Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDP94F3)

• DOT Name: Cytochrome c oxidase subunit 5B, mitochondrial (COX5B)
• Synonyms: Cytochrome c oxidase polypeptide Vb
• Gene Name: COX5B
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Glioma
  Head-neck squamous cell carcinoma
  Invasive ductal breast carcinoma
  Myocardial ischemia
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  High blood pressure
  Kennedy disease
  Non-insulin dependent diabetes
• UniProt ID: COX5B_HUMAN
• PDB ID: 5Z62
• Pfam ID: PF01215
• Sequence:
  MASRLLRGAGTLAAQALRARGPSGAAAMRSMASGGGVPTDEEQATGLEREIMLAAKKGLD
  PYNVLAPKGASGTREDPNLVPSISNKRIVGCICEEDNTSVVWFWLHKGEAQRCPRCGAHY
  KLVPQQLAH
• 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:HS06090-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[1]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[2]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[3]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[5]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[5]
High blood pressure	DISY2OHH	Disputed	Biomarker	[7]
Kennedy disease	DISXZVM1	Limited	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[9]

16 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 5B, mitochondrial (COX5B).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[16]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[17]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[18]
Zidovudine	DM4KI7O	Approved	Zidovudine decreases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[19]
Coprexa	DMA0WEK	Phase 3	Coprexa increases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[16]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[23]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[24]
Myricetin	DMTV4L0	Investigative	Myricetin increases the expression of Cytochrome c oxidase subunit 5B, mitochondrial (COX5B).	[25]

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 subunit 5B, mitochondrial (COX5B).	[21]

References

• [1] Identification of COX5B as a novel biomarker in high-grade glioma patients.Onco Targets Ther. 2017 Nov 15;10:5463-5470. doi: 10.2147/OTT.S139243. eCollection 2017.
• [2] Immunometabolic Determinants of Chemoradiotherapy Response and Survival in Head and Neck Squamous Cell Carcinoma.Am J Pathol. 2018 Jan;188(1):72-83. doi: 10.1016/j.ajpath.2017.09.013. Epub 2017 Oct 27.
• [3] High expression of COX5B is associated with poor prognosis in breast cancer.Future Oncol. 2017 Aug;13(19):1711-1719. doi: 10.2217/fon-2017-0058. Epub 2017 Jun 8.
• [4] 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.
• [5] Investigating key genes associated with ovarian cancer by integrating affinity propagation clustering and mutual information network analysis.Eur Rev Med Pharmacol Sci. 2016 Jun;20(12):2532-40.
• [6] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
• [7] The profile of cardiac cytochrome c oxidase (COX) expression in an accelerated cardiac-hypertrophy model.J Biomed Sci. 2005;12(4):601-10. doi: 10.1007/s11373-005-7373-2. Epub 2005 Nov 10.
• [8] Cytochrome c oxidase subunit Vb interacts with human androgen receptor: a potential mechanism for neurotoxicity in spinobulbar muscular atrophy.Brain Res Bull. 2001 Oct-Nov 1;56(3-4):285-97. doi: 10.1016/s0361-9230(01)00583-4.
• [9] Common variation in oxidative phosphorylation genes is not a major cause of insulin resistance or type 2 diabetes.Diabetologia. 2012 Feb;55(2):340-8. doi: 10.1007/s00125-011-2377-0. Epub 2011 Nov 18.
• [10] 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.
• [11] 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.
• [12] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [13] 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.
• [14] 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.
• [15] Proteomic analysis of liver cancer cells treated with suberonylanilide hydroxamic acid. Cancer Chemother Pharmacol. 2008 Apr;61(5):791-802.
• [16] Synergistic effect of trichostatin A and 5-aza-2'-deoxycytidine on growth inhibition of pancreatic endocrine tumour cell lines: a proteomic study. Proteomics. 2009 Apr;9(7):1952-66. doi: 10.1002/pmic.200701089.
• [17] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [18] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [19] Expression of cytochrome c oxidase subunits encoded by mitochondrial or nuclear DNA in the muscle of patients with zidovudine myopathy. J Neurol Sci. 1994 Sep;125(2):190-3. doi: 10.1016/0022-510x(94)90034-5.
• [20] Copper chelator ATN-224 inhibits endothelial function by multiple mechanisms. Microvasc Res. 2009 May;77(3):314-26.
• [21] 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.
• [22] 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.
• [23] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [24] In vitro gene expression data supporting a DNA non-reactive genotoxic mechanism for ochratoxin A. Toxicol Appl Pharmacol. 2007 Apr 15;220(2):216-24.
• [25] Potential role of nucleoside diphosphate kinase in myricetin-induced selective apoptosis in colon cancer HCT-15?cells. Food Chem Toxicol. 2018 Jun;116(Pt B):315-322. doi: 10.1016/j.fct.2018.04.053. Epub 2018 Apr 24.