NT5M

Summary

NT5M (5’,3’-nucleotidase, mitochondrial, HGNC:15769) is a protein-coding gene on chromosome 17p11.2, encoding 5’(3’)-deoxyribonucleotidase, mitochondrial (Q9NPB1). Dephosphorylates specifically the 5’ and 2’(3’)-phosphates of uracil and thymine deoxyribonucleotides, and so protects mitochondrial DNA replication from excess dTTP.

This gene encodes a 5’ nucleotidase that localizes to the mitochondrial matrix. This enzyme dephosphorylates the 5’- and 2’(3’)-phosphates of uracil and thymine deoxyribonucleotides. The gene is located within the Smith-Magenis syndrome region on chromosome 17.

Source: NCBI Gene 56953 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 46 total
• Druggable target: yes
• MANE Select transcript: NM_020201

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15769
Approved symbol	NT5M
Name	5’,3’-nucleotidase, mitochondrial
Location	17p11.2
Locus type	gene with protein product
Status	Approved
Aliases	dNT-2, dNT2, mdN
Ensembl gene	ENSG00000205309
Ensembl biotype	protein_coding
OMIM	605292
Entrez	56953

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 3 protein_coding, 3 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000389022, ENST00000470418, ENST00000478373, ENST00000480529, ENST00000483704, ENST00000582909, ENST00000616989, ENST00000879604

RefSeq mRNA: 1 — MANE Select: NM_020201 NM_020201

CCDS: CCDS32581

Canonical transcript exons

ENST00000389022 — 5 exons

Exon	Start	End
ENSE00001504694	17344794	17344908
ENSE00003503594	17306543	17306643
ENSE00003683043	17323185	17323245
ENSE00003846878	17346805	17347663
ENSE00003846894	17303373	17303817

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 87.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.9457 / max 110.0044, expressed in 1257 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159736	3.7158	1238
159737	0.2299	112

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	87.13	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.04	gold quality
mononuclear cell	CL:0000842	86.79	gold quality
apex of heart	UBERON:0002098	86.54	gold quality
leukocyte	CL:0000738	85.97	gold quality
hindlimb stylopod muscle	UBERON:0004252	84.71	gold quality
right frontal lobe	UBERON:0002810	84.34	gold quality
anterior cingulate cortex	UBERON:0009835	83.52	gold quality
cingulate cortex	UBERON:0003027	83.46	gold quality
gastrocnemius	UBERON:0001388	83.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.19	gold quality
left testis	UBERON:0004533	83.12	gold quality
right testis	UBERON:0004534	82.97	gold quality
prefrontal cortex	UBERON:0000451	82.31	gold quality
muscle of leg	UBERON:0001383	82.26	gold quality
right hemisphere of cerebellum	UBERON:0014890	81.39	gold quality
Brodmann (1909) area 9	UBERON:0013540	81.25	gold quality
testis	UBERON:0000473	80.89	gold quality
cerebellar hemisphere	UBERON:0002245	80.88	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	80.85	gold quality
cerebellar cortex	UBERON:0002129	80.69	gold quality
neocortex	UBERON:0001950	80.32	gold quality
heart left ventricle	UBERON:0002084	80.23	gold quality
amygdala	UBERON:0001876	79.84	gold quality
nucleus accumbens	UBERON:0001882	79.83	gold quality
frontal cortex	UBERON:0001870	79.76	gold quality
cardiac ventricle	UBERON:0002082	79.68	gold quality
primary visual cortex	UBERON:0002436	79.56	gold quality
cerebellum	UBERON:0002037	79.20	gold quality
caudate nucleus	UBERON:0001873	79.17	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.97

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

28 targeting NT5M, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-6868-5P	99.06	65.69	1284
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-493-3P	97.50	66.44	731
HSA-MIR-4786-5P	97.45	67.89	924
HSA-MIR-1225-3P	97.29	64.60	876
HSA-MIR-342-5P	97.25	64.10	817
HSA-MIR-6762-5P	96.55	64.62	972
HSA-MIR-6845-5P	96.55	64.65	969
HSA-MIR-3135A	96.41	65.30	494
HSA-MIR-4772-5P	95.60	68.04	617
HSA-MIR-3174	94.63	63.64	577

Literature-anchored findings (GeneRIF, showing 4)

• Overproduction in cultured cells and functional aspects (PMID:12124385)
• structures of dNT-2 in complex with bound phosphate and beryllium trifluoride plus thymidine as model for a phosphoenzyme-product complex (PMID:12352955)
• substrate specificity analysis of the human mitochondrial deoxyribonucleotidase (PMID:16004879)
• An alternative splice variant of the mdN gene containing an 18-nucleotide insertion encoding 6 amino acids (GKWPAT) at the 3’-end of the penultimate exon 4 has been characterized. (PMID:24506201)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nt5m	ENSMUSG00000032615
rattus_norvegicus	Nt5m	ENSRNOG00000003332

Paralogs (1): NT5C (ENSG00000125458)

Protein

Protein identifiers

5’(3’)-deoxyribonucleotidase, mitochondrial — Q9NPB1 (reviewed: Q9NPB1)

Alternative names: Deoxy-5’-nucleotidase 2

All UniProt accessions (5): Q9NPB1, J3QLR5, J3QRN4, K7EPW8, Q2I378

UniProt curated annotations — full annotation on UniProt →

Function. Dephosphorylates specifically the 5’ and 2’(3’)-phosphates of uracil and thymine deoxyribonucleotides, and so protects mitochondrial DNA replication from excess dTTP. Has only marginal activity towards dIMP and dGMP.

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion.

Tissue specificity. Highly expressed in heart, brain and skeletal muscle. Detected at very low levels in kidney and pancreas.

Similarity. Belongs to the 5’(3’)-deoxyribonucleotidase family.

RefSeq proteins (1): NP_064586* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010708	5’(3’)-deoxyribonucleotidase	Family
IPR023214	HAD_sf	Homologous_superfamily
IPR036412	HAD-like_sf	Homologous_superfamily

Pfam: PF06941

UniProt features (34 total): binding site 11, helix 9, strand 6, turn 4, active site 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
4MUM	X-RAY DIFFRACTION	1.27
6G2M	X-RAY DIFFRACTION	1.37
4NFL	X-RAY DIFFRACTION	1.38
1Q92	X-RAY DIFFRACTION	1.4
4L6A	X-RAY DIFFRACTION	1.4
6G2L	X-RAY DIFFRACTION	1.48
4YIK	X-RAY DIFFRACTION	1.48
1Q91	X-RAY DIFFRACTION	1.6
4MWO	X-RAY DIFFRACTION	1.67
1Z4M	X-RAY DIFFRACTION	1.7
1Z4K	X-RAY DIFFRACTION	1.75
1MH9	X-RAY DIFFRACTION	1.8
1Z4J	X-RAY DIFFRACTION	1.8
1Z4L	X-RAY DIFFRACTION	1.8
2JAU	X-RAY DIFFRACTION	1.8
4L6C	X-RAY DIFFRACTION	1.8
6G22	X-RAY DIFFRACTION	1.85
2JAW	X-RAY DIFFRACTION	1.95
1Z4I	X-RAY DIFFRACTION	1.98
1Z4P	X-RAY DIFFRACTION	2
1Z4Q	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NPB1-F1	91.24	0.87

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 (2): 41 (nucleophile); 43 (proton donor)

Ligand- & substrate-binding residues (11): 77; 96; 130; 165; 176; 41; 43; 43; 49; 75; 76

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-73621	Pyrimidine catabolism

MSigDB gene sets: 104 (showing top): REACTOME_PYRIMIDINE_CATABOLISM, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_PYRIMIDINE_CONTAINING_COMPOUND_CATABOLIC_PROCESS, GOBP_PYRIMIDINE_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_PYRIMIDINE_NUCLEOTIDE_CATABOLIC_PROCESS, GOBP_PYRIMIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_CATABOLIC_PROCESS, KEGG_PURINE_METABOLISM, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_NUCLEOSIDE_PHOSPHATE_CATABOLIC_PROCESS, GOBP_NUCLEOSIDE_MONOPHOSPHATE_METABOLIC_PROCESS, WONG_MITOCHONDRIA_GENE_MODULE

GO Biological Process (6): DNA replication (GO:0006260), pyrimidine deoxyribonucleotide catabolic process (GO:0009223), dUMP catabolic process (GO:0046079), nucleobase-containing compound metabolic process (GO:0006139), nucleotide metabolic process (GO:0009117), deoxyribonucleotide catabolic process (GO:0009264)

GO Molecular Function (5): nucleotide binding (GO:0000166), nucleotidase activity (GO:0008252), 5’-nucleotidase activity (GO:0008253), metal ion binding (GO:0046872), hydrolase activity (GO:0016787)

GO Cellular Component (2): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nucleotide catabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	1
DNA biosynthetic process	1
pyrimidine nucleotide catabolic process	1
pyrimidine deoxyribonucleotide metabolic process	1
deoxyribose phosphate catabolic process	1
pyrimidine deoxyribonucleoside monophosphate catabolic process	1
pyrimidine deoxyribonucleotide catabolic process	1
dUMP metabolic process	1
primary metabolic process	1
nucleoside phosphate metabolic process	1
catabolic process	1
deoxyribonucleotide metabolic process	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
phosphatase activity	1
nucleotidase activity	1
cation binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

538 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NT5M	COPS3	Q9UNS2	893
NT5M	TYMP	P19971	797
NT5M	NME4	O00746	790
NT5M	DGUOK	P78532	786
NT5M	NT5C3A	Q9H0P0	773
NT5M	CMPK1	P30085	761
NT5M	AK3	Q9UIJ7	685
NT5M	AK4	P27144	681
NT5M	LLGL1	Q15334	671
NT5M	NT5C1A	Q9BXI3	654
NT5M	DTYMK	P23919	633
NT5M	CMPK2	Q5EBM0	632
NT5M	TK2	O00142	628
NT5M	NT5C1B	Q96P26	627
NT5M	TK1	P04183	624

IntAct

2 interactions, top by confidence:

A	B	Type	Score
PB2		psi-mi:“MI:0914”(association)	0.350

BioGRID (8): NT5M (Synthetic Growth Defect), NT5M (Negative Genetic), PIK3CD (Negative Genetic), NT5M (Negative Genetic), NT5M (Positive Genetic), NT5M (Positive Genetic), NT5M (Positive Genetic), NT5M (Positive Genetic)

ESM2 similar proteins: A4FV98, A4IFH5, A5PK51, A6NDG6, D3YWP0, D3ZDK7, P10950, P24298, P25325, P50336, P60487, Q0VD18, Q12788, Q1JPJ0, Q2KJJ5, Q2T9S4, Q32NY4, Q3UGR5, Q3ZBF9, Q501J2, Q5BJJ5, Q5F4B1, Q5I0D5, Q5R4B4, Q5U2W5, Q5ZIW1, Q60HD5, Q6AYR6, Q6SKR2, Q6XQN6, Q86VU5, Q8BIG7, Q8C4J7, Q8CG76, Q8CHP8, Q8IZ69, Q8NE01, Q8R2H9, Q8TCD5, Q8TCT1

Diamond homologs: P59935, Q5UPP9, Q5UQH3, Q7W066, Q7WC96, Q7WQA0, Q9NPB1, Q8TCD5, Q8VCE6, Q9JM14

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1694 predictions. Top by Δscore:

Variant	Effect	Δscore
17:17303715:G:GT	donor_gain	1.0000
17:17303790:G:GG	donor_gain	1.0000
17:17303810:GGC:G	donor_gain	1.0000
17:17303816:GC:G	donor_gain	1.0000
17:17306641:AAAG:A	donor_loss	1.0000
17:17306643:AGT:A	donor_loss	1.0000
17:17306644:G:GG	donor_gain	1.0000
17:17306645:T:A	donor_loss	1.0000
17:17323183:A:AG	acceptor_gain	1.0000
17:17323184:G:GG	acceptor_gain	1.0000
17:17344769:C:G	acceptor_gain	1.0000
17:17344785:T:TA	acceptor_gain	1.0000
17:17344787:C:CA	acceptor_gain	1.0000
17:17344790:CCA:C	acceptor_loss	1.0000
17:17344792:A:AG	acceptor_gain	1.0000
17:17344793:G:GC	acceptor_gain	1.0000
17:17344793:GT:G	acceptor_gain	1.0000
17:17344793:GTAT:G	acceptor_gain	1.0000
17:17303787:GCA:G	donor_gain	0.9900
17:17303814:GAGC:G	donor_gain	0.9900
17:17303818:G:GG	donor_gain	0.9900
17:17306537:TCTCA:T	acceptor_loss	0.9900
17:17306538:CTCA:C	acceptor_loss	0.9900
17:17306540:CA:C	acceptor_loss	0.9900
17:17306541:A:AG	acceptor_gain	0.9900
17:17306542:G:GG	acceptor_gain	0.9900
17:17306542:GGA:G	acceptor_gain	0.9900
17:17306641:AAA:A	donor_gain	0.9900
17:17306642:AA:A	donor_gain	0.9900
17:17306644:GT:G	donor_gain	0.9900

AlphaMissense

1482 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:17323203:C:G	C129W	0.999
17:17344859:G:C	K165N	0.999
17:17344859:G:T	K165N	0.999
17:17344885:T:A	I174K	0.998
17:17344891:A:T	D176V	0.998
17:17346825:T:A	W189R	0.998
17:17346825:T:C	W189R	0.998
17:17346900:T:A	W214R	0.998
17:17346900:T:C	W214R	0.998
17:17346902:G:C	W214C	0.998
17:17346902:G:T	W214C	0.998
17:17303677:G:C	D43H	0.997
17:17303678:A:T	D43V	0.997
17:17323202:G:A	C129Y	0.997
17:17323205:C:T	T130I	0.997
17:17344857:A:C	K165Q	0.997
17:17344857:A:G	K165E	0.997
17:17344882:T:C	L173P	0.997
17:17344891:A:C	D176A	0.997
17:17344892:C:A	D176E	0.997
17:17344892:C:G	D176E	0.997
17:17346827:G:C	W189C	0.997
17:17346827:G:T	W189C	0.997
17:17346840:T:C	F194L	0.997
17:17346842:C:A	F194L	0.997
17:17346842:C:G	F194L	0.997
17:17303679:C:A	D43E	0.996
17:17303679:C:G	D43E	0.996
17:17323193:T:A	V126D	0.996
17:17323199:T:A	I128N	0.996

dbSNP variants (sampled 300 via entrez): RS1000031266 (17:17322619 G>A), RS1000044415 (17:17306194 C>T), RS1000046179 (17:17328359 C>T), RS1000069304 (17:17311561 T>A), RS1000101140 (17:17323754 GAGC>G), RS1000293823 (17:17317226 T>A), RS1000371979 (17:17339808 G>C), RS1000486578 (17:17340092 A>C,G), RS1000487433 (17:17326192 C>T), RS1000504652 (17:17322990 T>G), RS1000514540 (17:17334629 C>T), RS1000531820 (17:17328408 G>C,T), RS1000570837 (17:17307398 T>C,G), RS1000582203 (17:17317500 C>T), RS1000717822 (17:17331814 T>A,C)

Disease associations

OMIM: gene MIM:605292 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010107_15	L-selectin levels	2.000000e-06
GCST010396_85	Gut microbiota (bacterial taxa, hurdle binary method)	9.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008202	L-Selectin measurement
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3751654 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Adenosine turnover

ChEMBL bioactivities

1 potent at pChembl≥5 of 2 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.89	Ki	128	nM	CHEMBL3752084

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Tenofovir	decreases expression	1
Resveratrol	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Amiodarone	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Fluorouracil	increases expression	1
Niclosamide	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Okadaic Acid	decreases expression	1
S-Nitrosoglutathione	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3755233	Binding	Inhibition of N-terminal hexaHis-tagged human mitochondrial 5’(3’)-deoxynucleotidase using dUMP as substrate	Structure-based design of a bisphosphonate 5(3)-deoxyribonucleotidase inhibitor — Medchemcomm

Clinical trials (associated diseases)

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