Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXL7EP2)

• DOT Name: Cytochrome c oxidase assembly protein COX20, mitochondrial (COX20)
• Gene Name: COX20
• Related Disease:
  Mitochondrial disease
  Cerebellar ataxia
  Dystonia
  Isolated congenital microcephaly
  Mitochondrial complex 4 deficiency, nuclear type 11
  Intellectual disability
  Cytochrome-c oxidase deficiency disease
• UniProt ID: COX20_HUMAN
• Pfam ID: PF12597
• Sequence:
  MAAPPEPGEPEERKSLKLLGFLDVENTPCARHSILYGSLGSVVAGFGHFLFTSRIRRSCD
  VGVGGFILVTLGCWFHCRYNYAKQRIQERIAREEIKKKILYEGTHLDPERKHNGSSSN
• Function: Essential for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase. Acts as a chaperone in the early steps of cytochrome c oxidase subunit II (MT-CO2/COX2) maturation, stabilizing the newly synthesized protein and presenting it to metallochaperones SCO1/2 which in turn facilitates the incorporation of the mature MT-CO2/COX2 into the assembling CIV holoenzyme.
• KEGG Pathway: Thermogenesis (hsa04714)
• 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

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[2]
Dystonia	DISJLFGW	Strong	Biomarker	[3]
Isolated congenital microcephaly	DISUXHZ6	Strong	Biomarker	[4]
Mitochondrial complex 4 deficiency, nuclear type 11	DIS5CFA7	Strong	Autosomal recessive	[5]
Intellectual disability	DISMBNXP	moderate	Genetic Variation	[4]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Supportive	Autosomal recessive	[6]

8 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 Cytochrome c oxidase assembly protein COX20, mitochondrial (COX20).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytochrome c oxidase assembly protein COX20, mitochondrial (COX20).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome c oxidase assembly protein COX20, mitochondrial (COX20).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytochrome c oxidase assembly protein COX20, mitochondrial (COX20).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome c oxidase assembly protein COX20, mitochondrial (COX20).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cytochrome c oxidase assembly protein COX20, mitochondrial (COX20).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cytochrome c oxidase assembly protein COX20, mitochondrial (COX20).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cytochrome c oxidase assembly protein COX20, mitochondrial (COX20).	[14]

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] Observation of novel COX20 mutations related to autosomal recessive axonal neuropathy and static encephalopathy.Hum Genet. 2019 Jul;138(7):749-756. doi: 10.1007/s00439-019-02026-4. Epub 2019 May 11.
• [3] Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module.J Biol Chem. 2017 May 12;292(19):7774-7783. doi: 10.1074/jbc.M117.778514. Epub 2017 Mar 22.
• [4] Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures. Am J Med Genet A. 2012 Jul;158A(7):1633-40. doi: 10.1002/ajmg.a.35423. Epub 2012 Jun 7.
• [5] How caustics were used to treat skin cancer. J Dermatol Surg Oncol. 1979 Dec;5(12):949-50. doi: 10.1111/j.1524-4725.1979.tb00791.x.
• [6] A mutation in the FAM36A gene, the human ortholog of COX20, impairs cytochrome c oxidase assembly and is associated with ataxia and muscle hypotonia. Hum Mol Genet. 2013 Feb 15;22(4):656-67. doi: 10.1093/hmg/dds473. Epub 2012 Nov 2.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] 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.
• [11] 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.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [14] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.