Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVFRL8G)

• DOT Name: Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A)
• Synonyms: Inner membrane preprotein translocase Tim17a
• Gene Name: TIMM17A
• Related Disease:
  Neoplasm
  Breast cancer
  Breast carcinoma
  Mitochondrial disease
• UniProt ID: TI17A_HUMAN
• Pfam ID: PF02466
• Sequence:
  MEEYAREPCPWRIVDDCGGAFTMGTIGGGIFQAIKGFRNSPVGVNHRLRGSLTAIKTRAP
  QLGGSFAVWGGLFSMIDCSMVQVRGKEDPWNSITSGALTGAILAARNGPVAMVGSAAMGG
  ILLALIEGAGILLTRFASAQFPNGPQFAEDPSQLPSTQLPSSPFGDYRQYQ
• Function: Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane.
• Reactome Pathway: Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paraquat	DMR8O3X	Investigative	Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A) decreases the response to substance of Paraquat.	[14]

2 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 Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[11]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[12]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[13]
Adenosine triphosphate	DM79F6G	Approved	Adenosine triphosphate decreases the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[14]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[6]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[15]
Phenol	DM1QSM3	Phase 2/3	Phenol decreases the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[16]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Mitochondrial import inner membrane translocase subunit Tim17-A (TIMM17A).	[18]

References

• [1] High TIMM17A expression is associated with adverse pathological and clinical outcomes in human breast cancer.Breast Cancer. 2012 Apr;19(2):153-60. doi: 10.1007/s12282-010-0228-3. Epub 2010 Oct 23.
• [2] LncRNA NEAT1 Silenced miR-133b Promotes Migration and Invasion of Breast Cancer Cells.Int J Mol Sci. 2019 Jul 24;20(15):3616. doi: 10.3390/ijms20153616.
• [3] The conserved translocase Tim17 prevents mitochondrial DNA loss.Hum Mol Genet. 2009 Jan 1;18(1):65-74. doi: 10.1093/hmg/ddn313. Epub 2008 Sep 30.
• [4] 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.
• [5] 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.
• [6] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [13] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [14] Stress-regulated translational attenuation adapts mitochondrial protein import through Tim17A degradation. Cell Metab. 2013 Dec 3;18(6):908-19. doi: 10.1016/j.cmet.2013.11.006.
• [15] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [16] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [17] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] Stress-regulated translational attenuation adapts mitochondrial protein import through Tim17A degradation. Cell Metab. 2013 Dec 3;18(6):908-19. doi: 10.1016/j.cmet.2013.11.006.