Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB98B21)

• DOT Name: Cytochrome c oxidase subunit 4 isoform 2, mitochondrial (COX4I2)
• Synonyms: Cytochrome c oxidase subunit IV isoform 2; COX IV-2
• Gene Name: COX4I2
• Related Disease:
  Anemia
  Cytochrome-c oxidase deficiency disease
  Dilated cardiomyopathy 1A
  Exocrine pancreatic insufficiency
  Hyperglycemia
  Malabsorption syndrome
  Myocardial ischemia
  Myopathy
  Neoplasm
  Pancreatic insufficiency-anemia-hyperostosis syndrome
  Mitochondrial disease
• UniProt ID: COX42_HUMAN
• Pfam ID: PF02936
• Sequence:
  MLPRAAWSLVLRKGGGGRRGMHSSEGTTRGGGKMSPYTNCYAQRYYPMPEEPFCTELNAE
  EQALKEKEKGSWTQLTHAEKVALYRLQFNETFAEMNRRSNEWKTVMGCVFFFIGFAALVI
  WWQRVYVFPPKPITLTDERKAQQLQRMLDMKVNPVQGLASRWDYEKKQWKK
• 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: Highly expressed in lung.
• 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)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anemia	DISTVL0C	Strong	Genetic Variation	[1]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Biomarker	[2]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[3]
Exocrine pancreatic insufficiency	DISCZYU2	Strong	Biomarker	[1]
Hyperglycemia	DIS0BZB5	Strong	Altered Expression	[4]
Malabsorption syndrome	DISGMUVS	Strong	Biomarker	[1]
Myocardial ischemia	DISFTVXF	Strong	Altered Expression	[5]
Myopathy	DISOWG27	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Pancreatic insufficiency-anemia-hyperostosis syndrome	DISSE2Y8	Supportive	Autosomal recessive	[8]
Mitochondrial disease	DISKAHA3	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome c oxidase subunit 4 isoform 2, mitochondrial (COX4I2).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cytochrome c oxidase subunit 4 isoform 2, mitochondrial (COX4I2).	[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 subunit 4 isoform 2, mitochondrial (COX4I2).	[12]

References

• [1] Exocrine pancreatic insufficiency, dyserythropoeitic anemia, and calvarial hyperostosis are caused by a mutation in the COX4I2 gene.Am J Hum Genet. 2009 Mar;84(3):412-7. doi: 10.1016/j.ajhg.2009.02.006. Epub 2009 Mar 5.
• [2] Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy.Antioxid Redox Signal. 2011 Jul 15;15(2):353-62. doi: 10.1089/ars.2010.3520. Epub 2011 Feb 25.
• [3] Myocardial insufficiency is related to reduced subunit 4 content of cytochrome c oxidase.J Cardiothorac Surg. 2018 Sep 17;13(1):95. doi: 10.1186/s13019-018-0785-7.
• [4] Transcutaneous carbon dioxide attenuates impaired oxidative capacity in skeletal muscle in hyperglycemia model.Gen Physiol Biophys. 2019 May;38(3):237-244. doi: 10.4149/gpb_2018048.
• [5] Mitochondrial Morphology, Dynamics, and Function in Human Pressure Overload or Ischemic Heart Disease With Preserved or Reduced Ejection Fraction.Circ Heart Fail. 2019 Feb;12(2):e005131. doi: 10.1161/CIRCHEARTFAILURE.118.005131.
• [6] Cytochrome c oxidase deficiency in the muscle of patients with zidovudine myopathy is segmental and affects both mitochondrial DNA- and nuclear DNA-encoded subunits.Acta Neuropathol. 2000 Jul;100(1):82-6. doi: 10.1007/s004010051196.
• [7] Caffeine induces metformin anticancer effect on fibrosarcoma in hamsters.Eur Rev Med Pharmacol Sci. 2018 Apr;22(8):2461-2467. doi: 10.26355/eurrev_201804_14840.
• [8] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [9] High-resolution melting analysis of 15 genes in 60 patients with cytochrome-c oxidase deficiency.J Hum Genet. 2012 Jul;57(7):442-8. doi: 10.1038/jhg.2012.49. Epub 2012 May 17.
• [10] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [11] 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.
• [12] 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.