Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVT146E)

• DOT Name: Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2)
• Synonyms: Cytochrome c oxidase subunit VIIa-liver/heart; Cytochrome c oxidase subunit VIIa-L; Cytochrome c oxidase subunit VIIaL
• Gene Name: COX7A2
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Glioblastoma multiforme
  Glioma
  Neoplasm
• UniProt ID: CX7A2_HUMAN
• PDB ID: 5Z62
• Pfam ID: PF02238
• Sequence:
  MLRNLLALRQIGQRTISTASRRHFKNKVPEKQKLFQEDDEIPLYLKGGVADALLYRATMI
  LTVGGTAYAIYELAVASFPKKQE
• 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)
• BioCyc Pathway: MetaCyc:HS03606-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 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	[1]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]

15 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 7A2, mitochondrial (COX7A2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[7]
Marinol	DM70IK5	Approved	Marinol increases the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[8]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[10]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[11]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[16]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[17]

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 affects the methylation of Cytochrome c oxidase subunit 7A2, mitochondrial (COX7A2).	[13]

References

• [1] Overexpression of COX7A2 is associated with a good prognosis in patients with glioma.J Neurooncol. 2018 Jan;136(1):41-50. doi: 10.1007/s11060-017-2637-z. Epub 2017 Oct 27.
• [2] 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.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] 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.
• [8] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] 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.
• [11] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [12] Morphological and molecular course of mitochondrial pathology in cultured human cells exposed long-term to Zidovudine. Environ Mol Mutagen. 2007 Apr-May;48(3-4):179-89. doi: 10.1002/em.20245.
• [13] 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.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [15] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [17] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.