Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT52V2I)

• DOT Name: Cytochrome c oxidase assembly factor 6 homolog (COA6)
• Gene Name: COA6
• Related Disease:
  Hypertrophic cardiomyopathy
  Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4
  Cardiomyopathy
  Cerebellar ataxia
  Cytochrome-c oxidase deficiency disease
  Dystonia
  Progressive pseudorheumatoid arthropathy of childhood
• UniProt ID: COA6_HUMAN
• PDB ID: 6NL3; 6PCE; 6PCF
• Pfam ID: PF02297
• Sequence:
  MGPGGPLLSPSRGFLLCKTGWHSNRLLGDCGPHTPVSTALSFIAVGMAAPSMKERQVCWG
  ARDEYWKCLDENLEDASQCKKLRSSFESSCPQQWIKYFDKRRDYLKFKEKFEAGQFEPSE
  TTAKS
• Function: Involved in the maturation of the mitochondrial respiratory chain complex IV subunit MT-CO2/COX2. Thereby, may regulate early steps of complex IV assembly. Mitochondrial respiratory chain complex IV or cytochrome c oxidase is the component of the respiratory chain that catalyzes the transfer of electrons from intermembrane space cytochrome c to molecular oxygen in the matrix and as a consequence contributes to the proton gradient involved in mitochondrial ATP synthesis. May also be required for efficient formation of respiratory supercomplexes comprised of complexes III and IV.
• KEGG Pathway: Thermogenesis (hsa04714)
• Reactome Pathway: Mitochondrial protein import (R-HSA-1268020)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypertrophic cardiomyopathy	DISQG2AI	Definitive	Genetic Variation	[1]
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4	DISXJWBI	Strong	Unknown	[2]
Cardiomyopathy	DISUPZRG	Strong	Biomarker	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Biomarker	[4]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Genetic Variation	[1]
Dystonia	DISJLFGW	Strong	Biomarker	[4]
Progressive pseudorheumatoid arthropathy of childhood	DISBMRIW	Strong	Altered Expression	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cytochrome c oxidase assembly factor 6 homolog (COA6).	[6]

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 Cytochrome c oxidase assembly factor 6 homolog (COA6).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cytochrome c oxidase assembly factor 6 homolog (COA6).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cytochrome c oxidase assembly factor 6 homolog (COA6).	[9]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Cytochrome c oxidase assembly factor 6 homolog (COA6).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cytochrome c oxidase assembly factor 6 homolog (COA6).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cytochrome c oxidase assembly factor 6 homolog (COA6).	[12]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Cytochrome c oxidase assembly factor 6 homolog (COA6).	[13]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Cytochrome c oxidase assembly factor 6 homolog (COA6).	[14]

References

• [1] Mutations in COA6 cause cytochrome c oxidase deficiency and neonatal hypertrophic cardiomyopathy.Hum Mutat. 2015 Jan;36(1):34-8. doi: 10.1002/humu.22715. Epub 2014 Nov 18.
• [2] Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med. 2012 Jan 25;4(118):118ra10. doi: 10.1126/scitranslmed.3003310.
• [3] Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies.Cell Metab. 2015 Jun 2;21(6):823-33. doi: 10.1016/j.cmet.2015.04.012. Epub 2015 May 7.
• [4] Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module.J Biol Chem. 2017 May 12;292(19):7774-7783. doi: 10.1074/jbc.M117.778514. Epub 2017 Mar 22.
• [5] RNAi inhibition of feruloyl CoA 6'-hydroxylase reduces scopoletin biosynthesis and post-harvest physiological deterioration in cassava (Manihot esculenta Crantz) storage roots.Plant Mol Biol. 2017 May;94(1-2):185-195. doi: 10.1007/s11103-017-0602-z. Epub 2017 Mar 18.
• [6] 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.
• [7] 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.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [11] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [14] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.