Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0CA0GF)

• DOT Name: Nucleoside diphosphate kinase 3 (NME3)
• Synonyms: NDK 3; NDP kinase 3; EC 2.7.4.6; DR-nm23; Nucleoside diphosphate kinase C; NDPKC; nm23-H3
• Gene Name: NME3
• Related Disease:
  Colorectal carcinoma
  Neoplasm
  Adult glioblastoma
  Breast carcinoma
  Cardiac failure
  Ciliopathy
  Congestive heart failure
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Ovarian cancer
  Ovarian neoplasm
  Neuroblastoma
• UniProt ID: NDK3_HUMAN
• PDB ID: 1ZS6
• EC Number: 2.7.4.6
• Pfam ID: PF00334
• Sequence:
  MICLVLTIFANLFPAACTGAHERTFLAVKPDGVQRRLVGEIVRRFERKGFKLVALKLVQA
  SEELLREHYAELRERPFYGRLVKYMASGPVVAMVWQGLDVVRTSRALIGATNPADAPPGT
  IRGDFCIEVGKNLIHGSDSVESARREIALWFRADELLCWEDSAGHWLYE
• Function: Catalyzes the phosphorylation of ribonucleosides and deoxyribonucleoside diphosphates, other than ATP, into the corresponding triphosphates with ATP as the major phosphate donor. The ATP gamma phosphate is transferred to the nucleoside diphosphate beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate. Through the catalyzed exchange of gamma-phosphate between di- and triphosphonucleosides participates in regulation of intracellular nucleotide homeostasis. Inhibits granulocyte differentiation. May be required for ciliary function during renal development; Independently of its kinase activity, facilitates mitochondrial tethering prior to membrane fusion through its direct membrane-binding and hexamerization. Implicated in repair of both single- and double-stranded breaks in DNA through its association with the ribonucleotide reductase complex (RNR complex) via its interaction with the histone acetyltransferase KAT5, this interaction enables recruitment of NME3 at DNA damage sites where it plays a role in the repair of DNA, independently of its kinase activity.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Pyrimidine metabolism (hsa00240)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Interconversion of nucleotide di- and triphosphates (R-HSA-499943)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Cardiac failure	DISDC067	Strong	Biomarker	[3]
Ciliopathy	DIS10G4I	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[5]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[5]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Nucleoside diphosphate kinase 3 (NME3) decreases the response to substance of Afimoxifene.	[20]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Nucleoside diphosphate kinase 3 (NME3).	[7]

13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nucleoside diphosphate kinase 3 (NME3).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nucleoside diphosphate kinase 3 (NME3).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Nucleoside diphosphate kinase 3 (NME3).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nucleoside diphosphate kinase 3 (NME3).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Nucleoside diphosphate kinase 3 (NME3).	[12]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Nucleoside diphosphate kinase 3 (NME3).	[13]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Nucleoside diphosphate kinase 3 (NME3).	[14]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Nucleoside diphosphate kinase 3 (NME3).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Nucleoside diphosphate kinase 3 (NME3).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nucleoside diphosphate kinase 3 (NME3).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nucleoside diphosphate kinase 3 (NME3).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Nucleoside diphosphate kinase 3 (NME3).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Nucleoside diphosphate kinase 3 (NME3).	[19]

References

• [1] Inhibitory effect of upregulated DR-nm23 expression on invasion and metastasis in colorectal cancer.Eur J Cancer Prev. 2013 Nov;22(6):512-22. doi: 10.1097/CEJ.0b013e328361625d.
• [2] Gene structure, promoter activity, and chromosomal location of the DR-nm23 gene, a related member of the nm23 gene family.Cancer Res. 1997 Mar 15;57(6):1180-7.
• [3] Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure.Circulation. 2017 Feb 28;135(9):881-897. doi: 10.1161/CIRCULATIONAHA.116.022852. Epub 2016 Dec 7.
• [4] The nucleoside-diphosphate kinase NME3 associates with nephronophthisis proteins and is required for ciliary function during renal development.J Biol Chem. 2018 Sep 28;293(39):15243-15255. doi: 10.1074/jbc.RA117.000847. Epub 2018 Aug 15.
• [5] Nucleoside Diphosphate Kinase-3 (NME3) Enhances TLR5-Induced NFB Activation.Mol Cancer Res. 2018 Jun;16(6):986-999. doi: 10.1158/1541-7786.MCR-17-0603. Epub 2018 Mar 9.
• [6] DR-nm23 gene expression in neuroblastoma cells: relationship to integrin expression, adhesion characteristics, and differentiation.J Natl Cancer Inst. 1997 Sep 3;89(17):1300-10. doi: 10.1093/jnci/89.17.1300.
• [7] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [8] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [9] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [10] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [13] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [14] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [17] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [18] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.