Details of Drug Off-Target (DOT)

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

• DOT Name: ATP synthase subunit epsilon, mitochondrial (ATP5F1E)
• Synonyms: ATPase subunit epsilon; ATP synthase F1 subunit epsilon
• Gene Name: ATP5F1E
• Related Disease:
  Anemia
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Carcinoma
  CLN2 Batten disease
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Cystic fibrosis
  Dermatomyositis
  Lactic acidosis
  Leukodystrophy
  Neuralgia
  Obesity
  Neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Thyroid tumor
  Mitochondrial proton-transporting ATP synthase complex deficiency
  Mitochondrial complex V (ATP synthase) deficiency nuclear type 3
  Mitochondrial disease
• UniProt ID: ATP5E_HUMAN
• PDB ID: 8H9F; 8H9J; 8H9M; 8H9Q; 8H9S; 8H9T; 8H9U; 8H9V
• Pfam ID: PF04627
• Sequence: MVAYWRQAGLSYIRYSQICAKAVRDALKTEFKANAEKTSGSNVKIVKVKKE
• Function: Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(1) domain and of the central stalk which is part of the complex rotary element. Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Thermogenesis (hsa04714)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Cristae formation (R-HSA-8949613)
  Formation of ATP by chemiosmotic coupling (R-HSA-163210)
• BioCyc Pathway: MetaCyc:HS04727-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anemia	DISTVL0C	Strong	Genetic Variation	[1]
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Posttranslational Modification	[2]
Carcinoma	DISH9F1N	Strong	Altered Expression	[3]
CLN2 Batten disease	DISZC5YB	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[5]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[6]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[7]
Dermatomyositis	DIS50C5O	Strong	Biomarker	[8]
Lactic acidosis	DISZI1ZK	Strong	Genetic Variation	[9]
Leukodystrophy	DISVY1TT	Strong	Genetic Variation	[10]
Neuralgia	DISWO58J	Strong	Biomarker	[11]
Obesity	DIS47Y1K	Strong	Genetic Variation	[12]
Neoplasm	DISZKGEW	moderate	Biomarker	[13]
Thyroid cancer	DIS3VLDH	moderate	Altered Expression	[13]
Thyroid gland carcinoma	DISMNGZ0	moderate	Altered Expression	[13]
Thyroid gland papillary carcinoma	DIS48YMM	moderate	Altered Expression	[13]
Thyroid tumor	DISLVKMD	moderate	Altered Expression	[13]
Mitochondrial proton-transporting ATP synthase complex deficiency	DISX6N3H	Supportive	Autosomal recessive	[14]
Mitochondrial complex V (ATP synthase) deficiency nuclear type 3	DIS3BTBU	Limited	Autosomal recessive	[15]
Mitochondrial disease	DISKAHA3	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[21]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[22]
Aspirin	DM672AH	Approved	Aspirin increases the expression of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[23]
Nicotine	DMWX5CO	Approved	Nicotine increases the splicing of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[24]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[29]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of ATP synthase subunit epsilon, mitochondrial (ATP5F1E).	[30]

References

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• [2] Down-regulation of mitochondrial ATPase by hypermethylation mechanism in chronic myeloid leukemia is associated with multidrug resistance.Ann Oncol. 2010 Jul;21(7):1506-1514. doi: 10.1093/annonc/mdp569. Epub 2009 Dec 27.
• [3] The mitochondrial ATPase inhibitory factor 1 triggers a ROS-mediated retrograde prosurvival and proliferative response.Mol Cell. 2012 Mar 30;45(6):731-42. doi: 10.1016/j.molcel.2012.01.008. Epub 2012 Feb 16.
• [4] An Autophagy Modifier Screen Identifies Small Molecules Capable of Reducing Autophagosome Accumulation in a Model of CLN3-Mediated Neurodegeneration.Cells. 2019 Nov 27;8(12):1531. doi: 10.3390/cells8121531.
• [5] ATP Synthase Subunit Epsilon Overexpression Promotes Metastasis by Modulating AMPK Signaling to Induce Epithelial-to-Mesenchymal Transition and Is a Poor Prognostic Marker in Colorectal Cancer Patients.J Clin Med. 2019 Jul 21;8(7):1070. doi: 10.3390/jcm8071070.
• [6] Identification of mitochondrial F(1)F(0)-ATP synthase interacting with galectin-3 in colon cancer cells.Cancer Sci. 2008 Oct;99(10):1884-91. doi: 10.1111/j.1349-7006.2008.00901.x.
• [7] Culture-Independent Identification of Nontuberculous Mycobacteria in Cystic Fibrosis Respiratory Samples.PLoS One. 2016 Apr 19;11(4):e0153876. doi: 10.1371/journal.pone.0153876. eCollection 2016.
• [8] Pyruvate kinase M2 and the mitochondrial ATPase Inhibitory Factor 1 provide novel biomarkers of dermatomyositis: a metabolic link to oncogenesis.J Transl Med. 2017 Feb 10;15(1):29. doi: 10.1186/s12967-017-1136-5.
• [9] Defective mitochondrial ATPase due to rare mtDNA m.8969G>A mutation-causing lactic acidosis, intellectual disability, and poor growth.Neurogenetics. 2018 Jan;19(1):49-53. doi: 10.1007/s10048-018-0537-9. Epub 2018 Jan 19.
• [10] A previously undescribed leukodystrophy in Leigh syndrome associated with T9176C mutation of the mitochondrial ATPase 6 gene.Dev Med Child Neurol. 2007 Jan;49(1):65-7. doi: 10.1017/s0012162207000163.x.
• [11] An integrated review on new targets in the treatment of neuropathic pain.Korean J Physiol Pharmacol. 2019 Jan;23(1):1-20. doi: 10.4196/kjpp.2019.23.1.1. Epub 2018 Dec 26.
• [12] Tall stature and progressive overweight in mitochondrial encephalopathy.J Inherit Metab Dis. 2003;26(7):720-2. doi: 10.1023/b:boli.0000005647.71704.25.
• [13] Molecular Analysis by Gene Expression of Mitochondrial ATPase Subunits in Papillary Thyroid Cancer: Is ATP5E Transcript a Possible Early Tumor Marker?.Med Sci Monit. 2015 Jun 16;21:1745-51. doi: 10.12659/MSM.893597.
• [14] Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit. Hum Mol Genet. 2010 Sep 1;19(17):3430-9. doi: 10.1093/hmg/ddq254. Epub 2010 Jun 21.
• [15] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [16] Infantile mitochondrial disorder associated with subclinical hypothyroidism is caused by a rare mitochondrial DNA 8691A>G mutation: a case report.Neuroreport. 2015 Jul 8;26(10):588-92. doi: 10.1097/WNR.0000000000000392.
• [17] 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.
• [18] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [19] 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.
• [20] Extremely low copper concentrations affect gene expression profiles of human prostate epithelial cell lines. Chem Biol Interact. 2010 Oct 6;188(1):214-9.
• [21] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [22] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [23] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [24] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [25] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [26] 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.
• [27] 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.
• [28] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [30] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.