General Information of Drug Off-Target (DOT) (ID: OT3V7JE5)

DOT Name Cytochrome c oxidase subunit 6C (COX6C)
Synonyms Cytochrome c oxidase polypeptide VIc
Gene Name COX6C
Related Disease
Breast cancer ( )
Breast carcinoma ( )
Cohen syndrome ( )
Melanoma ( )
Uterine fibroids ( )
Neoplasm ( )
UniProt ID
COX6C_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
5Z62
Pfam ID
PF02937
Sequence
MAPEVLPKPRMRGLLARRLRNHMAVAFVLSLGVAALYKFRVADQRKKAYADFYRNYDVMK
DFEEMRKAGIFQSVK
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:HS09158-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Breast cancer DIS7DPX1 Strong Genetic Variation [1]
Breast carcinoma DIS2UE88 Strong Genetic Variation [1]
Cohen syndrome DISOOFEZ Strong Genetic Variation [2]
Melanoma DIS1RRCY Strong Genetic Variation [1]
Uterine fibroids DISBZRMJ Strong Biomarker [3]
Neoplasm DISZKGEW Limited Biomarker [4]
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⏷ Show the Full List of 6 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
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 6C (COX6C). [5]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Cytochrome c oxidase subunit 6C (COX6C). [6]
Doxorubicin DMVP5YE Approved Doxorubicin increases the expression of Cytochrome c oxidase subunit 6C (COX6C). [7]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of Cytochrome c oxidase subunit 6C (COX6C). [8]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Cytochrome c oxidase subunit 6C (COX6C). [9]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of Cytochrome c oxidase subunit 6C (COX6C). [10]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide decreases the expression of Cytochrome c oxidase subunit 6C (COX6C). [11]
Fluorouracil DMUM7HZ Approved Fluorouracil affects the expression of Cytochrome c oxidase subunit 6C (COX6C). [12]
Cocaine DMSOX7I Approved Cocaine decreases the expression of Cytochrome c oxidase subunit 6C (COX6C). [13]
Zidovudine DM4KI7O Approved Zidovudine decreases the expression of Cytochrome c oxidase subunit 6C (COX6C). [14]
THAPSIGARGIN DMDMQIE Preclinical THAPSIGARGIN decreases the expression of Cytochrome c oxidase subunit 6C (COX6C). [16]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Cytochrome c oxidase subunit 6C (COX6C). [17]
Milchsaure DM462BT Investigative Milchsaure decreases the expression of Cytochrome c oxidase subunit 6C (COX6C). [18]
chloropicrin DMSGBQA Investigative chloropicrin affects the expression of Cytochrome c oxidase subunit 6C (COX6C). [19]
AHPN DM8G6O4 Investigative AHPN decreases the expression of Cytochrome c oxidase subunit 6C (COX6C). [20]
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⏷ Show the Full List of 15 Drug(s)
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 6C (COX6C). [15]
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References

1 Mitochondrial protein enriched extracellular vesicles discovered in human melanoma tissues can be detected in patient plasma.J Extracell Vesicles. 2019 Aug 27;8(1):1635420. doi: 10.1080/20013078.2019.1635420. eCollection 2019.
2 Modeled Fetal Risk of Genetic Diseases Identified by Expanded Carrier Screening.JAMA. 2016 Aug 16;316(7):734-42. doi: 10.1001/jama.2016.11139.
3 Novel gene fusion of COX6C at 8q22-23 to HMGIC at 12q15 in a uterine leiomyoma.Genes Chromosomes Cancer. 2000 Mar;27(3):303-7. doi: 10.1002/(sici)1098-2264(200003)27:3<303::aid-gcc11>3.0.co;2-3.
4 Rearrangement involving chromosomes 1 and 8 in a retroperitoneal lipoma.Cancer Genet Cytogenet. 2002 Mar;133(2):156-9. doi: 10.1016/s0165-4608(01)00573-8.
5 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
6 Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
7 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.
8 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.
9 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.
10 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.
11 Tea polyphenols ameliorates neural redox imbalance and mitochondrial dysfunction via mechanisms linking the key circadian regular Bmal1. Food Chem Toxicol. 2017 Dec;110:189-199. doi: 10.1016/j.fct.2017.10.031. Epub 2017 Oct 20.
12 New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
13 Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
14 Expression of cytochrome c oxidase subunits encoded by mitochondrial or nuclear DNA in the muscle of patients with zidovudine myopathy. J Neurol Sci. 1994 Sep;125(2):190-3. doi: 10.1016/0022-510x(94)90034-5.
15 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.
16 Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
17 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.
18 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
19 Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
20 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.