Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWF6HBP)

• DOT Name: ATPase family AAA domain-containing protein 3A (ATAD3A)
• Gene Name: ATAD3A
• Related Disease:
  Cervical cancer
  Harel-Yoon syndrome
  Human papillomavirus infection
  Breast cancer
  Breast carcinoma
  Cardiomyopathy
  Dystonia
  Endometriosis
  Hereditary spastic paraplegia
  Huntington disease
  Hypertrophic cardiomyopathy
  Lactic acidosis
  Lung adenocarcinoma
  Neoplasm
  Peripheral neuropathy
  Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal
  Prostate neoplasm
  Spinal muscular atrophy
  Vascular purpura
  Advanced cancer
  Prostate cancer
  Prostate carcinoma
• UniProt ID: ATD3A_HUMAN
• Pfam ID: PF00004 ; PF12037
• Sequence:
  MSWLFGINKGPKGEGAGPPPPLPPAQPGAEGGGDRGLGDRPAPKDKWSNFDPTGLERAAK
  AARELEHSRYAKDALNLAQMQEQTLQLEQQSKLKMRLEALSLLHTLVWAWSLCRAGAVQT
  QERLSGSASPEQVPAGECCALQEYEAAVEQLKSEQIRAQAEERRKTLSEETRQHQARAQY
  QDKLARQRYEDQLKQQQLLNEENLRKQEESVQKQEAMRRATVEREMELRHKNEMLRVEAE
  ARARAKAERENADIIREQIRLKAAEHRQTVLESIRTAGTLFGEGFRAFVTDWDKVTATVA
  GLTLLAVGVYSAKNATLVAGRFIEARLGKPSLVRETSRITVLEALRHPIQVSRRLLSRPQ
  DALEGVVLSPSLEARVRDIAIATRNTKKNRSLYRNILMYGPPGTGKTLFAKKLALHSGMD
  YAIMTGGDVAPMGREGVTAMHKLFDWANTSRRGLLLFVDEADAFLRKRATEKISEDLRAT
  LNAFLYRTGQHSNKFMLVLASNQPEQFDWAINDRINEMVHFDLPGQEERERLVRMYFDKY
  VLKPATEGKQRLKLAQFDYGRKCSEVARLTEGMSGREIAQLAVSWQATAYASEDGVLTEA
  MMDTRVQDAVQQHQQKMCWLKAEGPGRGDEPSPS
• Function: Essential for mitochondrial network organization, mitochondrial metabolism and cell growth at organism and cellular level. May play an important role in mitochondrial protein synthesis. May also participate in mitochondrial DNA replication. May bind to mitochondrial DNA D-loops and contribute to nucleoid stability. Required for enhanced channeling of cholesterol for hormone-dependent steroidogenesis. Involved in mitochondrial-mediated antiviral innate immunity.
• Tissue Specificity: Overexpressed in lung adenocarcinomas (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Definitive	Altered Expression	[1]
Harel-Yoon syndrome	DISM070O	Definitive	Semidominant	[2]
Human papillomavirus infection	DISX61LX	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[2]
Dystonia	DISJLFGW	Strong	Genetic Variation	[4]
Endometriosis	DISX1AG8	Strong	Biomarker	[5]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[6]
Huntington disease	DISQPLA4	Strong	Biomarker	[7]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[6]
Lactic acidosis	DISZI1ZK	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[2]
Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal	DISYLVKM	Strong	Autosomal recessive	[4]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[10]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[2]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[6]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[9]
Prostate cancer	DISF190Y	Limited	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[10]

3 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 ATPase family AAA domain-containing protein 3A (ATAD3A).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATPase family AAA domain-containing protein 3A (ATAD3A).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of ATPase family AAA domain-containing protein 3A (ATAD3A).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ATPase family AAA domain-containing protein 3A (ATAD3A).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ATPase family AAA domain-containing protein 3A (ATAD3A).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATPase family AAA domain-containing protein 3A (ATAD3A).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of ATPase family AAA domain-containing protein 3A (ATAD3A).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of ATPase family AAA domain-containing protein 3A (ATAD3A).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of ATPase family AAA domain-containing protein 3A (ATAD3A).	[17]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of ATPase family AAA domain-containing protein 3A (ATAD3A).	[18]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol decreases the expression of ATPase family AAA domain-containing protein 3A (ATAD3A).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ATPase family AAA domain-containing protein 3A (ATAD3A).	[20]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of ATPase family AAA domain-containing protein 3A (ATAD3A).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATPase family AAA domain-containing protein 3A (ATAD3A).	[24]

References

• [1] Human papillomavirus infection and expression of ATPase family AAA domain containing 3A, a novel anti-autophagy factor, in uterine cervical cancer.Int J Mol Med. 2011 Nov;28(5):689-96. doi: 10.3892/ijmm.2011.743. Epub 2011 Jul 8.
• [2] Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes. Am J Hum Genet. 2016 Oct 6;99(4):831-845. doi: 10.1016/j.ajhg.2016.08.007. Epub 2016 Sep 15.
• [3] Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein.Oncogene. 2016 Jan 21;35(3):333-43. doi: 10.1038/onc.2015.86. Epub 2015 Mar 30.
• [4] ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. Brain. 2017 Jun 1;140(6):1595-1610. doi: 10.1093/brain/awx094.
• [5] Identification of endometriosis-related genes by representational difference analysis of cDNA.Aust N Z J Obstet Gynaecol. 2012 Apr;52(2):140-5. doi: 10.1111/j.1479-828X.2011.01405.x. Epub 2012 Jan 25.
• [6] ATPase-deficient mitochondrial inner membrane protein ATAD3A disturbs mitochondrial dynamics in dominant hereditary spastic paraplegia.Hum Mol Genet. 2017 Apr 15;26(8):1432-1443. doi: 10.1093/hmg/ddx042.
• [7] ATAD3A oligomerization causes neurodegeneration by coupling mitochondrial fragmentation and bioenergetics defects.Nat Commun. 2019 Mar 26;10(1):1371. doi: 10.1038/s41467-019-09291-x.
• [8] ATPase family AAA domain-containing 3A is a novel anti-apoptotic factor in lung adenocarcinoma cells.J Cell Sci. 2010 Apr 1;123(Pt 7):1171-80. doi: 10.1242/jcs.062034.
• [9] ATAD3A on the Path to Cancer.Adv Exp Med Biol. 2019;1134:259-269. doi: 10.1007/978-3-030-12668-1_14.
• [10] ATPase family AAA domain containing 3A is an anti-apoptotic factor and a secretion regulator of PSA in prostate cancer.Int J Mol Med. 2011 Jul;28(1):9-15. doi: 10.3892/ijmm.2011.670. Epub 2011 Apr 6.
• [11] 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.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [16] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [17] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [18] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [19] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [22] 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.
• [23] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [24] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.