Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZWW1FX)

• DOT Name: Ubiquinone biosynthesis monooxygenase COQ6, mitochondrial (COQ6)
• Synonyms: EC 1.14.13.-; Coenzyme Q10 monooxygenase 6
• Gene Name: COQ6
• Related Disease:
  Coenzyme Q10 deficiency
  Familial steroid-resistant nephrotic syndrome with sensorineural deafness
  Nephrotic syndrome
  Sensorineural hearing loss disorder
  Steroid-resistant nephrotic syndrome
  Focal segmental glomerulosclerosis
  Schwannomatosis
  Schwannomatosis 1
• UniProt ID: COQ6_HUMAN
• EC Number: 1.14.13.-
• Pfam ID: PF01494
• Sequence:
  MAARLVSRCGAVRAAPHSGPLVSWRRWSGASTDTVYDVVVSGGGLVGAAMACALGYDIHF
  HDKKILLLEAGPKKVLEKLSETYSNRVSSISPGSATLLSSFGAWDHICNMRYRAFRRMQV
  WDACSEALIMFDKDNLDDMGYIVENDVIMHALTKQLEAVSDRVTVLYRSKAIRYTWPCPF
  PMADSSPWVHITLGDGSTFQTKLLIGADGHNSGVRQAVGIQNVSWNYDQSAVVATLHLSE
  ATENNVAWQRFLPSGPIALLPLSDTLSSLVWSTSHEHAAELVSMDEEKFVDAVNSAFWSD
  ADHTDFIDTAGAMLQYAVSLLKPTKVSARQLPPSVARVDAKSRVLFPLGLGHAAEYVRPR
  VALIGDAAHRVHPLAGQGVNMGFGDISSLAHHLSTAAFNGKDLGSVSHLTGYETERQRHN
  TALLAATDLLKRLYSTSASPLVLLRTWGLQATNAVSPLKEQIMAFASK
• Function: FAD-dependent monooxygenase required for the C5-ring hydroxylation during ubiquinone biosynthesis. Catalyzes the hydroxylation of 3-hexaprenyl-4-hydroxybenzoic acid (HHB) to 3-hexaprenyl-4,5-dihydroxybenzoic acid (DHHB). The electrons required for the hydroxylation reaction may be funneled indirectly from NADPH via a ferredoxin/ferredoxin reductase system to COQ6. Is able to perform the deamination reaction at C4 of 3-hexaprenyl-4-amino-5-hydroxybenzoic acid (HHAB) to produce DHHB when expressed in yeast cells lacking COQ9, even if utilization of para-aminobenzoic acid (pABA) involving C4-deamination seems not to occur in bacteria, plants and mammals, where only C5 hydroxylation of HHB has been shown.
• Tissue Specificity: Widely expressed.
• 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:ENSG00000119723-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coenzyme Q10 deficiency	DIS1HGDF	Strong	Genetic Variation	[1]
Familial steroid-resistant nephrotic syndrome with sensorineural deafness	DISIM44J	Strong	Autosomal recessive	[2]
Nephrotic syndrome	DISSPSC2	Strong	Genetic Variation	[1]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[1]
Steroid-resistant nephrotic syndrome	DISVEBC9	Strong	Genetic Variation	[3]
Focal segmental glomerulosclerosis	DISJNHH0	Limited	Genetic Variation	[4]
Schwannomatosis	DISDWAM1	Limited	Genetic Variation	[5]
Schwannomatosis 1	DISFDUF2	Limited	Autosomal dominant	[6]

6 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 monooxygenase COQ6, mitochondrial (COQ6).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ubiquinone biosynthesis monooxygenase COQ6, mitochondrial (COQ6).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ubiquinone biosynthesis monooxygenase COQ6, mitochondrial (COQ6).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Ubiquinone biosynthesis monooxygenase COQ6, mitochondrial (COQ6).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ubiquinone biosynthesis monooxygenase COQ6, mitochondrial (COQ6).	[11]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Ubiquinone biosynthesis monooxygenase COQ6, mitochondrial (COQ6).	[12]

References

• [1] Primary coenzyme Q10 Deficiency-6 (COQ10D6): Two siblings with variable expressivity of the renal phenotype.Eur J Med Genet. 2020 Jan;63(1):103621. doi: 10.1016/j.ejmg.2019.01.011. Epub 2019 Jan 22.
• [2] COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest. 2011 May;121(5):2013-24. doi: 10.1172/JCI45693. Epub 2011 Apr 11.
• [3] Treatment with 2,4-Dihydroxybenzoic Acid Prevents FSGS Progression and Renal Fibrosis in Podocyte-Specific Coq6 Knockout Mice.J Am Soc Nephrol. 2019 Mar;30(3):393-405. doi: 10.1681/ASN.2018060625. Epub 2019 Feb 8.
• [4] New Mutation of Coenzyme Q(10) Monooxygenase 6 Causing Podocyte Injury in a Focal Segmental Glomerulosclerosis Patient.Chin Med J (Engl). 2018 Nov 20;131(22):2666-2675. doi: 10.4103/0366-6999.245158.
• [5] A germline missense mutation in COQ6 is associated with susceptibility to familial schwannomatosis.Genet Med. 2014 Oct;16(10):787-92. doi: 10.1038/gim.2014.39. Epub 2014 Apr 24.
• [6] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] 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.
• [11] 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.
• [12] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.