Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT67PIDP)

• DOT Name: Cytochrome c oxidase subunit 7B, mitochondrial (COX7B)
• Synonyms: Cytochrome c oxidase polypeptide VIIb
• Gene Name: COX7B
• Related Disease:
  Linear skin defects with multiple congenital anomalies 2
  Advanced cancer
  Bladder cancer
  Familial hypercholesterolemia
  Hypercholesterolemia, familial, 1
  Linear skin defects with multiple congenital anomalies 1
  Urinary bladder cancer
  Isolated congenital microcephaly
  Microphthalmia
  Nasopharyngeal carcinoma
  Linear skin defects with multiple congenital anomalies
• UniProt ID: COX7B_HUMAN
• PDB ID: 5Z62
• Pfam ID: PF05392
• Sequence:
  MFPLVKSALNRLQVRSIQQTMARQSHQKRTPDFHDKYGNAVLASGATFCIVTWTYVATQV
  GIEWNLSPVGRVTPKEWRNQ
• 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. Plays a role in proper central nervous system (CNS) development in vertebrates.
• 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:HS05498-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Linear skin defects with multiple congenital anomalies 2	DISLYTR8	Definitive	X-linked	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[2]
Familial hypercholesterolemia	DISC06IX	Strong	Biomarker	[3]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Biomarker	[3]
Linear skin defects with multiple congenital anomalies 1	DISNYKBT	Strong	Genetic Variation	[4]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[2]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[1]
Microphthalmia	DISGEBES	moderate	Biomarker	[1]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[5]
Linear skin defects with multiple congenital anomalies	DIS5BT4L	Supportive	X-linked	[1]

16 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 7B, mitochondrial (COX7B).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[13]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[15]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[16]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[20]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[21]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[22]

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 increases the methylation of Cytochrome c oxidase subunit 7B, mitochondrial (COX7B).	[18]

References

• [1] Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease. Am J Hum Genet. 2012 Nov 2;91(5):942-9. doi: 10.1016/j.ajhg.2012.09.016.
• [2] Single-cell RNA-seq analysis reveals the platinum resistance gene COX7B and the surrogate marker CD63.Cancer Med. 2018 Dec;7(12):6193-6204. doi: 10.1002/cam4.1828. Epub 2018 Oct 26.
• [3] Cytochrome c oxidase subunit VIIb as a potential target in familial hypercholesterolemia by bioinformatical analysis.Eur Rev Med Pharmacol Sci. 2015 Nov;19(21):4139-45.
• [4] Mutations in NDUFB11, encoding a complex I component of the mitochondrial respiratory chain, cause microphthalmia with linear skin defects syndrome. Am J Hum Genet. 2015 Apr 2;96(4):640-50. doi: 10.1016/j.ajhg.2015.02.002. Epub 2015 Mar 12.
• [5] Identification of candidate molecular markers of nasopharyngeal carcinoma by tissue microarray and in situ hybridization.Med Oncol. 2011 Dec;28 Suppl 1:S341-8. doi: 10.1007/s12032-010-9727-5. Epub 2010 Nov 5.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] 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.
• [8] 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.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] 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.
• [12] 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.
• [13] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [14] 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.
• [15] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [20] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [21] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [22] 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.