Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1ETSA2)

• DOT Name: Atypical kinase COQ8A, mitochondrial (COQ8A)
• Synonyms: EC 2.7.-.-; Chaperone activity of bc1 complex-like; Chaperone-ABC1-like; Coenzyme Q protein 8A; aarF domain-containing protein kinase 3
• Gene Name: COQ8A
• Related Disease:
  Coenzyme Q10 deficiency
  Coenzyme Q10 deficiency, primary, 1
  Anxiety
  Charlevoix-Saguenay spastic ataxia
  Dystonia
  Epilepsy
  Familial isolated deficiency of vitamin E
  Friedreich ataxia 1
  Intellectual disability
  Kearns-Sayre syndrome
  Leigh syndrome
  Marinesco-Sjogren syndrome
  MELAS syndrome
  Mental disorder
  Autosomal recessive ataxia due to ubiquinone deficiency
  Cerebellar ataxia
• UniProt ID: COQ8A_HUMAN
• PDB ID: 4PED; 5I35; 7UDP; 7UDQ
• EC Number: 2.7.-.-
• Pfam ID: PF03109
• Sequence:
  MAAILGDTIMVAKGLVKLTQAAVETHLQHLGIGGELIMAARALQSTAVEQIGMFLGKVQG
  QDKHEEYFAENFGGPEGEFHFSVPHAAGASTDFSSASAPDQSAPPSLGHAHSEGPAPAYV
  ASGPFREAGFPGQASSPLGRANGRLFANPRDSFSAMGFQRRFFHQDQSPVGGLTAEDIEK
  ARQAKARPENKQHKQTLSEHARERKVPVTRIGRLANFGGLAVGLGFGALAEVAKKSLRSE
  DPSGKKAVLGSSPFLSEANAERIVRTLCKVRGAALKLGQMLSIQDDAFINPHLAKIFERV
  RQSADFMPLKQMMKTLNNDLGPNWRDKLEYFEERPFAAASIGQVHLARMKGGREVAMKIQ
  YPGVAQSINSDVNNLMAVLNMSNMLPEGLFPEHLIDVLRRELALECDYQREAACARKFRD
  LLKGHPFFYVPEIVDELCSPHVLTTELVSGFPLDQAEGLSQEIRNEICYNILVLCLRELF
  EFHFMQTDPNWSNFFYDPQQHKVALLDFGATREYDRSFTDLYIQIIRAAADRDRETVRAK
  SIEMKFLTGYEVKVMEDAHLDAILILGEAFASDEPFDFGTQSTTEKIHNLIPVMLRHRLV
  PPPEETYSLHRKMGGSFLICSKLKARFPCKAMFEEAYSNYCKRQAQQ
• Function: Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration. Its substrate specificity is unclear: does not show any protein kinase activity. Probably acts as a small molecule kinase, possibly a lipid kinase that phosphorylates a prenyl lipid in the ubiquinone biosynthesis pathway, as suggested by its ability to bind coenzyme Q lipid intermediates. Shows an unusual selectivity for binding ADP over ATP.
• Tissue Specificity: Widely expressed, with highest levels in adrenal gland, heart, pancreas, nasal mucosa, stomach, uterus and skeletal muscle.

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coenzyme Q10 deficiency	DIS1HGDF	Definitive	Autosomal recessive	[1]
Coenzyme Q10 deficiency, primary, 1	DISD9V13	Definitive	Autosomal recessive	[2]
Anxiety	DISIJDBA	Strong	Genetic Variation	[3]
Charlevoix-Saguenay spastic ataxia	DISE8X81	Strong	Genetic Variation	[4]
Dystonia	DISJLFGW	Strong	Genetic Variation	[5]
Epilepsy	DISBB28L	Strong	Genetic Variation	[6]
Familial isolated deficiency of vitamin E	DIS53306	Strong	Genetic Variation	[4]
Friedreich ataxia 1	DIS285GE	Strong	Genetic Variation	[4]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[7]
Kearns-Sayre syndrome	DIS9UK5R	Strong	Genetic Variation	[8]
Leigh syndrome	DISWQU45	Strong	Genetic Variation	[8]
Marinesco-Sjogren syndrome	DISKEU0B	Strong	Genetic Variation	[4]
MELAS syndrome	DIS81Z3S	Strong	Genetic Variation	[8]
Mental disorder	DIS3J5R8	Strong	Biomarker	[6]
Autosomal recessive ataxia due to ubiquinone deficiency	DISCQ6YL	Supportive	Autosomal recessive	[9]
Cerebellar ataxia	DIS9IRAV	Limited	Genetic Variation	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Artesunate	DMR27C8	Approved	Atypical kinase COQ8A, mitochondrial (COQ8A) decreases the response to substance of Artesunate.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[14]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[17]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[21]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Atypical kinase COQ8A, mitochondrial (COQ8A).	[22]

References

• [1] CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures. Am J Hum Genet. 2008 Mar;82(3):623-30. doi: 10.1016/j.ajhg.2007.12.022.
• [2] 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.
• [3] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [4] Epidemiological, clinical, paraclinical and molecular study of a cohort of 102 patients affected with autosomal recessive progressive cerebellar ataxia from Alsace, Eastern France: implications for clinical management.Neurogenetics. 2010 Feb;11(1):1-12. doi: 10.1007/s10048-009-0196-y. Epub 2009 May 14.
• [5] Dystonia-Ataxia with early handwriting deterioration in COQ8A mutation carriers: A case series and literature review.Parkinsonism Relat Disord. 2019 Nov;68:8-16. doi: 10.1016/j.parkreldis.2019.09.015. Epub 2019 Sep 28.
• [6] ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: a POLG mimic?.Eur J Neurol. 2016 Jul;23(7):1188-94. doi: 10.1111/ene.13003. Epub 2016 Apr 23.
• [7] Childhood-onset autosomal recessive ataxias: a cross-sectional study from Turkey.Neurogenetics. 2020 Jan;21(1):59-66. doi: 10.1007/s10048-019-00597-y. Epub 2019 Nov 19.
• [8] Movement disorders in mitochondrial diseases.Rev Neurol (Paris). 2016 Aug-Sep;172(8-9):524-529. doi: 10.1016/j.neurol.2016.07.003. Epub 2016 Jul 28.
• [9] Hereditary Ataxia Overview. 1998 Oct 28 [updated 2023 Nov 16]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [10] 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.
• [11] 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.
• [12] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [15] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [16] 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.
• [17] Effect of mitochondrial dysfunction and oxidative stress on endogenous levels of coenzyme Q(10) in human cells. J Biochem Mol Toxicol. 2011 Sep-Oct;25(5):280-9. doi: 10.1002/jbt.20387. Epub 2011 Feb 9.
• [18] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [19] 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.
• [20] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [23] Factors determining sensitivity or resistance of tumor cell lines towards artesunate. Chem Biol Interact. 2010 Apr 15;185(1):42-52.