Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIU7FAZ)

• DOT Name: Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (COQ4)
• Synonyms: Coenzyme Q biosynthesis protein 4 homolog
• Gene Name: COQ4
• Related Disease:
  Mitochondrial disease
  Leigh syndrome
  Mitochondrial encephalomyopathy
  Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
  Coenzyme Q10 deficiency
  Intellectual disability
  Cardiomyopathy
• UniProt ID: COQ4_HUMAN
• Pfam ID: PF05019
• Sequence:
  MATLLRPVLRRLCGLPGLQRPAAEMPLRARSDGAGPLYSHHLPTSPLQKGLLAAGSAAMA
  LYNPYRHDMVAVLGETTGHRTLKVLRDQMRRDPEGAQILQERPRISTSTLDLGKLQSLPE
  GSLGREYLRFLDVNRVSPDTRAPTRFVDDEELAYVIQRYREVHDMLHTLLGMPTNILGEI
  VVKWFEAVQTGLPMCILGAFFGPIRLGAQSLQVLVSELIPWAVQNGRRAPCVLNLYYERR
  WEQSLRALREELGITAPPMHVQGLA
• Function: Component of the coenzyme Q biosynthetic pathway. May play a role in organizing a multi-subunit COQ enzyme complex required for coenzyme Q biosynthesis. Required for steady-state levels of other COQ polypeptides.
• Tissue Specificity: Expressed ubiquitously, but at high levels in liver, lung and pancreas.

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]
Leigh syndrome	DISWQU45	Strong	Genetic Variation	[2]
Mitochondrial encephalomyopathy	DISA6PTN	Strong	Genetic Variation	[3]
Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome	DIS4PEKG	Strong	Autosomal recessive	[4]
Coenzyme Q10 deficiency	DIS1HGDF	Disputed	Genetic Variation	[5]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[6]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (COQ4).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (COQ4).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (COQ4).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (COQ4).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (COQ4).	[13]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (COQ4).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (COQ4).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (COQ4).	[16]

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 Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial (COQ4).	[11]

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] Clinical phenotype, in silico and biomedical analyses, and intervention for an East Asian population-specific c.370G>A (p.G124S) COQ4 mutation in a Chinese family with CoQ10 deficiency-associated Leigh syndrome.J Hum Genet. 2019 Apr;64(4):297-304. doi: 10.1038/s10038-019-0563-y. Epub 2019 Jan 18.
• [3] Mutations in COQ4, an essential component of coenzyme Q biosynthesis, cause lethal neonatal mitochondrial encephalomyopathy.J Med Genet. 2015 Sep;52(9):627-35. doi: 10.1136/jmedgenet-2015-103140. Epub 2015 Jul 16.
• [4] COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency. Am J Hum Genet. 2015 Feb 5;96(2):309-17. doi: 10.1016/j.ajhg.2014.12.023.
• [5] Coenzyme Q10 deficiency due to a COQ4 gene defect causes childhood-onset spinocerebellar ataxia and stroke-like episodes.Mol Genet Metab Rep. 2018 Sep 13;17:19-21. doi: 10.1016/j.ymgmr.2018.09.002. eCollection 2018 Dec.
• [6] Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q(10) Deficiency.Stem Cells. 2017 Jul;35(7):1687-1703. doi: 10.1002/stem.2634. Epub 2017 May 23.
• [7] Clinical whole-exome sequencing reveals a common pathogenic variant in patients with CoQ(10) deficiency: An underdiagnosed cause of mitochondriopathy.Clin Chim Acta. 2019 Oct;497:88-94. doi: 10.1016/j.cca.2019.07.016. Epub 2019 Jul 17.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.