Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBY50BD)

• DOT Name: Atypical kinase COQ8B, mitochondrial (COQ8B)
• Synonyms: EC 2.7.-.-; AarF domain-containing protein kinase 4; Coenzyme Q protein 8B
• Gene Name: COQ8B
• Related Disease:
  Mitochondrial disease
  Nephrotic syndrome, type 9
  Alport syndrome
  Aortic aneurysm
  Coenzyme Q10 deficiency
  End-stage renal disease
  Focal segmental glomerulosclerosis
  Kidney failure
  Nephropathy
  Nephrotic syndrome, type 2
  Retinitis pigmentosa
  Steroid-resistant nephrotic syndrome
  Chronic kidney disease
  Chronic renal failure
  Familial idiopathic steroid-resistant nephrotic syndrome
  Autosomal dominant polycystic kidney disease
  Familial nephrotic syndrome
  Nephrotic syndrome
• UniProt ID: COQ8B_HUMAN
• EC Number: 2.7.-.-
• Pfam ID: PF03109
• Sequence:
  MWLKVGGLLRGTGGQLGQTVGWPCGALGPGPHRWGPCGGSWAQKFYQDGPGRGLGEEDIR
  RAREARPRKTPRPQLSDRSRERKVPASRISRLANFGGLAVGLGLGVLAEMAKKSMPGGRL
  QSEGGSGLDSSPFLSEANAERIVQTLCTVRGAALKVGQMLSIQDNSFISPQLQHIFERVR
  QSADFMPRWQMLRVLEEELGRDWQAKVASLEEVPFAAASIGQVHQGLLRDGTEVAVKIQY
  PGIAQSIQSDVQNLLAVLKMSAALPAGLFAEQSLQALQQELAWECDYRREAACAQNFRQL
  LANDPFFRVPAVVKELCTTRVLGMELAGGVPLDQCQGLSQDLRNQICFQLLTLCLRELFE
  FRFMQTDPNWANFLYDASSHQVTLLDFGASREFGTEFTDHYIEVVKAAADGDRDCVLQKS
  RDLKFLTGFETKAFSDAHVEAVMILGEPFATQGPYDFGSGETARRIQDLIPVLLRHRLCP
  PPEETYALHRKLAGAFLACAHLRAHIACRDLFQDTYHRYWASRQPDAATAGSLPTKGDSW
  VDPS
• 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. Required for podocyte migration.
• Tissue Specificity: Widely expressed, including renal podocytes.
• BioCyc Pathway: MetaCyc:ENSG00000123815-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[1]
Nephrotic syndrome, type 9	DIS8XZUX	Definitive	Autosomal recessive	[2]
Alport syndrome	DIS25AB4	Strong	Genetic Variation	[3]
Aortic aneurysm	DISQ5KRA	Strong	Genetic Variation	[4]
Coenzyme Q10 deficiency	DIS1HGDF	Strong	Genetic Variation	[5]
End-stage renal disease	DISXA7GG	Strong	Genetic Variation	[6]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Biomarker	[7]
Kidney failure	DISOVQ9P	Strong	Genetic Variation	[8]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[9]
Nephrotic syndrome, type 2	DISIRFO1	Strong	GermlineCausalMutation	[10]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[11]
Steroid-resistant nephrotic syndrome	DISVEBC9	Strong	Genetic Variation	[12]
Chronic kidney disease	DISW82R7	moderate	Genetic Variation	[6]
Chronic renal failure	DISGG7K6	moderate	Genetic Variation	[6]
Familial idiopathic steroid-resistant nephrotic syndrome	DISQ53RS	Supportive	Autosomal dominant	[10]
Autosomal dominant polycystic kidney disease	DISBHWUI	Limited	Genetic Variation	[13]
Familial nephrotic syndrome	DISADF8G	Limited	Genetic Variation	[14]
Nephrotic syndrome	DISSPSC2	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Atypical kinase COQ8B, mitochondrial (COQ8B).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Atypical kinase COQ8B, mitochondrial (COQ8B).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Atypical kinase COQ8B, mitochondrial (COQ8B).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Atypical kinase COQ8B, mitochondrial (COQ8B).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Atypical kinase COQ8B, mitochondrial (COQ8B).	[20]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Atypical kinase COQ8B, mitochondrial (COQ8B).	[21]

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] 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.
• [3] Reassessing the pathogenicity of c.2858G>T(p.(G953V)) in COL4A5 Gene: report of 19 Chinese families.Eur J Hum Genet. 2020 Feb;28(2):244-252. doi: 10.1038/s41431-019-0523-1. Epub 2019 Oct 1.
• [4] Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity.J Cardiovasc Transl Res. 2017 Aug;10(4):423-432. doi: 10.1007/s12265-017-9753-1. Epub 2017 May 26.
• [5] 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.
• [6] Follow-up results of patients with ADCK4 mutations and the efficacy of CoQ10 treatment.Pediatr Nephrol. 2017 Aug;32(8):1369-1375. doi: 10.1007/s00467-017-3634-3. Epub 2017 Mar 24.
• [7] Focal segmental glomerulosclerosis and medullary nephrocalcinosis in children with ADCK4 mutations.Pediatr Nephrol. 2017 Sep;32(9):1547-1554. doi: 10.1007/s00467-017-3657-9. Epub 2017 Apr 12.
• [8] Early-onset of ADCK4 glomerulopathy with renal failure: a case report.BMC Med Genet. 2017 Mar 16;18(1):28. doi: 10.1186/s12881-017-0392-9.
• [9] A novel ADCK4 mutation in a Chinese family with ADCK4-Associated glomerulopathy.Biochem Biophys Res Commun. 2018 Nov 30;506(3):444-449. doi: 10.1016/j.bbrc.2018.10.102. Epub 2018 Oct 21.
• [10] 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.
• [11] ADCK4-Associated Glomerulopathy Causes Adolescence-Onset FSGS.J Am Soc Nephrol. 2016 Jan;27(1):63-8. doi: 10.1681/ASN.2014121240. Epub 2015 May 12.
• [12] Mutations in COQ8B (ADCK4) found in patients with steroid-resistant nephrotic syndrome alter COQ8B function.Hum Mutat. 2018 Mar;39(3):406-414. doi: 10.1002/humu.23376. Epub 2017 Dec 18.
• [13] Urinary proteome signature of Renal Cysts and Diabetes syndrome in children.Sci Rep. 2019 Feb 18;9(1):2225. doi: 10.1038/s41598-019-38713-5.
• [14] Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome.Pediatr Nephrol. 2017 Jul;32(7):1181-1192. doi: 10.1007/s00467-017-3590-y. Epub 2017 Feb 15.
• [15] ADCK4 "reenergizes" nephrotic syndrome.J Clin Invest. 2013 Dec;123(12):4996-9. doi: 10.1172/JCI73168. Epub 2013 Nov 25.
• [16] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [17] 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.
• [18] 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.
• [19] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [20] 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.
• [21] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.