Details of Drug Off-Target (DOT)

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

• DOT Name: 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7)
• Synonyms: DMQ hydroxylase; EC 1.14.99.60; Timing protein clk-1 homolog; Ubiquinone biosynthesis monooxygenase COQ7
• Gene Name: COQ7
• Related Disease:
  Coenzyme Q10 deficiency
  Primary coenzyme Q10 deficiency 8
  Steroid-resistant nephrotic syndrome
• UniProt ID: COQ7_HUMAN
• PDB ID: 7SSP; 7SSS
• EC Number: 1.14.99.60
• Pfam ID: PF03232
• Sequence:
  MSCAGAAAAPRLWRLRPGARRSLSAYGRRTSVRFRSSGMTLDNISRAAVDRIIRVDHAGE
  YGANRIYAGQMAVLGRTSVGPVIQKMWDQEKDHLKKFNELMVTFRVRPTVLMPLWNVLGF
  ALGAGTALLGKEGAMACTVAVEESIAHHYNNQIRTLMEEDPEKYEELLQLIKKFRDEELE
  HHDIGLDHDAELAPAYAVLKSIIQAGCRVAIYLSERL
• Function: Catalyzes the hydroxylation of 2-polyprenyl-3-methyl-6-methoxy-1,4-benzoquinol (DMQH2) during ubiquinone biosynthesis. Has also a structural role in the COQ enzyme complex, stabilizing other COQ polypeptides. Involved in lifespan determination in a ubiquinone-independent manner. Plays a role in modulating mitochondrial stress responses, acting in the nucleus, perhaps via regulating gene expression, independent of its characterized mitochondrial function in ubiquinone biosynthesis.
• Tissue Specificity: Expressed dominantly in heart and skeletal muscle.
• KEGG Pathway:
  Ubiquinone and other terpenoid-quinone biosynthesis (hsa00130)
  Metabolic pathways (hsa01100)
  Biosynthesis of cofactors (hsa01240)
• Reactome Pathway: Ubiquinol biosynthesis (R-HSA-2142789)
• BioCyc Pathway: MetaCyc:ENSG00000167186-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coenzyme Q10 deficiency	DIS1HGDF	Strong	Genetic Variation	[1]
Primary coenzyme Q10 deficiency 8	DIS5Z1NR	Strong	Autosomal recessive	[1]
Steroid-resistant nephrotic syndrome	DISVEBC9	Strong	Biomarker	[2]

10 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 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7).	[3]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7).	[10]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7).	[11]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7).	[7]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the methylation of 5-demethoxyubiquinone hydroxylase, mitochondrial (COQ7).	[13]

References

• [1] Rescue of primary ubiquinone deficiency due to a novel COQ7 defect using 2,4-dihydroxybensoic acid. J Med Genet. 2015 Nov;52(11):779-83. doi: 10.1136/jmedgenet-2015-102986. Epub 2015 Jun 17.
• [2] ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest. 2013 Dec;123(12):5179-89. doi: 10.1172/JCI69000. Epub 2013 Nov 25.
• [3] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [8] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [9] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [13] Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women. Environ Health Perspect. 2022 Apr;130(4):47001. doi: 10.1289/EHP10174. Epub 2022 Apr 4.