Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIRSG4N)

• DOT Name: Cytochrome c oxidase assembly protein COX18, mitochondrial (COX18)
• Synonyms: COX18Hs; Cytochrome c oxidase assembly protein 18
• Gene Name: COX18
• Related Disease:
  Cytochrome-c oxidase deficiency disease
  Mitochondrial disease
• UniProt ID: COX18_HUMAN
• Pfam ID: PF02096
• Sequence:
  MLCRLGGRWLRPLPALQLWARDLPLAPVPTSGAKRPTLPVWAVAPVSAVHANGWYEALAA
  SSPVRVAEEVLLGVHAATGLPWWGSILLSTVALRGAVTLPLAAYQHYILAKVENLQPEIK
  TIARHLNQEVAVRANQLGWSKRDARLTYLKNMRRLISELYVRDNCHPFKATVLVWIQLPM
  WIFMSFALRNLSTGAAHSEGFSVQEQLATGGILWFPDLTAPDSTWILPISVGVINLLIVE
  ICALQKIGMSRFQTYITYFVRAMSVLMIPIAATVPSSIVLYWLCSSFVGLSQNLLLRSPG
  FRQLCRIPSTKSDSETPYKDIFAAFNTKFISRK
• Function: Mitochondrial membrane insertase required for the translocation of the C-terminus of cytochrome c oxidase subunit II (MT-CO2/COX2) across the mitochondrial inner membrane. Plays a role in MT-CO2/COX2 maturation following the COX20-mediated stabilization of newly synthesized MT-CO2/COX2 protein and before the action of the metallochaperones SCO1/2. Essential for the assembly and stability of the mitochondrial respiratory chain complex IV (also known as cytochrome c oxidase).
• KEGG Pathway: Thermogenesis (hsa04714)
• Reactome Pathway:
  Respiratory electron transport (R-HSA-611105)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Genetic Variation	[1]
Mitochondrial disease	DISKAHA3	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 Cytochrome c oxidase assembly protein COX18, mitochondrial (COX18).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytochrome c oxidase assembly protein COX18, mitochondrial (COX18).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cytochrome c oxidase assembly protein COX18, mitochondrial (COX18).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome c oxidase assembly protein COX18, mitochondrial (COX18).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytochrome c oxidase assembly protein COX18, mitochondrial (COX18).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytochrome c oxidase assembly protein COX18, mitochondrial (COX18).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Cytochrome c oxidase assembly protein COX18, mitochondrial (COX18).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cytochrome c oxidase assembly protein COX18, mitochondrial (COX18).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cytochrome c oxidase assembly protein COX18, mitochondrial (COX18).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cytochrome c oxidase assembly protein COX18, mitochondrial (COX18).	[13]

1 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 increases the methylation of Cytochrome c oxidase assembly protein COX18, mitochondrial (COX18).	[11]

References

• [1] Mutation analysis of COX18 in 29 patients with isolated cytochrome c oxidase deficiency.J Hum Genet. 2009 Jul;54(7):419-21. doi: 10.1038/jhg.2009.36. Epub 2009 Apr 17.
• [2] 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.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] 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.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.