Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU3MCTN)

• DOT Name: ATP synthase subunit O, mitochondrial (ATP5PO)
• Synonyms: ATP synthase peripheral stalk subunit OSCP; Oligomycin sensitivity conferral protein; OSCP
• Gene Name: ATP5PO
• Related Disease:
  Alzheimer disease
  Hypothyroidism
  Autoimmune disease
  Non-insulin dependent diabetes
• UniProt ID: ATPO_HUMAN
• PDB ID: 8H9E; 8H9I; 8H9L; 8H9P; 8H9S; 8H9T; 8H9U; 8H9V
• Pfam ID: PF00213
• Sequence:
  MAAPAVSGLSRQVRCFSTSVVRPFAKLVRPPVQVYGIEGRYATALYSAASKQNKLEQVEK
  ELLRVAQILKEPKVAASVLNPYVKRSIKVKSLNDITAKERFSPLTTNLINLLAENGRLSN
  TQGVVSAFSTMMSVHRGEVPCTVTSASPLEEATLSELKTVLKSFLSQGQVLKLEAKTDPS
  ILGGMIVRIGEKYVDMSVKTKIQKLGRAMREIV
• 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 and the peripheric stalk, which acts as a stator to hold the catalytic alpha(3)beta(3) subcomplex and subunit a/ATP6 static relative to the rotary elements.
• 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:HS08368-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Hypothyroidism	DISR0H6D	Strong	Therapeutic	[2]
Autoimmune disease	DISORMTM	Limited	Biomarker	[3]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	ATP synthase subunit O, mitochondrial (ATP5PO) affects the response to substance of Josamycin.	[18]

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 O, mitochondrial (ATP5PO).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP synthase subunit O, mitochondrial (ATP5PO).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of ATP synthase subunit O, mitochondrial (ATP5PO).	[15]

9 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 O, mitochondrial (ATP5PO).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP synthase subunit O, mitochondrial (ATP5PO).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of ATP synthase subunit O, mitochondrial (ATP5PO).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP synthase subunit O, mitochondrial (ATP5PO).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP synthase subunit O, mitochondrial (ATP5PO).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of ATP synthase subunit O, mitochondrial (ATP5PO).	[11]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of ATP synthase subunit O, mitochondrial (ATP5PO).	[12]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of ATP synthase subunit O, mitochondrial (ATP5PO).	[16]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of ATP synthase subunit O, mitochondrial (ATP5PO).	[17]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Dihydroartemisinin	DMBXVMZ	Approved	Dihydroartemisinin affects the binding of ATP synthase subunit O, mitochondrial (ATP5PO).	[13]

References

• [1] Cyclophilin D deficiency attenuates mitochondrial F1Fo ATP synthase dysfunction via OSCP in Alzheimer's disease.Neurobiol Dis. 2019 Jan;121:138-147. doi: 10.1016/j.nbd.2018.09.020. Epub 2018 Sep 26.
• [2] 3,5-diiodo-L-thyronine upregulates rat-liver mitochondrial F(o)F(1)-ATP synthase by GA-binding protein/nuclear respiratory factor-2.Biochim Biophys Acta. 2010 Feb;1797(2):233-40. doi: 10.1016/j.bbabio.2009.10.009. Epub 2009 Oct 28.
• [3] Insulin resistance is associated with larger thyroid volume in adults with type 1 diabetes independently from presence of thyroid autoimmunity.Scand J Clin Lab Invest. 2018 Jul;78(4):287-292. doi: 10.1080/00365513.2018.1455221. Epub 2018 Apr 19.
• [4] Genetic variation in ATP5O is associated with skeletal muscle ATP50 mRNA expression and glucose uptake in young twins.PLoS One. 2009;4(3):e4793. doi: 10.1371/journal.pone.0004793. Epub 2009 Mar 10.
• [5] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Untargeted Proteomics and Systems-Based Mechanistic Investigation of Artesunate in Human Bronchial Epithelial Cells. Chem Res Toxicol. 2015 Oct 19;28(10):1903-13. doi: 10.1021/acs.chemrestox.5b00105. Epub 2015 Sep 21.
• [14] 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.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [17] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [18] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.