Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU0FC24)

• DOT Name: Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1)
• Synonyms: Cytochrome c oxidase polypeptide IV; Cytochrome c oxidase subunit IV isoform 1; COX IV-1
• Gene Name: COX4I1
• Related Disease:
  Depression
  Dilated cardiomyopathy 1A
  Fanconi anemia complementation group A
  Fanconi's anemia
  Glioma
  Hyperglycemia
  Myocardial ischemia
  Myopathy
  Neoplasm
  Non-insulin dependent diabetes
  Obesity
  Fetal growth restriction
  Leprosy
  Cytochrome-c oxidase deficiency disease
  Breast cancer
  Breast carcinoma
  High blood pressure
  Leigh syndrome
  Lysosomal storage disease
  Mitochondrial complex 4 deficiency, nuclear type 16
• UniProt ID: COX41_HUMAN
• PDB ID: 5Z62
• Pfam ID: PF02936
• Sequence:
  MLATRVFSLVGKRAISTSVCVRAHESVVKSEDFSLPAYMDRRDHPLPEVAHVKHLSASQK
  ALKEKEKASWSSLSMDEKVELYRIKFKESFAEMNRGSNEWKTVVGGAMFFIGFTALVIMW
  QKHYVYGPLPQSFDKEWVAKQTKRMLDMKVNPIQGLASKWDYEKNEWKK
• 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.
• Tissue Specificity: Ubiquitous.
• 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:HS05494-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Depression	DIS3XJ69	Strong	Biomarker	[1]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[2]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Genetic Variation	[3]
Fanconi's anemia	DISGW6Q8	Strong	Genetic Variation	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Hyperglycemia	DIS0BZB5	Strong	Altered Expression	[5]
Myocardial ischemia	DISFTVXF	Strong	Altered Expression	[6]
Myopathy	DISOWG27	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[9]
Obesity	DIS47Y1K	Strong	Biomarker	[1]
Fetal growth restriction	DIS5WEJ5	moderate	Biomarker	[10]
Leprosy	DISAA4UI	moderate	Genetic Variation	[11]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Supportive	Autosomal recessive	[3]
Breast cancer	DIS7DPX1	Limited	Biomarker	[12]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[12]
High blood pressure	DISY2OHH	Limited	Biomarker	[13]
Leigh syndrome	DISWQU45	Limited	Autosomal recessive	[14]
Lysosomal storage disease	DIS6QM6U	Limited	Altered Expression	[15]
Mitochondrial complex 4 deficiency, nuclear type 16	DISZ3GMO	Limited	Autosomal recessive	[16]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Zidovudine	DM4KI7O	Approved	Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1) increases the Cell-mediated cytotoxicity ADR of Zidovudine.	[32]
Chlorothiazide	DMLHESP	Approved	Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1) increases the Metabolic disorder ADR of Chlorothiazide.	[33]
Zalcitabine	DMH7MUV	Approved	Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1) increases the Cell-mediated cytotoxicity ADR of Zalcitabine.	[32]
Didanosine	DMI2QPE	Approved	Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1) increases the Cell-mediated cytotoxicity ADR of Didanosine.	[32]

15 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 subunit 4 isoform 1, mitochondrial (COX4I1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[21]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[22]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[23]
Mitotane	DMU1GX0	Approved	Mitotane decreases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[24]
SPI-1005	DM6XFHS	Phase 2 Trial	SPI-1005 increases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[26]
Metoprine	DM5GQD7	Phase 2	Metoprine decreases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[29]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[30]
D-glucose	DMMG2TO	Investigative	D-glucose increases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[31]
XCT790	DMZ7N8D	Investigative	XCT790 decreases the expression of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[27]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1).	[25]

References

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• [18] Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity. Toxicol Lett. 2017 Jun 5;275:28-38. doi: 10.1016/j.toxlet.2017.04.018. Epub 2017 Apr 27.
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• [20] Acquisition of temozolomide chemoresistance in gliomas leads to remodeling of mitochondrial electron transport chain. J Biol Chem. 2010 Dec 17;285(51):39759-67. doi: 10.1074/jbc.M110.147504. Epub 2010 Sep 24.
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• [22] HIF and reactive oxygen species regulate oxidative phosphorylation in cancer. Carcinogenesis. 2008 Aug;29(8):1528-37. doi: 10.1093/carcin/bgn125. Epub 2008 May 29.
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• [25] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
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