Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2OQ1UD)

• DOT Name: ATP synthase subunit s, mitochondrial (DMAC2L)
• Synonyms: ATP synthase-coupling factor B; FB; Distal membrane arm assembly complex 2-like protein; Mitochondrial ATP synthase regulatory component factor B
• Gene Name: DMAC2L
• Related Disease: Clear cell renal carcinoma
• UniProt ID: ATP5S_HUMAN
• Sequence:
  MMPFGKISQQLCGVKKLPWSCDSRYFWGWLNAVFNKVDYDRIRDVGPDRAASEWLLRCGA
  MVRYHGQERWQKDYNHLPTGPLDKYKIQAIDATDSCIMSIGFDHMEGLEHVEKIRLCKCH
  YIEDDCLLRLSQLENLQKTILEMEIISCGNITDKGIIALRHLRNLKYLLLSDLPGVREKE
  NLVQAFKTALPSLELKLQLK
• Function: Involved in regulation of mitochondrial membrane ATP synthase. Necessary for H(+) conduction of ATP synthase. Facilitates energy-driven catalysis of ATP synthesis by blocking a proton leak through an alternative proton exit pathway.
• Reactome Pathway:
  Cristae formation (R-HSA-8949613)
  Formation of ATP by chemiosmotic coupling (R-HSA-163210)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[1]

15 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 subunit s, mitochondrial (DMAC2L).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[6]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[7]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[10]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of ATP synthase subunit s, mitochondrial (DMAC2L).	[16]

References

• [1] Systematic Analysis of the Expression of the Mitochondrial ATP Synthase (Complex V) Subunits in Clear Cell Renal Cell Carcinoma.Transl Oncol. 2017 Aug;10(4):661-668. doi: 10.1016/j.tranon.2017.06.002. Epub 2017 Jun 30.
• [2] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] 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.
• [5] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [6] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [7] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [8] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] 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.
• [11] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [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] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.