Details of Drug Off-Target (DOT)

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

• DOT Name: Cytochrome c oxidase subunit 6B1 (COX6B1)
• Synonyms: Cytochrome c oxidase subunit VIb isoform 1; COX VIb-1
• Gene Name: COX6B1
• Related Disease:
  Cytochrome-c oxidase deficiency disease
  Mitochondrial disease
  Alzheimer disease
  Cardiomyopathy
  Clear cell renal carcinoma
  Hydrocephalus
  Mitochondrial complex 4 deficiency, nuclear type 7
• UniProt ID: CX6B1_HUMAN
• PDB ID: 5Z62
• Pfam ID: PF02297
• Sequence:
  MAEDMETKIKNYKTAPFDSRFPNQNQTRNCWQNYLDFHRCQKAMTAKGGDISVCEWYQRV
  YQSLCPTSWVTDWDEQRAEGTFPGKI
• Function: Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Cardiac muscle contraction (hsa04260)
  Thermogenesis (hsa04714)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Respiratory electron transport (R-HSA-611105)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
• BioCyc Pathway: MetaCyc:HS05010-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cytochrome-c oxidase deficiency disease	DISK7N3G	Definitive	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[3]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[5]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[4]
Mitochondrial complex 4 deficiency, nuclear type 7	DISE3BGM	Strong	Autosomal recessive	[6]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Vinblastine	DM5TVS3	Approved	Cytochrome c oxidase subunit 6B1 (COX6B1) affects the response to substance of Vinblastine.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Cytochrome c oxidase subunit 6B1 (COX6B1).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytochrome c oxidase subunit 6B1 (COX6B1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome c oxidase subunit 6B1 (COX6B1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytochrome c oxidase subunit 6B1 (COX6B1).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome c oxidase subunit 6B1 (COX6B1).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Cytochrome c oxidase subunit 6B1 (COX6B1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Cytochrome c oxidase subunit 6B1 (COX6B1).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Cytochrome c oxidase subunit 6B1 (COX6B1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cytochrome c oxidase subunit 6B1 (COX6B1).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Cytochrome c oxidase subunit 6B1 (COX6B1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Cytochrome c oxidase subunit 6B1 (COX6B1).	[12]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] 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.
• [3] Genetic association of the cytochrome c oxidase-related genes with Alzheimer's disease in Han Chinese.Neuropsychopharmacology. 2018 Oct;43(11):2264-2276. doi: 10.1038/s41386-018-0144-3. Epub 2018 Jul 6.
• [4] Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy.Eur J Hum Genet. 2015 Feb;23(2):159-64. doi: 10.1038/ejhg.2014.85. Epub 2014 Apr 30.
• [5] Systematic expression analysis of the mitochondrial respiratory chain protein subunits identifies COX5B as a prognostic marker in clear cell renal cell carcinoma.Int J Urol. 2019 Sep;26(9):910-916. doi: 10.1111/iju.14040. Epub 2019 Jul 7.
• [6] Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase. Am J Hum Genet. 2008 Jun;82(6):1281-9. doi: 10.1016/j.ajhg.2008.05.002. Epub 2008 May 22.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] 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.
• [9] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [10] 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.
• [11] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [12] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [13] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [14] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [17] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [18] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.