Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK7PDNN)

• DOT Name: Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9)
• Gene Name: TIMM9
• Related Disease:
  African trypanosomiasis
  Gastric cancer
  Neoplasm
  Stomach cancer
• UniProt ID: TIM9_HUMAN
• PDB ID: 2BSK; 7CGP
• Pfam ID: PF02953
• Sequence:
  MAAQIPESDQIKQFKEFLGTYNKLTETCFLDCVKDFTTREVKPEETTCSEHCLQKYLKMT
  QRISMRFQEYHIQQNEALAAKAGLLGQPR
• Function: Mitochondrial intermembrane chaperone that participates in the import and insertion of multi-pass transmembrane proteins into the mitochondrial inner membrane. May also be required for the transfer of beta-barrel precursors from the TOM complex to the sorting and assembly machinery (SAM complex) of the outer membrane. Acts as a chaperone-like protein that protects the hydrophobic precursors from aggregation and guide them through the mitochondrial intermembrane space.
• Tissue Specificity: Ubiquitous, with highest expression in heart, kidney, liver and skeletal muscle.
• 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
African trypanosomiasis	DISBIXK4	Strong	Altered Expression	[1]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[2]
Neoplasm	DISZKGEW	moderate	Altered Expression	[2]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[2]

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 Tim9 (TIMM9).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9).	[13]

12 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 Tim9 (TIMM9).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitochondrial import inner membrane translocase subunit Tim9 (TIMM9).	[16]

References

• [1] Divergent Small Tim Homologues Are Associated with TbTim17 and Critical for the Biogenesis of TbTim17 Protein Complexes in Trypanosoma brucei.mSphere. 2018 Jun 20;3(3):e00204-18. doi: 10.1128/mSphere.00204-18. Print 2018 Jun 27.
• [2] High expression of mitochondrial intermembrane chaperone TIMM9 represents a negative prognostic marker in gastric cancer.J Formos Med Assoc. 2017 Jun;116(6):476-483. doi: 10.1016/j.jfma.2016.08.007. Epub 2016 Oct 6.
• [3] 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.
• [4] 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.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] 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.
• [12] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [13] 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.
• [14] 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.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.