NME1

Summary

NME1 (NME/NM23 nucleoside diphosphate kinase 1, HGNC:7849) is a protein-coding gene on chromosome 17q21.33, encoding Nucleoside diphosphate kinase A (P15531). Catalyzes the transfer of a gamma-phosphoryl group from a nucleoside triphosphate, mainly ATP, to a nucleoside diphosphate via a ping-pong mechanism involving a phosphohistidine intermediate, therefore contributing to the nucleoside triphosphate homeostasis.

This gene (NME1) was identified because of its reduced mRNA transcript levels in highly metastatic cells. Nucleoside diphosphate kinase (NDK) exists as a hexamer composed of ‘A’ (encoded by this gene) and ‘B’ (encoded by NME2) isoforms. Mutations in this gene have been identified in aggressive neuroblastomas. Two transcript variants encoding different isoforms have been found for this gene. Co-transcription of this gene and the neighboring downstream gene (NME2) generates naturally-occurring transcripts (NME1-NME2), which encodes a fusion protein comprised of sequence sharing identity with each individual gene product.

Source: NCBI Gene 4830 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 11 total
• Druggable target: yes
• MANE Select transcript: NM_000269

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7849
Approved symbol	NME1
Name	NME/NM23 nucleoside diphosphate kinase 1
Location	17q21.33
Locus type	gene with protein product
Status	Approved
Aliases	NM23, NM23-H1, NDPKA
Ensembl gene	ENSG00000239672
Ensembl biotype	protein_coding
OMIM	156490
Entrez	4830

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 19 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000013034, ENST00000336097, ENST00000393196, ENST00000456492, ENST00000465188, ENST00000475573, ENST00000480143, ENST00000487481, ENST00000511355, ENST00000512768, ENST00000880220, ENST00000880221, ENST00000880222, ENST00000911790, ENST00000911791, ENST00000911792, ENST00000911793, ENST00000911794, ENST00000911795, ENST00000911796, ENST00000911797, ENST00000911798, ENST00000911799

RefSeq mRNA: 2 — MANE Select: NM_000269 NM_000269, NM_198175

CCDS: CCDS11578, CCDS11579

Canonical transcript exons

ENST00000393196 — 5 exons

Exon	Start	End
ENSE00001874573	51153559	51153662
ENSE00001956093	51161728	51162168
ENSE00003555245	51159980	51160081
ENSE00003566364	51161160	51161272
ENSE00003614168	51155651	51155780

Expression profiles

Bgee: expression breadth ubiquitous, 151 present calls, max score 98.04.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6285 / max 339.3377, expressed in 23 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161735	136.0416	1819
161737	0.6169	22
161736	0.0116	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	98.04	gold quality
prefrontal cortex	UBERON:0000451	98.00	gold quality
hypothalamus	UBERON:0001898	97.65	gold quality
superior frontal gyrus	UBERON:0002661	97.56	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.56	gold quality
frontal cortex	UBERON:0001870	97.48	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.47	gold quality
islet of Langerhans	UBERON:0000006	97.41	gold quality
cerebral cortex	UBERON:0000956	97.38	gold quality
ganglionic eminence	UBERON:0004023	97.31	gold quality
right frontal lobe	UBERON:0002810	97.30	gold quality
Ammon’s horn	UBERON:0001954	97.25	gold quality
primary visual cortex	UBERON:0002436	97.23	gold quality
anterior cingulate cortex	UBERON:0009835	97.00	gold quality
vermiform appendix	UBERON:0001154	96.97	gold quality
frontal pole	UBERON:0002795	96.96	gold quality
amygdala	UBERON:0001876	96.90	gold quality
ventricular zone	UBERON:0003053	96.90	gold quality
temporal lobe	UBERON:0001871	96.86	gold quality
left adrenal gland	UBERON:0001234	96.73	gold quality
right adrenal gland	UBERON:0001233	96.72	gold quality
substantia nigra	UBERON:0002038	96.67	gold quality
mucosa of transverse colon	UBERON:0004991	96.65	gold quality
rectum	UBERON:0001052	96.56	gold quality
esophagus mucosa	UBERON:0002469	96.53	gold quality
left adrenal gland cortex	UBERON:0035825	96.42	gold quality
nucleus accumbens	UBERON:0001882	96.34	gold quality
epithelium of bronchus	UBERON:0002031	96.32	gold quality
adrenal gland	UBERON:0002369	96.32	gold quality
brain	UBERON:0000955	96.25	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	575.79
E-HCAD-8	yes	548.66
E-MTAB-8271	yes	315.05
E-HCAD-4	yes	140.32
E-CURD-88	yes	82.18
E-HCAD-10	yes	34.05
E-MTAB-9467	yes	31.55
E-MTAB-7316	yes	26.96
E-HCAD-13	yes	26.04
E-GEOD-125970	yes	21.67
E-HCAD-9	yes	14.62
E-CURD-46	yes	10.78
E-CURD-112	yes	8.67
E-MTAB-7052	no	645.59
E-ENAD-20	no	515.98

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

19 targeting NME1, 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-3148	99.97	75.06	6478
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-1272	99.34	68.79	878
HSA-MIR-4641	99.28	66.64	744
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-4764-5P	98.88	65.53	894
HSA-MIR-3908	98.75	67.31	1160
HSA-MIR-6852-3P	98.54	67.60	1468
HSA-MIR-1470	98.11	63.53	399
HSA-MIR-6783-5P	97.67	67.21	1528
HSA-MIR-708-3P	97.50	68.67	1082

Literature-anchored findings (GeneRIF, showing 40)

• There is an inverse correlation between nm23-H1 gene product expression and lymphatic vessel invasion in esophageal squamous cell carcinoma. (PMID:11319942)
• Identification of structural domains affecting transactivation potential (PMID:11726210)
• There was a significant difference of nm23-H1 protein expression level between 3-year survival and 7-year survival group (P < 0.05), and there was a relation between nm23-H1 protein expression level and prognosis of OSCC in single-factor Cox analysis. (PMID:11776896)
• The crystal struction of NDKA was determined. Comparison of NDK isoform structure was used to understand differences in NDKA metastasis suppressor functions. (PMID:11835509)
• MMTV-associated transcription factor binding sites increase nm23-H1 expression in human breast carcinoma cell lines. (PMID:11918081)
• metastasis-suppressive effect involves down-regulation of alpha1,3-FucT-VII and its product, sialyl Lewis X (PMID:11935309)
• The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2. (PMID:11960382)
• expression of nm23-H1 showed a negative relation to invasion, suggesting its use as a potential marker of myometrial invasion in complete hydatidiform moles (PMID:11963831)
• findings suggest that nm23-H1 is involved in the differentiation process of the trophoblast (PMID:11998956)
• NM23-H1 protein expression in human leukemia cell lines is related to cellular lineage and differentiation stages. (PMID:12007505)
• evidence for interaction of Nm23-H1 and the suppressor of kinase Ras(KSR)in mammalian cells; can phosphorylate KSR via a histidine-dependent pathway (PMID:12105213)
• Extracellular nucleoside diphosphate kinase NM23/NDPK modulates normal hematopoietic differentiation. The concentrations of NM23 present in plasma could have a physiologic role in supporting erythropoiesis and inhibiting excessive macrophage formation. (PMID:12135660)
• expression of NM23-H(1) gene in acute leukemia (AL) and evaluate the relationship between NM23-H(1) expression and clinical features (PMID:12137595)
• interacts with EBNA3C at sequences located between the glutamine- and proline-rich domains and can cooperate in activation of transcription in EBV-infected cells (PMID:12163590)
• Correlation of gene expression with histopathological findings and clinical outcome in ovarian and breast cancer patients (PMID:12174914)
• expression of nucleoside diphosphate kinase in Alzheimer disease and Down syndrome brains (PMID:12200143)
• has a possible role in tumor metastasis (review) (PMID:12405283)
• abnormal expressions of COX-2, p53, PCNA, and nm23 associate with malignant potential, lymph node metastasis and clinical stage, and they might therefore play a role in development of gastric cancer (PMID:12452062)
• Expression of this protein does not predict outcome in colorectal cancer patients. (PMID:12474051)
• isolation and characterization of the NM23-H1B gene (PMID:12601555)
• High nm23-H1 expression may induce cellular proliferation for the progression from low- to high- grade intraepithelial neoplasia of the uterine cervix. (PMID:12624546)
• p53 gene regulates this metastasis suppressor gene in cultured tumor cells (PMID:12669312)
• Nm23-H1 may play an important role in suppressing the early steps of metastasis in sporadic cases of colorectal carcinomas (PMID:12684753)
• Data suggest that the metastasis-suppressing activity of Nm23-H1 may depend on its oligomeric structure, but not on its NDP kinase activity. (PMID:12859952)
• Nm23-H1 activity is tissue-specific and is not associated with colorectal cancer progression and prognosis (PMID:12883690)
• expression of nm 23 and c-erbB-2 in primary tumor and metastases of colorectal adenocarcinoma showed that the incidence and expression of both protein markers in primary tumor tissue tended to increase after the appearance of liver metastases (PMID:12910292)
• Data report an X-ray structure at 2.0A resolution of nucleoside diphosphate kinase-A in complex with ADP, calcium and inorganic phosphate, products of ATP hydrolysis. (PMID:12972261)
• found that Nm23-H5 and NDP kinases A and B are differently distributed in spermatids and mature spermatozoa and could therefore be involved at various levels of sperm differentiation and function (PMID:14499630)
• The expression of nm23 is inversely correlated with the malignancy of gliomas,i.e.the lower expression indicates the higher malignancy. (PMID:14558955)
• expression of NM 23protein may reflect biological behaviour of the tumour and may appear to be an important factor in development of colorectal cancer metastases. (PMID:14664140)
• NM23-H1 possesses 3’-5’ exonuclease activity (PMID:14960567)
• Heparanase, CD44v6 and nm23 may play important roles in the invasive infiltration and lymph node metastasis in gastric carcinomas. (PMID:15040016)
• nm23-H1 has a role in development of diffuse large B-cell lymphoma (PMID:15073128)
• a role of these tumor suppressor and metastasis suppressor genes in the evolution and progression of NSCLC (PMID:15129904)
• NDPK-A behaves as a metastasis promoter at least in human neuroblastoma derived from NB69 cells. (PMID:15280446)
• Enhanced expression of nm23H(1) protein can effectively inhibit colon cancer metastasis and improve prognosis of sporadic colon cancer patients. (PMID:15334673)
• Decreased nm23 was seen in poorly differentiated retinoblastomas and in retinoblastomas with invasiveness. May relate to molecular mechanisms and more accurate prediction of invasion and metastasis of retinoblastoma. (PMID:15512982)
• Nm23 protein is involved in the process of metastasis development in squamous cell carcinoma of the vulva. (PMID:15568401)
• Semi-quantitative RT-PCR revealed reduced mRNA expression of Nm23 in breast cancer brain metastasis. (PMID:15592684)
• results suggest nm23H1 might be involved in invasion and metastasis of esophageal squamous cell carcinoma but had no statistical correlation with HPV16 (PMID:15645378)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nme2b.2	ENSDARG00000099420
danio_rerio	nme2b.1	ENSDARG00000103791
mus_musculus	Nme1	ENSMUSG00000037601
rattus_norvegicus	Nme1	ENSRNOG00000002693
rattus_norvegicus		ENSRNOG00000062879

Paralogs (8): NME8 (ENSG00000086288), NME3 (ENSG00000103024), NME4 (ENSG00000103202), NME5 (ENSG00000112981), NME7 (ENSG00000143156), NME6 (ENSG00000172113), NME9 (ENSG00000181322), NME2 (ENSG00000243678)

Protein

Protein identifiers

Nucleoside diphosphate kinase A — P15531 (reviewed: P15531)

Alternative names: Farnesyl diphosphate kinase NME1, Histidine protein kinase NME1, Metastasis inhibition factor nm23, NM23-H1, Non-specific serine/threonine protein kinase NME1, Nucleoside diphoshate kinase 1, Putative 3’-5’-DNA exonuclease NDK1, Putative granzyme A-activated DNA endonuclease, Tumor metastatic process-associated protein

All UniProt accessions (5): A0A384MTW7, C9K028, E5RHP0, E7ERL0, P15531

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the transfer of a gamma-phosphoryl group from a nucleoside triphosphate, mainly ATP, to a nucleoside diphosphate via a ping-pong mechanism involving a phosphohistidine intermediate, therefore contributing to the nucleoside triphosphate homeostasis. Also phosphorylates geranyl pyrophosphate (GPP) and farnesyl pyrophosphate (FPP), linking it to isoprenoid metabolism. Additionally, functions as a non-specific serine/threonine kinase and histidine protein kinase, transferring phosphoryl groups from its active site to target proteins. May function as a Mg(2+)-dependent single-stranded DNA endonuclease as part of the SET complex, cooperating with the 3’-5’ exonuclease TREX1 to mediate apoptotic DNA fragmentation in cytotoxic T lymphocytes. Reported to nick one DNA strand, enabling TREX1 to remove nucleotides from the free 3’ end, enhancing DNA damage and suppressing DNA end reannealing and repair. Has been shown to cleave double strands DNA within the 3’-portions of both 5’-SHS silencer and NHE basal promoter element of the PDGFA gene, potentially repressing its transcription. May also function as a Mg(2+)-dependent 3’-5’ DNA exonuclease, excising nucleotides from 3’ single-stranded DNA or DNA with 3’ single strand overhangs, suggesting a role in DNA nucleolytic processing. Involved in the regulation of tumor metastasis and cellular differentiation. Also required for cell motility. May control, with NME2, AcCoA usage between histone acetylation and fatty acid synthesis, possibly by binding and releasing AcCoA at transcriptionally active chromatin regions in proximity to histone acetyltransferase (HAT).

Subunit / interactions. Homohexamer. Homodimer; disulfide-linked; under oxidative stress, the hexameric form is dissociated into dimers. Homotrimer. Heterohexamer of two different chains: A/NME1 and B/NME2 resulting in different ratios of the respective subunits (A5B or A4B2 or A3B3 or A2B4 or AB5). Interacts (hexameric form) with PRUNE1: this interaction requires phosphorylation of NME1. Component of the SET complex, composed of at least ANP32A, APEX1, HMGB2, NME1, SET and TREX1. Interacts directly with SET; this interaction inhibits single-stranded DNA endonuclease activity of NME1 and this inhibition is released by GZMA cleavage of SET. Interacts with TREX1; this interaction is initiated only following translocation to the nucleus. NDP kinase isoenzymes result from random association of two different kinds of polypeptides. Interacts (oxidized form) with TXNRD1; this interaction is probably indirect and TXN is necessary for reduction of oxidized form through the NADPH-TXNRD1-TXN system. Interacts with FBXO24.

Subcellular location. Cytoplasm. Nucleus. Cell membrane.

Tissue specificity. Ubiquitously expressed. Expressed in tumor cell lines.

Post-translational modifications. Autophosphorylated at His-118 results in the formation of a phospho-enzyme intermediate and consequently activation of nucleoside diphosphate kinase activity and serine/threonine protein kinase activity. Cys-109 is oxidized to various oxidation states including intra- and inter-disulfide cross-links, glutathionylation and sulfonic acid formation in response to oxidative stress. Glutathionylation and sulfonic acid formation lead to the loss of nucleoside diphosphate activity. Glutathionylation, and sulfonic acid formation are dependent of dimeric state and intramolecular disulfide bond formation between Cys-4 and Cys-145. The intramolecular disulfide bond between Cys-4 and Cys-145 is formed under oxidative stress and triggers a large conformational change that destabilizes and dissociates the hexamer into dimers thus creating a suitable environment for the oxidation of Cys-109 to sulfonic acid and glutathionylation. An intra-disulfide cross-link can be reduced through the NADPH-TXNRD1-TXN system resulting into a fully activated hexamer; this system reduces the Cys-4-Cys-145 intra-disulfide bond to free sulfhydryls by interacting with the redox-active center of TXN that can be sequentially reduced by TXNRD1 and NADPH. CoAlation at Cys-109, in response to oxidative stress, negatively regulates the nucleoside diphosphate kinase activity. The N-terminus is blocked. Acetylated by GCN5, which prevents recognition by the SCF-FBXO24 E3 ubiquitin ligase, thereby protecting the protein from ubiquitination and proteasomal degradation. Ubiquitinated by the SCF-FBXO24 E3 ubiquitin ligase, leading to proteasomal degradation.

Activity regulation. Autophosphorylation at His-118 increases nucleoside diphosphate kinase activity and serine/threonine protein kinase activity. Under cellular stress conditions, nucleoside diphosphate kinase activity is inhibited through both covalent and non-covalent binding by CoenzymeA (CoA); a non-covalent binding of coenzyme A (CoA) via its ADP moiety to the nucleotide-binding pocket of NME1 and a covalent binding of CoA through CoAlation (disulfide linkage to cysteine) at Cys-109. Nucleoside diphosphate kinase activity is regulated by oxido-reduction system coupled to its oligomeric state; disulfide bond formation, glutathionylation and oxidation at Cys-109 inhibit the nucleoside diphosphate kinase activity; intra- and specific inter-disulfide bonds are reduced through the NADPH-TXNRD1-TXN system thus activating nucleoside diphosphate kinase activity. Interaction with the SET complex inhibits the DNA endonuclease activity. 3’-5’-DNA exonuclease activity is inhibited by potassium chloride (KCL), with the optimal KCl concentration less than or equal to 20 mM and ATP.

Miscellaneous. The role of this protein in tumor development and progression is uncertain. This protein is found in reduced amount in some tumor cells of high metastatic potential. However, increased NME1 levels correlate with aggressive tumor features in neuroblastoma. May have distinct if not opposite roles in different tumors.

Similarity. Belongs to the NDK family.

Isoforms (3)

UniProt ID	Names	Canonical?
P15531-1	1, NM23-H1A	yes
P15531-2	2, NM23-H1B
P22392-2	3, NM23-LV

RefSeq proteins (2): NP_000260, NP_937818 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001564	Nucleoside_diP_kinase	Family
IPR023005	Nucleoside_diP_kinase_AS	Active_site
IPR034907	NDK-like_dom	Domain
IPR036850	NDK-like_dom_sf	Homologous_superfamily

Pfam: PF00334

Enzyme classification (BRENDA):

• EC 2.7.13.3 — histidine kinase (BRENDA: 124 organisms, 213 substrates, 62 inhibitors, 5 Km, 2 kcat entries)
• EC 2.7.4.6 — nucleoside-diphosphate kinase (BRENDA: 102 organisms, 269 substrates, 41 inhibitors, 131 Km, 29 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
GTP	0.07–5.5	22
ADP	0.024–1.26	17
ATP	0.005–4.6	14
DTDP	0.001–1.1	11
CTP	0.04–12	8
UTP	0.11–27	8
DCDP	0.01–0.56	6
GDP	0.02–0.049	5
UDP	0.1–0.28	5
TTP	0.89–5.28	4
ATP	0.1–5.75	2
8-BROMO-IDP	0.033–0.06	2
CDP	0.05–0.69	2
DGDP	0.14–0.25	2
DCTP	0.02	1

Catalyzed reactions (Rhea), 12 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• a ribonucleoside 5’-diphosphate + ATP = a ribonucleoside 5’-triphosphate + ADP (RHEA:18113)
• (2E,6E)-farnesyl diphosphate + ATP = (2E,6E)-farnesyl triphosphate + ADP (RHEA:21544)
• UDP + ATP = UTP + ADP (RHEA:25098)
• CDP + ATP = CTP + ADP (RHEA:25237)
• dCDP + ATP = dCTP + ADP (RHEA:27678)
• dTDP + ATP = dTTP + ADP (RHEA:27682)
• GDP + ATP = GTP + ADP (RHEA:27686)
• IDP + ATP = ITP + ADP (RHEA:30347)
• a 2’-deoxyribonucleoside 5’-diphosphate + ATP = a 2’-deoxyribonucleoside 5’-triphosphate + ADP (RHEA:44640)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)
• (2E)-geranyl diphosphate + ATP = (2E)-geranyl triphosphate + ADP (RHEA:84295)

UniProt features (99 total): binding site 39, mutagenesis site 24, helix 13, modified residue 7, strand 5, disulfide bond 4, cross-link 2, initiator methionine 1, chain 1, active site 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
8OOV	X-RAY DIFFRACTION	1.7
1UCN	X-RAY DIFFRACTION	2
3L7U	X-RAY DIFFRACTION	2.1
2HVD	X-RAY DIFFRACTION	2.15
1JXV	X-RAY DIFFRACTION	2.2
2HVE	X-RAY DIFFRACTION	2.4
5UI4	X-RAY DIFFRACTION	2.75
4ENO	X-RAY DIFFRACTION	2.8
9GD6	ELECTRON MICROSCOPY	2.8
9GD8	ELECTRON MICROSCOPY	3.3
9GD9	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15531-F1	97.47	0.98

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): 118 (pros-phosphohistidine intermediate)

Ligand- & substrate-binding residues (39): 52; 52; 52; 58; 58; 88; 88; 88; 88; 94; 94; 94 …

Post-translational modifications (9): 56, 109, 109, 109, 120, 122, 125, 85, 100

Disulfide bonds (4): 4–145, 4–109, 109–145, 109

Mutagenesis-validated functional residues (24):

Position	Phenotype
4	increases resistance to oxidative stress. impairs intramolecular disulfide bonds formation under oxidative stress. decre
5	almost completely loss of 3’-5’-dna exonuclease activity. slightly decreases nucleoside diphoshate kinase activity.
5	reduces of about 80% of wild type 3’-5’-dna exonuclease activity. slightly decreases nucleoside diphoshate kinase activi
12	does not affect homohexamer formation. dramatically reduces nucleoside diphosphate kinase activity. markedly decreases 3
33	almost completely loss of 3’-5’-dna exonuclease activity.
34	does not affect homohexamer formation. slightly reduces nucleoside diphosphate kinase activity. markedly decreases 3’-5’
44	does not affect autophosphorylation. significantly decreases nucleoside diphosphate kinase activity.
54	almost completely loss of 3’-5’-dna exonuclease activity. slightly decreases nucleoside diphoshate kinase activity.
56	reduced interaction with fbxo24.
56	increased interaction with fbxo24.
58	abolishes coa binding.
60	does not affect gtp binding; when associated with gly-118. does not affect atp binding; when associated with gly-118.
85	less ubiquitinated than wt in vitro.
94	abolishes coa binding.
96	increases motility of carcinoma cells. decreases farnesyl diphosphate kinase activity. decreases geranyl-diphosphate kin
109	does not affect nucleoside diphosphate kinase activity. impairs glutathionylation. does not affect nucleoside diphosphat
109	significantly increases resistance to oxidative stress. does not affect intramolecular disulfide bonds formation under o
118	decreases autophosphorylation. some loss of motility of carcinoma cells. loss of farnesyl diphosphate kinase activity. l
118	does not affect gtp binding; when associated with trp-60. does not affect atp binding; when associated with trp-60.
120	limited increase in motility of carcinoma cells. increases farnesyl diphosphate kinase activity. increases geranyl-dipho
121	almost completely loss of 3’-5’-dna exonuclease activity.
129	almost completely loss of 3’-5’-dna exonuclease activity. completely lost nucleoside diphoshate kinase activity.
145	increases resistance to oxidative stress. impairs intramolecular disulfide bonds formation under oxidative stress. decre

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-499943	Interconversion of nucleotide di- and triphosphates
R-HSA-9748787	Azathioprine ADME
R-HSA-9755088	Ribavirin ADME
R-HSA-1430728	Metabolism
R-HSA-15869	Metabolism of nucleotides
R-HSA-9748784	Drug ADME

MSigDB gene sets: 504 (showing top): TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOMF_ENDONUCLEASE_ACTIVITY, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, SHIPP_DLBCL_VS_FOLLICULAR_LYMPHOMA_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, MODULE_255, BASSO_B_LYMPHOCYTE_NETWORK, PAL_PRMT5_TARGETS_UP, GOMF_NUCLEASE_ACTIVITY, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_317, GOBP_PYRIMIDINE_NUCLEOSIDE_TRIPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (21): GTP biosynthetic process (GO:0006183), UTP biosynthetic process (GO:0006228), CTP biosynthetic process (GO:0006241), DNA catabolic process (GO:0006308), apoptotic DNA fragmentation (GO:0006309), isoprenoid metabolic process (GO:0006720), endocytosis (GO:0006897), nervous system development (GO:0007399), lactation (GO:0007595), negative regulation of cell population proliferation (GO:0008285), nucleoside diphosphate metabolic process (GO:0009132), nucleoside triphosphate biosynthetic process (GO:0009142), cell differentiation (GO:0030154), protein hexamerization (GO:0034214), regulation of fatty acid biosynthetic process (GO:0042304), regulation of apoptotic process (GO:0042981), ITP biosynthetic process (GO:0046042), acetyl-CoA catabolic process (GO:0046356), positive regulation of epithelial cell proliferation (GO:0050679), nucleotide metabolic process (GO:0009117), mammary gland development (GO:0030879)

GO Molecular Function (23): magnesium ion binding (GO:0000287), DNA binding (GO:0003677), RNA binding (GO:0003723), DNA endonuclease activity (GO:0004520), DNA nuclease activity (GO:0004536), nucleoside diphosphate kinase activity (GO:0004550), protein histidine kinase activity (GO:0004673), ATP binding (GO:0005524), 3’-5’-DNA exonuclease activity (GO:0008296), kinase activity (GO:0016301), phosphotransferase activity, phosphate group as acceptor (GO:0016776), GDP binding (GO:0019003), identical protein binding (GO:0042802), ribosomal small subunit binding (GO:0043024), ADP binding (GO:0043531), farnesyl diphosphate kinase activity (GO:0047887), coenzyme A binding (GO:0120225), succinyl-CoA binding (GO:0120226), acetyl-CoA binding (GO:1905502), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), cytoplasm (GO:0005737), early endosome (GO:0005769), cytosol (GO:0005829), membrane (GO:0016020), ruffle membrane (GO:0032587), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Drug ADME	2
Metabolism of nucleotides	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anion binding	3
cellular anatomical structure	3
purine ribonucleotide biosynthetic process	2
purine ribonucleoside triphosphate biosynthetic process	2
pyrimidine ribonucleoside triphosphate biosynthetic process	2
pyrimidine ribonucleotide biosynthetic process	2
DNA nuclease activity	2
nucleoside phosphate metabolic process	2
nucleic acid binding	2
phosphotransferase activity, phosphate group as acceptor	2
adenyl ribonucleotide binding	2
transferase activity, transferring phosphorus-containing groups	2
nucleoside phosphate binding	2
heterocyclic compound binding	2
acyl-CoA binding	2
GTP metabolic process	1
UTP metabolic process	1
CTP metabolic process	1
DNA metabolic process	1
nucleic acid catabolic process	1
DNA catabolic process	1
apoptotic nuclear changes	1
lipid metabolic process	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
system development	1
body fluid secretion	1
mammary gland development	1
milk ejection reflex	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
nucleoside triphosphate metabolic process	1
nucleoside phosphate biosynthetic process	1
cellular developmental process	1
protein complex oligomerization	1
fatty acid biosynthetic process	1
regulation of fatty acid metabolic process	1

Protein interactions and networks

STRING

6379 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NME1	APEX1	P27695	980
NME1	ANP32A	P39687	978
NME1	TIAM1	Q13009	953
NME1	PRUNE1	Q86TP1	912
NME1	SET	Q01105	864
NME1	GZMA	P12544	863
NME1	STRAP	Q9Y3F4	813
NME1	ITGB1BP1	O14713	710
NME1	MEN1	O00255	694
NME1	TREX1	Q9NSU2	659
NME1	BRMS1	Q9HCU9	643
NME1	GAPDH	P00354	635
NME1	ARF6	P26438	625
NME1	BRMS1L	Q5PSV4	621
NME1	TP53	P04637	591

IntAct

203 interactions, top by confidence:

A	B	Type	Score
NME1	NME1	psi-mi:“MI:0915”(physical association)	0.950
NME1	NME1	psi-mi:“MI:0844”(phosphotransfer reaction)	0.950
NME4	NME1	psi-mi:“MI:0915”(physical association)	0.900
NME1	NME4	psi-mi:“MI:0915”(physical association)	0.900
NME1	NME4	psi-mi:“MI:0914”(association)	0.900
NME1	POLR1C	psi-mi:“MI:0915”(physical association)	0.870
POLR1C	NME1	psi-mi:“MI:0915”(physical association)	0.870
NME1	NTAQ1	psi-mi:“MI:0915”(physical association)	0.820
NTAQ1	NME1	psi-mi:“MI:0915”(physical association)	0.820

BioGRID (291): NME1 (Two-hybrid), NME3 (Two-hybrid), NME4 (Two-hybrid), POLR1C (Two-hybrid), TNPO2 (Two-hybrid), PID1 (Two-hybrid), SREK1IP1 (Two-hybrid), NME1 (Affinity Capture-MS), WDYHV1 (Two-hybrid), NME4 (Two-hybrid), POLR1C (Two-hybrid), GORASP2 (Two-hybrid), NME3 (Two-hybrid), NME1 (Two-hybrid), NME1 (Co-fractionation)

ESM2 similar proteins: A4J0S4, A5D5U8, A6N0M9, B0C4I0, B0JHT4, B0TBN6, B1WQB7, B1XIE7, B2IX22, B4FK49, B8DBZ7, B8FZD1, B8HUM7, C0ZCD6, C1KWM9, O81372, P15531, P19804, P39207, P47919, P47921, P49740, P52174, P52175, P70010, P70011, P74494, Q02254, Q07661, Q0W8X1, Q251Q1, Q2FRE6, Q2JPL4, Q3AFJ7, Q3M7K5, Q50KA8, Q56E62, Q5KXU2, Q5RC56, Q63DL7

Diamond homologs: A0A3Q0KJ78, A2BNH4, A2BU01, A2CDK0, A2VD68, A4J0S4, A5D5U8, A6N0M9, A8G244, B0C4I0, B0JHT4, B0TBN6, B1I1P4, B1WQB7, B2IX22, B4FK49, B8DBZ7, B8FZD1, B8HUM7, B9E6K9, C0ZCD6, C1KWM9, O00746, O29491, O49203, O57535, O60361, O64903, O81372, P08879, P15531, P15532, P19804, P22392, P22887, P27950, P31103, P36010, P39207, P47919

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
CDK1	up-regulates	NME1	phosphorylation
NME1	up-regulates	NME1	phosphorylation
CyclinB/CDK1	up-regulates	NME1	phosphorylation
NME1	“up-regulates activity”	NME1	phosphorylation
NME1	“down-regulates quantity by repression”	CCN2	“transcriptional regulation”
NME1	“down-regulates quantity by repression”	L1CAM	“transcriptional regulation”
NME1	“down-regulates quantity by repression”	FZD1	“transcriptional regulation”
NME1	“down-regulates quantity by repression”	LPAR1	“transcriptional regulation”
NME1	“down-regulates quantity by repression”	MET	“transcriptional regulation”
NME1	“down-regulates quantity by repression”	MMP2	“transcriptional regulation”
NME1	“down-regulates quantity by repression”	NETO2	“transcriptional regulation”
NME1	“down-regulates quantity by repression”	PTN	“transcriptional regulation”
NME1	“down-regulates quantity by repression”	SMO	“transcriptional regulation”
NME1	down-regulates	KSR1	phosphorylation
SET	down-regulates	NME1	binding
NME1	unknown	NME1	phosphorylation
NME1	unknown	KSR1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial protein import	5	14.2×	3e-03
Complex I biogenesis	5	14.0×	3e-03
Aerobic respiration and respiratory electron transport	7	10.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial electron transport, NADH to ubiquinone	5	21.3×	1e-03
proton motive force-driven mitochondrial ATP synthesis	6	18.8×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	2
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1006 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:51155690:A:C	K12N	0.997
17:51155690:A:T	K12N	0.997
17:51161736:T:A	I117K	0.997
17:51160031:T:C	F60L	0.996
17:51160033:C:A	F60L	0.996
17:51160033:C:G	F60L	0.996
17:51161163:T:A	W78R	0.996
17:51161163:T:C	W78R	0.996
17:51161206:G:A	G92E	0.994
17:51161206:G:T	G92V	0.994
17:51161258:C:G	C109W	0.994
17:51161738:C:G	H118D	0.994
17:51161744:A:C	S120R	0.994
17:51161746:T:A	S120R	0.994
17:51161746:T:G	S120R	0.994
17:51155697:G:T	G15W	0.993
17:51161731:C:A	N115K	0.993
17:51161731:C:G	N115K	0.993
17:51155688:A:G	K12E	0.992
17:51155698:G:A	G15E	0.992
17:51161194:G:C	R88P	0.992
17:51161244:C:A	R105S	0.992
17:51161742:G:A	G119D	0.992
17:51161786:T:C	F134L	0.992
17:51161788:T:A	F134L	0.992
17:51161788:T:G	F134L	0.992
17:51155689:A:T	K12I	0.991
17:51161257:G:A	C109Y	0.991
17:51161736:T:G	I117R	0.991
17:51161738:C:A	H118N	0.991

dbSNP variants (sampled 300 via entrez): RS1000492510 (17:51151603 A>C), RS1000530944 (17:51156408 G>A), RS1000652012 (17:51155423 TAAATC>T), RS1000668282 (17:51156083 G>A,T), RS1000931976 (17:51162040 A>G,T), RS1001220633 (17:51162426 A>G,T), RS1001879779 (17:51161971 C>A,T), RS1002199874 (17:51155086 A>C,G), RS1002878432 (17:51160412 A>G), RS1003378381 (17:51159767 G>C), RS1003613487 (17:51153666 A>G), RS1004374672 (17:51162394 G>C), RS1004407330 (17:51162619 G>C), RS1004712998 (17:51156989 G>A), RS1005280029 (17:51152055 G>A,T)

Disease associations

OMIM: gene MIM:156490 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2159 (SINGLE PROTEIN), CHEMBL4296074 (PROTEIN FAMILY)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.70	Kd	2019	nM	CHEMBL5653589
5.70	ED50	2019	nM	CHEMBL5653589
5.12	Kd	7652	nM	CHEMBL3752910
5.12	ED50	7652	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 23 total; 2 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148873: Binding affinity to human NME1 incubated for 45 mins by Kinobead based pull down assay	kd	2.0194	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148873: Binding affinity to human NME1 incubated for 45 mins by Kinobead based pull down assay	kd	7.6518	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	9
sodium arsenite	decreases expression, increases expression	5
(+)-JQ1 compound	decreases expression	5
Benzo(a)pyrene	increases expression, increases methylation	5
bisphenol A	affects binding, increases reaction, decreases expression	3
trichostatin A	affects cotreatment, increases expression	3
Cisplatin	affects cotreatment, increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression, increases metabolic processing	3
Tretinoin	affects cotreatment, decreases expression	3
Aflatoxin B1	affects expression, increases expression	3
Particulate Matter	affects cotreatment, decreases expression, increases abundance	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	2
Arsenic Trioxide	increases expression	2
Atrazine	decreases expression, decreases phosphorylation	2
Copper	affects binding	2
Doxorubicin	decreases response to substance, decreases expression	2
Estradiol	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Zinc	affects binding, decreases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
Okadaic Acid	affects cotreatment, decreases expression, increases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
naringenin	increases expression	1
chlorophyllin	decreases expression	1
methylselenic acid	decreases expression	1
arsenite	affects localization	1
o,p’-DDT	increases expression	1
sulforaphane	affects binding	1
cobaltous chloride	decreases expression	1

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4700053	Binding	Binding affinity to NDKA in human K562 cells at 1 mM incubated for 2 hrs by LC-MS/MS analysis based pull down assay relative to control	Understanding the mechanism of action of pyrrolo[3,2-b]quinoxaline-derivatives as kinase inhibitors — RSC Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3CF	Abcam HEK293T NME1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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