Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK1WUBL)

• DOT Name: Translational activator of cytochrome c oxidase 1 (TACO1)
• Synonyms: Coiled-coil domain-containing protein 44; Translational activator of mitochondrially-encoded cytochrome c oxidase I
• Gene Name: TACO1
• Related Disease:
  Cytochrome-c oxidase deficiency disease
  Mitochondrial complex 4 deficiency, nuclear type 8
  Mitochondrial disease
  Leigh syndrome
  Obsolete Leigh syndrome with leukodystrophy
• UniProt ID: TACO1_HUMAN
• Pfam ID: PF20772 ; PF01709
• Sequence:
  MSAWAAASLSRAAARCLLARGPGVRAAPPRDPRPSHPEPRGCGAAPGRTLHFTAAVPAGH
  NKWSKVRHIKGPKDVERSRIFSKLCLNIRLAVKEGGPNPEHNSNLANILEVCRSKHMPKS
  TIETALKMEKSKDTYLLYEGRGPGGSSLLIEALSNSSHKCQADIRHILNKNGGVMAVGAR
  HSFDKKGVIVVEVEDREKKAVNLERALEMAIEAGAEDVKETEDEEERNVFKFICDASSLH
  QVRKKLDSLGLCSVSCALEFIPNSKVQLAEPDLEQAAHLIQALSNHEDVIHVYDNIE
• Function: Acts as a translational activator of mitochondrially-encoded cytochrome c oxidase 1.
• Reactome Pathway:
  Respiratory electron transport (R-HSA-611105)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Autosomal recessive	[1]
Mitochondrial complex 4 deficiency, nuclear type 8	DISP2EUO	Strong	Autosomal recessive	[2]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[3]
Leigh syndrome	DISWQU45	Moderate	Autosomal recessive	[4]
Obsolete Leigh syndrome with leukodystrophy	DISABU9D	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Translational activator of cytochrome c oxidase 1 (TACO1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Translational activator of cytochrome c oxidase 1 (TACO1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Translational activator of cytochrome c oxidase 1 (TACO1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Translational activator of cytochrome c oxidase 1 (TACO1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Translational activator of cytochrome c oxidase 1 (TACO1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Translational activator of cytochrome c oxidase 1 (TACO1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Translational activator of cytochrome c oxidase 1 (TACO1).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Translational activator of cytochrome c oxidase 1 (TACO1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Translational activator of cytochrome c oxidase 1 (TACO1).	[10]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat Genet. 2009 Jul;41(7):833-7. doi: 10.1038/ng.390. Epub 2009 Jun 7.
• [3] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [4] 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.
• [5] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.