Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP6OKPJ)

• DOT Name: Elongation factor Ts, mitochondrial (TSFM)
• Synonyms: EF-Ts; EF-TsMt
• Gene Name: TSFM
• Related Disease:
  Cardiomyopathy
  Cerebellar ataxia
  Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3
  Multiple sclerosis
  Peripheral neuropathy
  Leigh syndrome
  Mitochondrial disease
  Sensorineural hearing loss disorder
  Asthma
• UniProt ID: EFTS_HUMAN
• PDB ID: 2CP9
• Pfam ID: PF00889
• Sequence:
  MSLLRSLRVFLVARTGSYPAGSLLRQSPQPRHTFYAGPRLSASASSKELLMKLRRKTGYS
  FVNCKKALETCGGDLKQAEIWLHKEAQKEGWSKAAKLQGRKTKEGLIGLLQEGNTTVLVE
  VNCETDFVSRNLKFQLLVQQVALGTMMHCQTLKDQPSAYSKGFLNSSELSGLPAGPDREG
  SLKDQLALAIGKLGENMILKRAAWVKVPSGFYVGSYVHGAMQSPSLHKLVLGKYGALVIC
  ETSEQKTNLEDVGRRLGQHVVGMAPLSVGSLDDEPGGEAETKMLSQPYLLDPSITLGQYV
  QPQGVSVVDFVRFECGEGEEAAETE
• Function: Associates with the EF-Tu.GDP complex and induces the exchange of GDP to GTP. It remains bound to the aminoacyl-tRNA.EF-Tu.GTP complex up to the GTP hydrolysis stage on the ribosome.
• Tissue Specificity: Expressed in all tissues, with the highest levels of expression in skeletal muscle, liver and kidney.
• Reactome Pathway: Mitochondrial translation elongation (R-HSA-5389840)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[1]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[2]
Fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3	DISIT3W8	Strong	Autosomal recessive	[3]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[4]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[5]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[6]
Mitochondrial disease	DISKAHA3	moderate	Biomarker	[7]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Genetic Variation	[7]
Asthma	DISW9QNS	Limited	Genetic Variation	[8]

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 Elongation factor Ts, mitochondrial (TSFM).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Elongation factor Ts, mitochondrial (TSFM).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Elongation factor Ts, mitochondrial (TSFM).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Elongation factor Ts, mitochondrial (TSFM).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Elongation factor Ts, mitochondrial (TSFM).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Elongation factor Ts, mitochondrial (TSFM).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Elongation factor Ts, mitochondrial (TSFM).	[15]

References

• [1] Novel compound mutations in the mitochondrial translation elongation factor (TSFM) gene cause severe cardiomyopathy with myocardial fibro-adipose replacement.Sci Rep. 2019 Mar 25;9(1):5108. doi: 10.1038/s41598-019-41483-9.
• [2] Molecular-genetic characterization and rescue of a TSFM mutation causing childhood-onset ataxia and nonobstructive cardiomyopathy.Eur J Hum Genet. 2016 Jan;25(1):153-156. doi: 10.1038/ejhg.2016.124. Epub 2016 Sep 28.
• [3] Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs. Am J Hum Genet. 2006 Nov;79(5):869-77. doi: 10.1086/508434. Epub 2006 Sep 15.
• [4] Integrative analysis revealed potential causal genetic and epigenetic factors for multiple sclerosis.J Neurol. 2019 Nov;266(11):2699-2709. doi: 10.1007/s00415-019-09476-w. Epub 2019 Jul 18.
• [5] Mitochondrial EFTs defects in juvenile-onset Leigh disease, ataxia, neuropathy, and optic atrophy.Neurology. 2014 Aug 19;83(8):743-51. doi: 10.1212/WNL.0000000000000716. Epub 2014 Jul 18.
• [6] 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.
• [7] Novel homozygous TSFM pathogenic variant associated with encephalocardiomyopathy with sensorineural hearing loss and peculiar neuroradiologic findings.Neurogenetics. 2019 Aug;20(3):165-172. doi: 10.1007/s10048-019-00582-5. Epub 2019 Jul 2.
• [8] The splice site variant rs11078928 may be associated with a genotype-dependent alteration in expression of GSDMB transcripts.BMC Genomics. 2013 Sep 17;14:627. doi: 10.1186/1471-2164-14-627.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [14] 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.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.