Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYQQR53)

• DOT Name: ATP synthase protein 8 (ATP8)
• Synonyms: A6L; F-ATPase subunit 8
• Gene Name: ATP8
• Related Disease:
  Acute intermittent hepatic porphyria
  Autoimmune disease
  Childhood acute lymphoblastic leukemia
  Leigh syndrome
  Optic nerve disorder
  Trichohepatoenteric syndrome
  Breast cancer
  Breast carcinoma
  Mitochondrial proton-transporting ATP synthase complex deficiency
  Periodic paralysis with later-onset distal motor neuropathy
  Multiple sclerosis
  Non-insulin dependent diabetes
  Mitochondrial disease
  Post-traumatic stress disorder
• UniProt ID: ATP8_HUMAN
• PDB ID: 8H9F; 8H9J; 8H9M; 8H9Q; 8H9S; 8H9T; 8H9U; 8H9V
• Pfam ID: PF00895
• Sequence:
  MPQLNTTVWPTMITPMLLTLFLITQLKMLNTNYHLPPSPKPMKMKNYNKPWEPKWTKICS
  LHSLPPQS
• 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. Minor subunit located with subunit a in the membrane.
• 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:HS00025-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute intermittent hepatic porphyria	DIS80J7E	Strong	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[1]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[2]
Leigh syndrome	DISWQU45	Strong	Biomarker	[3]
Optic nerve disorder	DISSOQM8	Strong	Genetic Variation	[4]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	moderate	Biomarker	[5]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[5]
Mitochondrial proton-transporting ATP synthase complex deficiency	DISX6N3H	Supportive	Autosomal recessive	[6]
Periodic paralysis with later-onset distal motor neuropathy	DIS0GEC0	Supportive	Mitochondrial	[7]
Multiple sclerosis	DISB2WZI	Disputed	Genetic Variation	[8]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Genetic Variation	[9]
Mitochondrial disease	DISKAHA3	Limited	Mitochondrial	[10]
Post-traumatic stress disorder	DISHL1EY	Limited	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of ATP synthase protein 8 (ATP8).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP synthase protein 8 (ATP8).	[13]
Nefazodone	DM4ZS8M	Approved	Nefazodone decreases the expression of ATP synthase protein 8 (ATP8).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of ATP synthase protein 8 (ATP8).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATP synthase protein 8 (ATP8).	[16]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of ATP synthase protein 8 (ATP8).	[17]

References

• [1] The mtDNA nt7778 G/T polymorphism augments formation of lymphocytic foci but does not aggravate cerulein-induced acute pancreatitis in mice.PLoS One. 2014 Jul 10;9(7):e102266. doi: 10.1371/journal.pone.0102266. eCollection 2014.
• [2] Novel non-neutral mitochondrial DNA mutations found in childhood acute lymphoblastic leukemia.Clin Genet. 2018 Feb;93(2):275-285. doi: 10.1111/cge.13100. Epub 2017 Dec 20.
• [3] A novel mutation m.8561C>G in MT-ATP6/8 causing a mitochondrial syndrome with ataxia, peripheral neuropathy, diabetes mellitus, and hypergonadotropic hypogonadism.J Neurol. 2016 Nov;263(11):2188-2195. doi: 10.1007/s00415-016-8249-2. Epub 2016 Aug 8.
• [4] In silico analysis for predicting pathogenicity of five unclassified mitochondrial DNA mutations associated with mitochondrial cytopathies' phenotypes.Eur J Med Genet. 2017 Mar;60(3):172-177. doi: 10.1016/j.ejmg.2016.12.009. Epub 2016 Dec 24.
• [5] Mitochondrial complex I and V gene polymorphisms associated with breast cancer in mizo-mongloid population.Breast Cancer. 2016 Jul;23(4):607-16. doi: 10.1007/s12282-015-0611-1. Epub 2015 Apr 21.
• [6] A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy. BMJ Case Rep. 2009;2009:bcr07.2008.0504. doi: 10.1136/bcr.07.2008.0504. Epub 2009 Jan 23.
• [7] Episodic weakness due to mitochondrial DNA MT-ATP6/8 mutations. Neurology. 2013 Nov 19;81(21):1810-8. doi: 10.1212/01.wnl.0000436067.43384.0b. Epub 2013 Oct 23.
• [8] Investigation on mitochondrial tRNA(Leu/Lys), NDI and ATPase 6/8 in Iranian multiple sclerosis patients.Cell Mol Neurobiol. 2007 Sep;27(6):695-700. doi: 10.1007/s10571-007-9160-2. Epub 2007 Jul 6.
• [9] Mitochondrial DNA Mutations Associated with Type 2 Diabetes Mellitus in Chinese Uyghur Population.Sci Rep. 2017 Dec 5;7(1):16989. doi: 10.1038/s41598-017-17086-7.
• [10] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [11] Mitochondrial genetic variants identified to be associated with posttraumatic stress disorder.Transl Psychiatry. 2015 Mar 10;5(3):e524. doi: 10.1038/tp.2015.18.
• [12] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [13] 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.
• [14] Involvement of mitochondrial dysfunction in nefazodone-induced hepatotoxicity. Food Chem Toxicol. 2016 Aug;94:148-58. doi: 10.1016/j.fct.2016.06.001. Epub 2016 Jun 8.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [17] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.