Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA5F480)

• DOT Name: ATP synthase F(0) complex subunit C2, mitochondrial (ATP5MC2)
• Synonyms: ATP synthase lipid-binding protein; ATP synthase membrane subunit c locus 2; ATP synthase proteolipid P2; ATP synthase proton-transporting mitochondrial F(0) complex subunit C2; ATPase protein 9; ATPase subunit c
• Gene Name: ATP5MC2
• Related Disease:
  Alzheimer disease
  B-cell neoplasm
  Clear cell renal carcinoma
  Head-neck squamous cell carcinoma
  Renal cell carcinoma
  Neoplasm
• UniProt ID: AT5G2_HUMAN
• Pfam ID: PF00137
• Sequence:
  MFACSKFVSTPSLVKSTSQLLSRPLSAVVLKRPEILTDESLSSLAVSCPLTSLVSSRSFQ
  TSAISRDIDTAAKFIGAGAATVGVAGSGAGIGTVFGSLIIGYARNPSLKQQLFSYAILGF
  ALSEAMGLFCLMVAFLILFAM
• 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:
  Cristae formation (R-HSA-8949613)
  Formation of ATP by chemiosmotic coupling (R-HSA-163210)
• BioCyc Pathway: MetaCyc:HS05994-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[3]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[4]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Limited	Biomarker	[5]

2 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 F(0) complex subunit C2, mitochondrial (ATP5MC2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of ATP synthase F(0) complex subunit C2, mitochondrial (ATP5MC2).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP synthase F(0) complex subunit C2, mitochondrial (ATP5MC2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP synthase F(0) complex subunit C2, mitochondrial (ATP5MC2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of ATP synthase F(0) complex subunit C2, mitochondrial (ATP5MC2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP synthase F(0) complex subunit C2, mitochondrial (ATP5MC2).	[10]

References

• [1] 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.
• [2] 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.
• [3] Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma.Oncogene. 2011 Mar 24;30(12):1390-401. doi: 10.1038/onc.2010.525. Epub 2010 Dec 6.
• [4] 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.
• [5] Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer.Epigenetics. 2016 Mar 3;11(3):237-46. doi: 10.1080/15592294.2016.1154246. Epub 2016 Mar 1.
• [6] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.