Details of Drug Off-Target (DOT)

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

• DOT Name: Mitochondrial import inner membrane translocase subunit TIM50 (TIMM50)
• Gene Name: TIMM50
• Related Disease:
  3-methylglutaconic aciduria type 9
  3-methylglutaconic aciduria
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Congestive heart failure
  Epilepsy
  Cardiomyopathy
  Leukopenia
  Neoplasm
  Non-small-cell lung cancer
  West syndrome
• UniProt ID: TIM50_HUMAN
• Pfam ID: PF03031
• Sequence:
  MAASAAVFSRLRSGLRLGSRGLCTRLATPPRRAPDQAAEIGSRGSTKAQGPQQQPGSEGP
  SYAKKVALWLAGLLGAGGTVSVVYIFGNNPVDENGAKIPDEFDNDPILVQQLRRTYKYFK
  DYRQMIIEPTSPCLLPDPLQEPYYQPPYTLVLELTGVLLHPEWSLATGWRFKKRPGIETL
  FQQLAPLYEIVIFTSETGMTAFPLIDSVDPHGFISYRLFRDATRYMDGHHVKDISCLNRD
  PARVVVVDCKKEAFRLQPYNGVALRPWDGNSDDRVLLDLSAFLKTIALNGVEDVRTVLEH
  YALEDDPLAAFKQRQSRLEQEEQQRLAELSKSNKQNLFLGSLTSRLWPRSKQP
• Function: Essential component of the TIM23 complex, a complex that mediates the translocation of transit peptide-containing proteins across the mitochondrial inner membrane. Has some phosphatase activity in vitro; however such activity may not be relevant in vivo; [Isoform 2]: May participate in the release of snRNPs and SMN from the Cajal body.
• Tissue Specificity: Widely expressed. Expressed at higher level in brain, kidney and liver (at protein level).
• Reactome Pathway: Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-methylglutaconic aciduria type 9	DISB39M5	Definitive	Autosomal recessive	[1]
3-methylglutaconic aciduria	DIS8G1WP	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	Genetic Variation	[5]
Cardiomyopathy	DISUPZRG	moderate	Genetic Variation	[2]
Leukopenia	DISJMBMM	moderate	Genetic Variation	[2]
Neoplasm	DISZKGEW	moderate	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Biomarker	[3]
West syndrome	DISLIAU9	moderate	Genetic Variation	[2]

7 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 Mitochondrial import inner membrane translocase subunit TIM50 (TIMM50).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial import inner membrane translocase subunit TIM50 (TIMM50).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitochondrial import inner membrane translocase subunit TIM50 (TIMM50).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mitochondrial import inner membrane translocase subunit TIM50 (TIMM50).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Mitochondrial import inner membrane translocase subunit TIM50 (TIMM50).	[11]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Mitochondrial import inner membrane translocase subunit TIM50 (TIMM50).	[12]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Mitochondrial import inner membrane translocase subunit TIM50 (TIMM50).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Mitochondrial import inner membrane translocase subunit TIM50 (TIMM50).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Mitochondrial import inner membrane translocase subunit TIM50 (TIMM50).	[13]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Mutations in TIMM50 cause severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology.Hum Mutat. 2019 Oct;40(10):1700-1712. doi: 10.1002/humu.23779. Epub 2019 May 17.
• [3] TIMM50 promotes tumor progression via ERK signaling and predicts poor prognosis of non-small cell lung cancer patients.Mol Carcinog. 2019 May;58(5):767-776. doi: 10.1002/mc.22969. Epub 2019 Jan 22.
• [4] Translocase of Inner Membrane 50 Functions as a Novel Protective Regulator of Pathological Cardiac Hypertrophy.J Am Heart Assoc. 2017 Apr 21;6(4):e004346. doi: 10.1161/JAHA.116.004346.
• [5] Mitochondrial epileptic encephalopathy, 3-methylglutaconic aciduria and variable complex V deficiency associated with TIMM50 mutations. Clin Genet. 2017 May;91(5):690-696. doi: 10.1111/cge.12855. Epub 2016 Oct 12.
• [6] 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.
• [7] 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.
• [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] 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] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [11] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [12] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [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] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.