Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT77MV8G)

• DOT Name: Cytochrome c oxidase subunit 6A1, mitochondrial (COX6A1)
• Synonyms: Cytochrome c oxidase polypeptide VIa-liver; Cytochrome c oxidase subunit VIA-liver; COX VIa-L
• Gene Name: COX6A1
• Related Disease:
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease recessive intermediate D
  Charcot-Marie-Tooth disease type 3
  Cytochrome-c oxidase deficiency disease
  Hereditary motor and sensory neuropathy
• UniProt ID: CX6A1_HUMAN
• PDB ID: 5Z62
• Pfam ID: PF02046
• Sequence:
  MAVVGVSSVSRLLGRSRPQLGRPMSSGAHGEEGSARMWKTLTFFVALPGVAVSMLNVYLK
  SHHGEHERPEFIAYPHLRIRTKPFPWGDGNHTLFHNPHVNPLPTGYEDE
• 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 unsing 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:HS03462-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
Charcot marie tooth disease	DIS3BT2L	Strong	Genetic Variation	[1]
Charcot-Marie-Tooth disease recessive intermediate D	DISJ0WG6	Strong	Autosomal recessive	[2]
Charcot-Marie-Tooth disease type 3	DIS6DQK1	Strong	Biomarker	[1]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Biomarker	[3]
Hereditary motor and sensory neuropathy	DISR0X2K	Strong	Biomarker	[1]

9 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 6A1, mitochondrial (COX6A1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cytochrome c oxidase subunit 6A1, mitochondrial (COX6A1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cytochrome c oxidase subunit 6A1, mitochondrial (COX6A1).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Cytochrome c oxidase subunit 6A1, mitochondrial (COX6A1).	[7]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Cytochrome c oxidase subunit 6A1, mitochondrial (COX6A1).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Cytochrome c oxidase subunit 6A1, mitochondrial (COX6A1).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Cytochrome c oxidase subunit 6A1, mitochondrial (COX6A1).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Cytochrome c oxidase subunit 6A1, mitochondrial (COX6A1).	[10]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Cytochrome c oxidase subunit 6A1, mitochondrial (COX6A1).	[11]

References

• [1] A mutation of COX6A1 causes a recessive axonal or mixed form of Charcot-Marie-Tooth disease. Am J Hum Genet. 2014 Sep 4;95(3):294-300. doi: 10.1016/j.ajhg.2014.07.013. Epub 2014 Aug 21.
• [2] Nephropathy and renal colic in patients treated with indinavir, ritonavir plus indinavir or ritonavir plus saquinavir. AIDS. 1999 Oct 22;13(15):2173-4. doi: 10.1097/00002030-199910220-00025.
• [3] Assembly of nuclear DNA-encoded subunits into mitochondrial complex IV, and their preferential integration into supercomplex forms in patient mitochondria.FEBS J. 2009 Nov;276(22):6701-13. doi: 10.1111/j.1742-4658.2009.07384.x. Epub 2009 Oct 16.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] 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.
• [7] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [8] 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.
• [9] 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.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [11] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.