Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQFD73H)

• DOT Name: ATPase inhibitor, mitochondrial (ATP5IF1)
• Synonyms: ATP synthase F1 subunit epsilon; Inhibitor of F(1)F(o)-ATPase; IF(1); IF1
• Gene Name: ATP5IF1
• Related Disease:
  Anemia
  Carcinoma
  Dermatomyositis
  Undifferentiated carcinoma
  Fatty liver disease
• UniProt ID: ATIF1_HUMAN
• PDB ID: 8H9E; 8H9L; 8H9S; 8H9U
• Pfam ID: PF04568
• Sequence:
  MAVTALAARTWLGVWGVRTMQARGFGSDQSENVDRGAGSIREAGGAFGKREQAEEERYFR
  AQSREQLAALKKHHEEEIVHHKKEIERLQKEIERHKQKIKMLKHDD
• Function: Endogenous F(1)F(o)-ATPase inhibitor limiting ATP depletion when the mitochondrial membrane potential falls below a threshold and the F(1)F(o)-ATP synthase starts hydrolyzing ATP to pump protons out of the mitochondrial matrix. Required to avoid the consumption of cellular ATP when the F(1)F(o)-ATP synthase enzyme acts as an ATP hydrolase. Indirectly acts as a regulator of heme synthesis in erythroid tissues: regulates heme synthesis by modulating the mitochondrial pH and redox potential, allowing FECH to efficiently catalyze the incorporation of iron into protoporphyrin IX to produce heme.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anemia	DISTVL0C	Strong	Genetic Variation	[1]
Carcinoma	DISH9F1N	Strong	Biomarker	[2]
Dermatomyositis	DIS50C5O	Strong	Biomarker	[3]
Undifferentiated carcinoma	DISIAZST	Strong	Biomarker	[2]
Fatty liver disease	DIS485QZ	Limited	Biomarker	[4]

2 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 ATPase inhibitor, mitochondrial (ATP5IF1).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of ATPase inhibitor, mitochondrial (ATP5IF1).	[17]

13 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 ATPase inhibitor, mitochondrial (ATP5IF1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATPase inhibitor, mitochondrial (ATP5IF1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATPase inhibitor, mitochondrial (ATP5IF1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ATPase inhibitor, mitochondrial (ATP5IF1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of ATPase inhibitor, mitochondrial (ATP5IF1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ATPase inhibitor, mitochondrial (ATP5IF1).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATPase inhibitor, mitochondrial (ATP5IF1).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of ATPase inhibitor, mitochondrial (ATP5IF1).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of ATPase inhibitor, mitochondrial (ATP5IF1).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of ATPase inhibitor, mitochondrial (ATP5IF1).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of ATPase inhibitor, mitochondrial (ATP5IF1).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ATPase inhibitor, mitochondrial (ATP5IF1).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ATPase inhibitor, mitochondrial (ATP5IF1).	[18]

References

• [1] Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts.Nature. 2012 Nov 22;491(7425):608-12. doi: 10.1038/nature11536. Epub 2012 Nov 7.
• [2] Global gene expression profiling of chemically induced rat mammary gland carcinomas and adenomas.Toxicol Pathol. 2005;33(7):768-75. doi: 10.1080/01926230500437027.
• [3] Pyruvate kinase M2 and the mitochondrial ATPase Inhibitory Factor 1 provide novel biomarkers of dermatomyositis: a metabolic link to oncogenesis.J Transl Med. 2017 Feb 10;15(1):29. doi: 10.1186/s12967-017-1136-5.
• [4] Characterization of chemically induced liver injuries using gene co-expression modules.PLoS One. 2014 Sep 16;9(9):e107230. doi: 10.1371/journal.pone.0107230. eCollection 2014.
• [5] 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.
• [6] 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.
• [7] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [11] 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.
• [12] 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.
• [13] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [14] 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.
• [15] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [16] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.