Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDAE8FP)

• DOT Name: ATP synthase-coupling factor 6, mitochondrial (ATP5PF)
• Synonyms: ATPase subunit F6; ATP synthase peripheral stalk subunit F6
• Gene Name: ATP5PF
• Related Disease:
  Myocardial infarction
  Alzheimer disease
  B-cell neoplasm
  Cardiac disease
  Cardiovascular disease
  Chronic renal failure
  Congestive heart failure
  Head-neck squamous cell carcinoma
  Leigh syndrome
  Myocardial ischemia
  Non-insulin dependent diabetes
  Pulmonary hypertension
  Type-1/2 diabetes
  Alopecia
  Colorectal carcinoma
  High blood pressure
• UniProt ID: ATP5J_HUMAN
• PDB ID: 8H9G; 8H9K; 8H9N; 8H9R; 8H9S; 8H9T; 8H9U; 8H9V
• Pfam ID: PF05511
• Sequence:
  MILQRLFRFSSVIRSAVSVHLRRNIGVTAVAFNKELDPIQKLFVDKIREYKSKRQTSGGP
  VDASSEYQQELERELFKLKQMFGNADMNTFPTFKFEDPKFEVIEKPQA
• 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. Also involved in the restoration of oligomycin-sensitive ATPase activity to depleted F1-F0 complexes.
• 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:ENSG00000154723-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myocardial infarction	DIS655KI	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Cardiac disease	DISVO1I5	Strong	Biomarker	[4]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[5]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[6]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[7]
Leigh syndrome	DISWQU45	Strong	Genetic Variation	[8]
Myocardial ischemia	DISFTVXF	Strong	Genetic Variation	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[5]
Pulmonary hypertension	DIS1RSP5	Strong	Therapeutic	[9]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[10]
Alopecia	DIS37HU4	moderate	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[12]
High blood pressure	DISY2OHH	moderate	Biomarker	[5]

1 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-coupling factor 6, mitochondrial (ATP5PF).	[13]

16 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-coupling factor 6, mitochondrial (ATP5PF).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[19]
Selenium	DM25CGV	Approved	Selenium decreases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[20]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[21]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[22]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[26]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[27]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[28]
15-deoxy-Delta(12, 14)-prostaglandin J(2)	DM8VUX3	Investigative	15-deoxy-Delta(12, 14)-prostaglandin J(2) decreases the expression of ATP synthase-coupling factor 6, mitochondrial (ATP5PF).	[22]

References

• [1] Plasma mitochondrial coupling factor 6 in patients with acute myocardial infarction.Hypertens Res. 2004 Oct;27(10):717-22. doi: 10.1291/hypres.27.717.
• [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] Critical pathways in heart function: bis(2-chloroethoxy)methane-induced heart gene transcript change in F344 rats.Toxicol Pathol. 2006;34(4):348-56. doi: 10.1080/01926230600798583.
• [5] Nutritional regulation of coupling factor 6, a novel vasoactive and proatherogenic peptide.Nutrition. 2017 May;37:74-78. doi: 10.1016/j.nut.2016.07.017. Epub 2016 Aug 6.
• [6] Plasma concentration of coupling factor 6 and cardiovascular events in patients with end-stage renal disease.Kidney Int. 2003 Dec;64(6):2291-7. doi: 10.1046/j.1523-1755.2003.00334.x.
• [7] 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.
• [8] Transmission and prenatal diagnosis of the T9176C mitochondrial DNA mutation.Mol Hum Reprod. 2005 Mar;11(3):223-8. doi: 10.1093/molehr/gah152. Epub 2005 Feb 11.
• [9] Lung-specific RNA interference of coupling factor 6, a novel peptide, attenuates pulmonary arterial hypertension in rats.Respir Res. 2016 Aug 4;17(1):99. doi: 10.1186/s12931-016-0409-5.
• [10] Coupling factor 6-induced activation of ecto-F1F(o) complex induces insulin resistance, mild glucose intolerance and elevated blood pressure in mice.Diabetologia. 2012 Feb;55(2):520-9. doi: 10.1007/s00125-011-2341-z. Epub 2011 Oct 25.
• [11] Novel anti-aging gene NM_026333 contributes to proton-induced aging via NCX1-pathway.J Mol Cell Cardiol. 2018 Dec;125:174-184. doi: 10.1016/j.yjmcc.2018.10.021. Epub 2018 Oct 29.
• [12] Identification of candidate genes and long non-coding RNAs associated with the effect of ATP5J in colorectal cancer.Int J Oncol. 2018 Apr;52(4):1129-1138. doi: 10.3892/ijo.2018.4281. Epub 2018 Feb 22.
• [13] 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.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] 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.
• [20] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [21] 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.
• [22] Troglitazone and 15-deoxy-delta(12,14)-prostaglandin J2 inhibit shear-induced coupling factor 6 release in endothelial cells. Cardiovasc Res. 2005 Jul 1;67(1):134-41. doi: 10.1016/j.cardiores.2005.02.022. Epub 2005 Mar 29.
• [23] 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.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.