Details of Drug Off-Target (DOT)

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

• DOT Name: Cytochrome c oxidase subunit 3 (COX3)
• Synonyms: EC 7.1.1.9; Cytochrome c oxidase polypeptide III
• Gene Name: COX3
• Related Disease:
  Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type
  Nephropathy
  Advanced cancer
  Alzheimer disease
  Carcinoma
  Childhood acute lymphoblastic leukemia
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Epilepsy
  Familial adenomatous polyposis
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Leber hereditary optic neuropathy
  MELAS syndrome
  Mitochondrial myopathy with reversible cytochrome C oxidase deficiency
  Neuromuscular disease
  Temporal lobe epilepsy
  Head-neck squamous cell carcinoma
  Autoimmune polyendocrinopathy
  Breast cancer
  Breast carcinoma
  Cataract
  Cytochrome-c oxidase deficiency disease
  Leigh syndrome
  Malaria
  Myopathy
  Neoplasm
• UniProt ID: COX3_HUMAN
• PDB ID: 5Z62
• EC Number: 7.1.1.9
• Pfam ID: PF00510
• Sequence:
  MTHQSHAYHMVKPSPWPLTGALSALLMTSGLAMWFHFHSMTLLMLGLLTNTLTMYQWWRD
  VTRESTYQGHHTPPVQKGLRYGMILFITSEVFFFAGFFWAFYHSSLAPTPQLGGHWPPTG
  ITPLNPLEVPLLNTSVLLASGVSITWAHHSLMENNRNQMIQALLITILLGLYFTLLQASE
  YFESPFTISDGIYGSTFFVATGFHGLHVIIGSTFLTICFIRQLMFHFTSKHHFGFEAAAW
  YWHFVDVVWLFLYVSIYWWGS
• 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:HS00028-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital lactic acidosis, Saguenay-Lac-Saint-Jean type	DISVZ0PJ	Definitive	Genetic Variation	[1]
Nephropathy	DISXWP4P	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[6]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[7]
Epilepsy	DISBB28L	Strong	Genetic Variation	[8]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[5]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[10]
Leber hereditary optic neuropathy	DIS7Y2EE	Strong	Genetic Variation	[11]
MELAS syndrome	DIS81Z3S	Strong	Genetic Variation	[12]
Mitochondrial myopathy with reversible cytochrome C oxidase deficiency	DISW3XTC	Strong	CausalMutation	[13]
Neuromuscular disease	DISQTIJZ	Strong	Genetic Variation	[14]
Temporal lobe epilepsy	DISNOPXX	Strong	Biomarker	[15]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[16]
Autoimmune polyendocrinopathy	DISOLDB2	Limited	Genetic Variation	[17]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[18]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[18]
Cataract	DISUD7SL	Limited	Altered Expression	[19]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Limited	GermlineCausalMutation	[13]
Leigh syndrome	DISWQU45	Limited	Genetic Variation	[20]
Malaria	DISQ9Y50	Limited	Biomarker	[21]
Myopathy	DISOWG27	Limited	Genetic Variation	[22]
Neoplasm	DISZKGEW	Limited	Altered Expression	[23]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gemcitabine	DMSE3I7	Approved	Cytochrome c oxidase subunit 3 (COX3) decreases the response to substance of Gemcitabine.	[38]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine triphosphate	DM79F6G	Approved	Cytochrome c oxidase subunit 3 (COX3) increases the abundance of Adenosine triphosphate.	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cytochrome c oxidase subunit 3 (COX3).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cytochrome c oxidase subunit 3 (COX3).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cytochrome c oxidase subunit 3 (COX3).	[26]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Cytochrome c oxidase subunit 3 (COX3).	[27]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Cytochrome c oxidase subunit 3 (COX3).	[28]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Cytochrome c oxidase subunit 3 (COX3).	[29]
Zalcitabine	DMH7MUV	Approved	Zalcitabine decreases the expression of Cytochrome c oxidase subunit 3 (COX3).	[30]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Cytochrome c oxidase subunit 3 (COX3).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the expression of Cytochrome c oxidase subunit 3 (COX3).	[32]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Cytochrome c oxidase subunit 3 (COX3).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cytochrome c oxidase subunit 3 (COX3).	[34]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cytochrome c oxidase subunit 3 (COX3).	[35]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Cytochrome c oxidase subunit 3 (COX3).	[36]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Cytochrome c oxidase subunit 3 (COX3).	[37]
Hydroxyestradiol	DMJXQME	Investigative	Hydroxyestradiol increases the expression of Cytochrome c oxidase subunit 3 (COX3).	[28]
2-hydroxy-17beta-estradiol	DMM9Z0B	Investigative	2-hydroxy-17beta-estradiol increases the expression of Cytochrome c oxidase subunit 3 (COX3).	[28]

References

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• [2] A novel mutation MT-COIII m.9267G>C and MT-COI m.5913G>A mutation in mitochondrial genes in a Tunisian family with maternally inherited diabetes and deafness (MIDD) associated with severe nephropathy.Biochem Biophys Res Commun. 2015 Apr 10;459(3):353-60. doi: 10.1016/j.bbrc.2015.01.151. Epub 2015 Feb 19.
• [3] The pattern of natural selection in somatic cancer mutations of human mtDNA.J Hum Genet. 2010 Sep;55(9):605-12. doi: 10.1038/jhg.2010.76. Epub 2010 Jul 8.
• [4] The T9861C Mutation in the mtDNA-Encoded Cytochrome C Oxidase Subunit III Gene Occurs in High Frequency but with Unequal Distribution in the Alzheimer's Disease Brain.J Alzheimers Dis. 2019;72(1):257-269. doi: 10.3233/JAD-190176.
• [5] Expression of mitochondrial cytochrome c oxidase in human colonic cell differentiation, transformation, and risk for colonic cancer.Cancer Res. 1990 Mar 1;50(5):1596-600.
• [6] Novel non-neutral mitochondrial DNA mutations found in childhood acute lymphoblastic leukemia.Clin Genet. 2018 Feb;93(2):275-285. doi: 10.1111/cge.13100. Epub 2017 Dec 20.
• [7] Effects of fatty acids on expression of genes encoding subunits of cytochrome c oxidase and cytochrome c oxidase activity in HT29 human colonic adenocarcinoma cells.J Biol Chem. 1991 Oct 5;266(28):19120-6.
• [8] In silico analysis for predicting pathogenicity of five unclassified mitochondrial DNA mutations associated with mitochondrial cytopathies' phenotypes.Eur J Med Genet. 2017 Mar;60(3):172-177. doi: 10.1016/j.ejmg.2016.12.009. Epub 2016 Dec 24.
• [9] Accurately mapping the location of the binding site for the interaction between hepatitis B virus X protein and cytochrome c oxidase III.Int J Mol Med. 2015 Feb;35(2):319-24. doi: 10.3892/ijmm.2014.2018. Epub 2014 Dec 2.
• [10] HBx co-localizes with COXIII in HL-7702 cells to upregulate mitochondrial function and ROS generation.Oncol Rep. 2015 May;33(5):2461-7. doi: 10.3892/or.2015.3852. Epub 2015 Mar 13.
• [11] Mitochondrial DNA mutations in Cuban optic and peripheral neuropathy.J Neuroophthalmol. 1994 Sep;14(3):135-40.
• [12] A MELAS syndrome family harboring two mutations in mitochondrial genome.Exp Mol Med. 2008 Jun 30;40(3):354-60. doi: 10.3858/emm.2008.40.3.354.
• [13] Childhood onset mitochondrial myopathy and lactic acidosis caused by a stop mutation in the mitochondrial cytochrome c oxidase III gene.J Med Genet. 2002 Nov;39(11):812-6. doi: 10.1136/jmg.39.11.812.
• [14] Novel single base pair COX III subunit deletion of mitochondrial DNA associated with rhabdomyolysis.J Clin Neurosci. 2011 Feb;18(2):290-2. doi: 10.1016/j.jocn.2010.06.001. Epub 2010 Dec 15.
• [15] Mitochondrial dysfunction and ultrastructural damage in the hippocampus of pilocarpine-induced epileptic rat.Neurosci Lett. 2007 Jan 10;411(2):152-7. doi: 10.1016/j.neulet.2006.10.022. Epub 2006 Nov 7.
• [16] Down-regulation of mitochondrial NADH and cytochrome b gene associated with high tumor stages in head and neck squamous cell carcinoma.Arch Oral Biol. 2019 Mar;99:107-112. doi: 10.1016/j.archoralbio.2019.01.005. Epub 2019 Jan 10.
• [17] Two novel cosegregating mutations in tRNAMet and COX III, in a patient with exercise intolerance and autoimmune polyendocrinopathy.Mitochondrion. 2009 Apr;9(2):123-9. doi: 10.1016/j.mito.2009.01.006. Epub 2009 Jan 21.
• [18] Detection of mitochondrial DNA mutations by high-throughput sequencing in the blood of breast cancer patients.Int J Mol Med. 2014 Jan;33(1):77-82. doi: 10.3892/ijmm.2013.1559. Epub 2013 Nov 19.
• [19] Changes in mitochondrial cytochrome c oxidase mRNA levels with cataract severity in lens epithelia of Japanese patients.Mol Med Rep. 2019 Jun;19(6):5464-5472. doi: 10.3892/mmr.2019.10214. Epub 2019 May 2.
• [20] Screening of mitochondrial mutations in Tunisian patients with mitochondrial disorders: an overview study.Mitochondrial DNA. 2013 Jun;24(3):163-78. doi: 10.3109/19401736.2012.748045. Epub 2013 Jan 9.
• [21] Rapid and sensitive multiplex single-tube nested PCR for the identification of five human Plasmodium species.Parasitol Int. 2018 Jun;67(3):277-283. doi: 10.1016/j.parint.2018.01.005. Epub 2018 Jan 31.
• [22] Mutations in mtDNA-encoded cytochrome c oxidase subunit genes causing isolated myopathy or severe encephalomyopathy.Neuromuscul Disord. 2005 Dec;15(12):851-7. doi: 10.1016/j.nmd.2005.09.005. Epub 2005 Nov 8.
• [23] Increased expression of genes encoding mitochondrial proteins in papillary thyroid carcinomas.Thyroid. 2003 Jul;13(7):613-20. doi: 10.1089/105072503322239943.
• [24] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [25] 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.
• [26] 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.
• [27] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [28] Enhanced levels of several mitochondrial mRNA transcripts and mitochondrial superoxide production during ethinyl estradiol-induced hepatocarcinogenesis and after estrogen treatment of HepG2 cells. Carcinogenesis. 1998 Dec;19(12):2187-93. doi: 10.1093/carcin/19.12.2187.
• [29] 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.
• [30] Small-scale immunopurification of cytochrome c oxidase for a high-throughput multiplexing analysis of enzyme activity and amount. Biotechnol Appl Biochem. 2007 Dec;48(Pt 4):167-78. doi: 10.1042/BA20060223.
• [31] Resveratrol induces apoptosis and alters gene expression in human fibrosarcoma cells. Anticancer Res. 2015 Feb;35(2):767-74.
• [32] High-throughput data integration of RNA-miRNA-circRNA reveals novel insights into mechanisms of benzo[a]pyrene-induced carcinogenicity. Nucleic Acids Res. 2015 Mar 11;43(5):2525-34. doi: 10.1093/nar/gkv115. Epub 2015 Feb 17.
• [33] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [34] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [35] In vitro blood brain barrier exposure to mycotoxins and carotenoids pumpkin extract alters mitochondrial gene expression and oxidative stress. Food Chem Toxicol. 2021 Jul;153:112261. doi: 10.1016/j.fct.2021.112261. Epub 2021 May 17.
• [36] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [37] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.
• [38] An increase of cytochrome C oxidase mediated disruption of gemcitabine incorporation into DNA in a resistant KB clone. Biochem Pharmacol. 2007 Jun 15;73(12):1927-38. doi: 10.1016/j.bcp.2007.03.014. Epub 2007 Mar 20.