Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2JTT42)

• DOT Name: Nucleoside diphosphate kinase, mitochondrial (NME4)
• Synonyms: NDK; NDP kinase, mitochondrial; EC 2.7.4.6; Nucleoside diphosphate kinase D; NDPKD; nm23-H4
• Gene Name: NME4
• Related Disease:
  Advanced cancer
  Childhood myelodysplastic syndrome
  Colon cancer
  Colon carcinoma
  Myelodysplastic syndrome
  Non-small-cell lung cancer
  Oral cancer
  Colorectal carcinoma
  Kidney neoplasm
  Neuroblastoma
• UniProt ID: NDKM_HUMAN
• PDB ID: 1EHW
• EC Number: 2.7.4.6
• Pfam ID: PF00334
• Sequence:
  MGGLFWRSALRGLRCGPRAPGPSLLVRHGSGGPSWTRERTLVAVKPDGVQRRLVGDVIQR
  FERRGFTLVGMKMLQAPESVLAEHYQDLRRKPFYPALIRYMSSGPVVAMVWEGYNVVRAS
  RAMIGHTDSAEAAPGTIRGDFSVHISRNVIHASDSVEGAQREIQLWFQSSELVSWADGGQ
  HSSIHPA
• Function: Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP 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. Binds to anionic phospholipids, predominantly to cardiolipin; the binding inhibits its phosphotransfer activity. Acts as a mitochondria-specific NDK; its association with cardiolipin-containing mitochondrial inner membrane is coupled to respiration suggesting that ADP locally regenerated in the mitochondrion innermembrane space by its activity is directly taken up via ANT ADP/ATP translocase into the matrix space to stimulate respiratory ATP regeneration. Proposed to increase GTP-loading on dynamin-related GTPase OPA1 in mitochondria. In vitro can induce liposome cross-linking suggesting that it can cross-link inner and outer membranes to form contact sites, and promotes intermembrane migration of anionic phosphoplipids. Promotes the redistribution of cardiolipin between the mitochondrial inner membrane and outer membrane which is implicated in pro-apoptotic signaling.
• Tissue Specificity: Widely distributed. Found at very high levels in prostate, heart, liver, small intestine, and skeletal muscle tissues, and in low amounts in the brain and in blood leukocytes.
• 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

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Altered Expression	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[1]
Oral cancer	DISLD42D	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[5]
Kidney neoplasm	DISBNZTN	Limited	Altered Expression	[5]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Nucleoside diphosphate kinase, mitochondrial (NME4) affects the response to substance of Fluorouracil.	[24]
Afimoxifene	DMFORDT	Phase 2	Nucleoside diphosphate kinase, mitochondrial (NME4) decreases the response to substance of Afimoxifene.	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[13]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[14]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[22]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Nucleoside diphosphate kinase, mitochondrial (NME4).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nucleoside diphosphate kinase, mitochondrial (NME4).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Nucleoside diphosphate kinase, mitochondrial (NME4).	[20]

References

• [1] NME4 may enhance nonsmall cell lung cancer progression by overcoming cell cycle arrest and promoting cellular proliferation.Mol Med Rep. 2019 Aug;20(2):1629-1636. doi: 10.3892/mmr.2019.10413. Epub 2019 Jun 24.
• [2] High expression of ERCC1, FLT1, NME4 and PCNA associated with poor prognosis and advanced stages in myelodysplastic syndrome.Leuk Lymphoma. 2008 Jul;49(7):1297-305. doi: 10.1080/10428190802129918.
• [3] Impact of Phytolacca americana extracts on gene expression of colon cancer cells.Phytother Res. 2014 Feb;28(2):219-23. doi: 10.1002/ptr.4979. Epub 2013 Apr 4.
• [4] OncomiR-196 promotes an invasive phenotype in oral cancer through the NME4-JNK-TIMP1-MMP signaling pathway.Mol Cancer. 2014 Sep 19;13:218. doi: 10.1186/1476-4598-13-218.
• [5] Overexpression of nm23-H4 RNA in colorectal and renal tumours.Anticancer Res. 2001 Jul-Aug;21(4A):2821-5.
• [6] Acetylation of NDPK-D Regulates Its Subcellular Localization and Cell Survival.PLoS One. 2015 Oct 1;10(10):e0139616. doi: 10.1371/journal.pone.0139616. eCollection 2015.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [11] 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.
• [12] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [13] 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.
• [14] Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells. Carcinogenesis. 2006 May;27(5):916-24. doi: 10.1093/carcin/bgi312. Epub 2005 Dec 16.
• [15] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [16] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [17] 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.
• [18] 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.
• [19] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [20] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [23] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [24] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [25] 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.