Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXTAG2V)

• DOT Name: ATP synthase subunit delta, mitochondrial (ATP5F1D)
• Synonyms: ATP synthase F1 subunit delta; F-ATPase delta subunit
• Gene Name: ATP5F1D
• Related Disease:
  Lung adenocarcinoma
  Common wart
  Dilated cardiomyopathy
  Hypoglycemia
  Metabolic disorder
  Patent ductus arteriosus
  Specific learning disability
  Urinary bladder cancer
  Urinary bladder neoplasm
  Colitis
  Mitochondrial disease
  Mitochondrial proton-transporting ATP synthase complex deficiency
  Obesity
  Mitochondrial complex 5 (ATP synthase) deficiency nuclear type 5
  Myocardial infarction
• UniProt ID: ATPD_HUMAN
• PDB ID: 8H9F; 8H9J; 8H9M; 8H9Q; 8H9S; 8H9T; 8H9U; 8H9V
• Pfam ID: PF02823 ; PF21335
• Sequence:
  MLPAALLRRPGLGRLVRHARAYAEAAAAPAAASGPNQMSFTFASPTQVFFNGANVRQVDV
  PTLTGAFGILAAHVPTLQVLRPGLVVVHAEDGTTSKYFVSSGSIAVNADSSVQLLAEEAV
  TLDMLDLGAAKANLEKAQAELVGTADEATRAEIQIRIEANEALVKALE
• 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 turnover 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.
• 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:HS01900-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[1]
Common wart	DISPREJ5	Strong	CausalMutation	[2]
Dilated cardiomyopathy	DISX608J	Strong	CausalMutation	[2]
Hypoglycemia	DISRCKR7	Strong	CausalMutation	[2]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[2]
Patent ductus arteriosus	DIS9P8YS	Strong	CausalMutation	[2]
Specific learning disability	DISNHKHK	Strong	CausalMutation	[2]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[3]
Colitis	DISAF7DD	moderate	Therapeutic	[4]
Mitochondrial disease	DISKAHA3	moderate	Genetic Variation	[2]
Mitochondrial proton-transporting ATP synthase complex deficiency	DISX6N3H	Supportive	Autosomal recessive	[2]
Obesity	DIS47Y1K	Disputed	Therapeutic	[5]
Mitochondrial complex 5 (ATP synthase) deficiency nuclear type 5	DISPZLW9	Limited	Autosomal recessive	[2]
Myocardial infarction	DIS655KI	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	ATP synthase subunit delta, mitochondrial (ATP5F1D) affects the response to substance of Methotrexate.	[25]

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 ATP synthase subunit delta, mitochondrial (ATP5F1D).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[18]

15 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 ATP synthase subunit delta, mitochondrial (ATP5F1D).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[15]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[16]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[20]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[22]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[23]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the expression of ATP synthase subunit delta, mitochondrial (ATP5F1D).	[24]

References

• [1] Proteomic analysis of lung adenocarcinoma: identification of a highly expressed set of proteins in tumors.Clin Cancer Res. 2002 Jul;8(7):2298-305.
• [2] Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. Am J Hum Genet. 2018 Mar 1;102(3):494-504. doi: 10.1016/j.ajhg.2018.01.020. Epub 2018 Feb 22.
• [3] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [4] Huang Qi Jian Zhong Pellet Attenuates TNBS-Induced Colitis in Rats via Mechanisms Involving Improvement of Energy Metabolism.Evid Based Complement Alternat Med. 2013;2013:574629. doi: 10.1155/2013/574629. Epub 2013 Jun 6.
• [5] A combination of resveratrol and quercetin induces browning in white adipose tissue of rats fed an obesogenic diet.Obesity (Silver Spring). 2017 Jan;25(1):111-121. doi: 10.1002/oby.21706. Epub 2016 Nov 22.
• [6] iTRAQ-Based Proteomic Analysis Reveals Recovery of Impaired Mitochondrial Function in Ischemic Myocardium by Shenmai Formula.J Proteome Res. 2018 Feb 2;17(2):794-803. doi: 10.1021/acs.jproteome.7b00450. Epub 2018 Jan 23.
• [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] 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.
• [10] 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.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] 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.
• [13] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [14] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [15] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [16] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [17] Morphological and molecular course of mitochondrial pathology in cultured human cells exposed long-term to Zidovudine. Environ Mol Mutagen. 2007 Apr-May;48(3-4):179-89. doi: 10.1002/em.20245.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [22] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [23] In vitro gene expression data supporting a DNA non-reactive genotoxic mechanism for ochratoxin A. Toxicol Appl Pharmacol. 2007 Apr 15;220(2):216-24.
• [24] Proteomic analysis reveals multiple patterns of response in cells exposed to a toxin mixture. Chem Res Toxicol. 2009 Jun;22(6):1077-85.
• [25] 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.