Details of Drug Off-Target (DOT)

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

• DOT Name: ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1)
• Synonyms: ATP synthase lipid-binding protein; ATP synthase membrane subunit c locus 1; ATP synthase proteolipid P1; ATP synthase proton-transporting mitochondrial F(0) complex subunit C1; ATPase protein 9; ATPase subunit c
• Gene Name: ATP5MC1
• Related Disease:
  Non-insulin dependent diabetes
  Alzheimer disease
  B-cell neoplasm
  Clear cell renal carcinoma
  CLN2 Batten disease
  Head-neck squamous cell carcinoma
  Late infantile neuronal ceroid lipofuscinosis
  Neuronal ceroid lipofuscinosis
• UniProt ID: AT5G1_HUMAN
• PDB ID: 8H9F; 8H9J; 8H9M; 8H9Q; 8H9S; 8H9T; 8H9U; 8H9V
• Pfam ID: PF00137
• Sequence:
  MQTAGALFISPALIRCCTRGLIRPVSASFLNSPVNSSKQPSYSNFPLQVARREFQTSVVS
  RDIDTAAKFIGAGAATVGVAGSGAGIGTVFGSLIIGYARNPSLKQQLFSYAILGFALSEA
  MGLFCLMVAFLILFAM
• 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(0) domain. A homomeric c-ring of probably 10 subunits is part of the complex rotary element.
• 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:
  Formation of ATP by chemiosmotic coupling (R-HSA-163210)
  Cristae formation (R-HSA-8949613)
  Mitochondrial protein import (R-HSA-1268020)
• BioCyc Pathway: MetaCyc:ENSG00000159199-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[4]
CLN2 Batten disease	DISZC5YB	Strong	Genetic Variation	[5]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[6]
Late infantile neuronal ceroid lipofuscinosis	DISI3RIL	Strong	Biomarker	[7]
Neuronal ceroid lipofuscinosis	DIS9A4K4	Strong	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[14]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[21]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[25]

1 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 ATP synthase F(0) complex subunit C1, mitochondrial (ATP5MC1).	[18]

References

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• [2] Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease.Hum Mol Genet. 2015 Nov 15;24(22):6492-504. doi: 10.1093/hmg/ddv358. Epub 2015 Sep 10.
• [3] Comparative analysis of testis transcriptomes associated with male infertility in triploid cyprinid fish.Reprod Fertil Dev. 2019 Jan;31(2):248-260. doi: 10.1071/RD18034.
• [4] Systematic Analysis of the Expression of the Mitochondrial ATP Synthase (Complex V) Subunits in Clear Cell Renal Cell Carcinoma.Transl Oncol. 2017 Aug;10(4):661-668. doi: 10.1016/j.tranon.2017.06.002. Epub 2017 Jun 30.
• [5] Distinct early molecular responses to mutations causing vLINCL and JNCL presage ATP synthase subunit C accumulation in cerebellar cells.PLoS One. 2011 Feb 17;6(2):e17118. doi: 10.1371/journal.pone.0017118.
• [6] Impaired mitochondrial protein synthesis in head and neck squamous cell carcinoma.Mitochondrion. 2015 Sep;24:113-21. doi: 10.1016/j.mito.2015.07.123. Epub 2015 Aug 1.
• [7] Abnormal degradative pathway of mitochondrial ATP synthase subunit c in late infantile neuronal ceroid-lipofuscinosis (Batten disease).Am J Med Genet. 1995 Jun 5;57(2):254-9. doi: 10.1002/ajmg.1320570229.
• [8] CLN6 p.I154del mutation causing late infantile neuronal ceroid lipofuscinosis in a large consanguineous Moroccan family.Indian J Pediatr. 2013 Aug;80(8):694-6. doi: 10.1007/s12098-012-0889-3. Epub 2012 Nov 22.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [15] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [16] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [23] 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.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.