Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX674BU)

• DOT Name: ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3)
• Synonyms: ATP synthase lipid-binding protein; ATP synthase membrane subunit c locus 3; ATP synthase proteolipid P3; ATP synthase proton-transporting mitochondrial F(0) complex subunit C3; ATPase protein 9; ATPase subunit c
• Gene Name: ATP5MC3
• Related Disease: Dystonia, early-onset, and/or spastic paraplegia
• UniProt ID: AT5G3_HUMAN
• Pfam ID: PF00137
• Sequence:
  MFACAKLACTPSLIRAGSRVAYRPISASVLSRPEASRTGEGSTVFNGAQNGVSQLIQREF
  QTSAISRDIDTAAKFIGAGAATVGVAGSGAGIGTVFGSLIIGYARNPSLKQQLFSYAILG
  FALSEAMGLFCLMVAFLILFAM
• 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:ENSG00000154518-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dystonia, early-onset, and/or spastic paraplegia	DISDSXC3	Moderate	Autosomal dominant	[1]

15 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 C3, mitochondrial (ATP5MC3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[6]
Marinol	DM70IK5	Approved	Marinol increases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[7]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[9]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[10]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[14]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[15]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[16]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[17]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of ATP synthase F(0) complex subunit C3, mitochondrial (ATP5MC3).	[13]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [8] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [11] 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.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men. PLoS One. 2017 Jun 5;12(6):e0178535. doi: 10.1371/journal.pone.0178535. eCollection 2017.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] 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.
• [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.