Details of Drug Off-Target (DOT)

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

• DOT Name: Cytochrome c oxidase assembly protein COX16 homolog, mitochondrial (COX16)
• Synonyms: hCOX16
• Gene Name: COX16
• Related Disease:
  Cytochrome-c oxidase deficiency disease
  Renal tubular acidosis
  Mitochondrial complex IV deficiency, nuclear type 22
• UniProt ID: COX16_HUMAN
• Pfam ID: PF14138
• Sequence:
  MFAPAVMRAFRKNKTLGYGVPMLLLIVGGSFGLREFSQIRYDAVKSKMDPELEKKLKENK
  ISLESEYEKIKDSKFDDWKNIRGPRPWEDPDLLQGRNPESLKTKTT
• Function: Required for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase. Promotes the insertion of copper into the active site of cytochrome c oxidase subunit II (MT-CO2/COX2). Interacts specifically with newly synthesized MT-CO2/COX and its copper center-forming metallochaperones SCO1, SCO2 and COA6. Probably facilitates MT-CO2/COX2 association with the MITRAC assembly intermediate containing MT-CO1/COX1, thereby participating in merging the MT-CO1/COX1 and MT-CO2/COX2 assembly lines.
• Tissue Specificity: Widely expressed. Expressed at higher level in skeletal muscle, heart and liver.
• 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

3 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]
Renal tubular acidosis	DISE1NDR	Strong	Genetic Variation	[2]
Mitochondrial complex IV deficiency, nuclear type 22	DISEYURW	Limited	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Cytochrome c oxidase assembly protein COX16 homolog, mitochondrial (COX16).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytochrome c oxidase assembly protein COX16 homolog, mitochondrial (COX16).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome c oxidase assembly protein COX16 homolog, mitochondrial (COX16).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cytochrome c oxidase assembly protein COX16 homolog, mitochondrial (COX16).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cytochrome c oxidase assembly protein COX16 homolog, mitochondrial (COX16).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytochrome c oxidase assembly protein COX16 homolog, mitochondrial (COX16).	[10]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Cytochrome c oxidase assembly protein COX16 homolog, mitochondrial (COX16).	[11]

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 decreases the methylation of Cytochrome c oxidase assembly protein COX16 homolog, mitochondrial (COX16).	[9]

References

• [1] Studies of COX16, COX19, and PET191 in human cytochrome-c oxidase deficiency.Arch Neurol. 2004 Dec;61(12):1935-7. doi: 10.1001/archneur.61.12.1935.
• [2] Sideroblastic anemia associated with multisystem mitochondrial disorders.Pediatr Blood Cancer. 2019 Apr;66(4):e27591. doi: 10.1002/pbc.27591. Epub 2018 Dec 26.
• [3] A novel variant in COX16 causes cytochrome c oxidase deficiency, severe fatal neonatal lactic acidosis, encephalopathy, cardiomyopathy, and liver dysfunction. Hum Mutat. 2021 Feb;42(2):135-141. doi: 10.1002/humu.24137. Epub 2020 Nov 30.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Human 3D multicellular microtissues: an upgraded model for the in vitro mechanistic investigation of inflammation-associated drug toxicity. Toxicol Lett. 2019 Sep 15;312:34-44.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [10] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [11] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.