0.988
6:46167914:A:G	W117R	0.988
6:46167914:A:T	W117R	0.988

dbSNP variants (sampled 300 via entrez): RS1000025781 (6:46167472 A>G), RS1000126170 (6:46164825 G>A), RS1000237618 (6:46164468 A>G), RS1000349599 (6:46171229 G>A), RS1000616781 (6:46159929 C>T), RS1001265650 (6:46172295 C>A,G), RS1001744779 (6:46165076 A>G), RS1002138181 (6:46169486 G>A), RS1002426634 (6:46169865 T>C), RS1002747769 (6:46163346 C>T), RS1002780048 (6:46163656 TAA>T), RS1002861071 (6:46172934 T>C), RS1003094304 (6:46166760 C>G,T), RS1004360568 (6:46165120 G>A,T), RS1004534785 (6:46171557 G>T)

Disease associations

OMIM: gene MIM:617001 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_1087	Blood protein levels	2.000000e-182

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	5
Nickel	decreases expression	3
sodium arsenite	affects methylation, decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
GSK-J4	decreases expression	1
biochanin A	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
incobotulinumtoxinA	increases expression	1
(+)-JQ1 compound	increases expression	1
Fulvestrant	decreases methylation	1
Vorinostat	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression, increases abundance	1
Cocaine	increases expression	1
Estradiol	decreases expression	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin M1	decreases expression	1

Clinical trials (associated diseases)

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