Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC45UGB)

• DOT Name: Protein SCO1 homolog, mitochondrial (SCO1)
• Gene Name: SCO1
• Related Disease:
  Cytochrome-c oxidase deficiency disease
  Mitochondrial disease
  Abscess
  Acute liver failure
  Adult glioblastoma
  Autoimmune disease
  Glioblastoma multiforme
  Liver failure
  Mitochondrial complex 4 deficiency, nuclear type 4
  Parasitic infection
  Myasthenia gravis
  Systemic lupus erythematosus
  Type-1 diabetes
  Brain disease
  Cardiac disease
  Cardiomyopathy
  Non-insulin dependent diabetes
• UniProt ID: SCO1_HUMAN
• PDB ID: 1WP0; 2GGT; 2GQK; 2GQL; 2GQM; 2GT5; 2GT6; 2GVP; 2HRF; 2HRN
• Pfam ID: PF02630
• Sequence:
  MAMLVLVPGRVMRPLGGQLWRFLPRGLEFWGPAEGTARVLLRQFCARQAEAWRASGRPGY
  CLGTRPLSTARPPPPWSQKGPGDSTRPSKPGPVSWKSLAITFAIGGALLAGMKHVKKEKA
  EKLEKERQRHIGKPLLGGPFSLTTHTGERKTDKDYLGQWLLIYFGFTHCPDVCPEELEKM
  IQVVDEIDSITTLPDLTPLFISIDPERDTKEAIANYVKEFSPKLVGLTGTREEVDQVARA
  YRVYYSPGPKDEDEDYIVDHTIIMYLIGPDGEFLDYFGQNKRKGEIAASIATHMRPYRKK
  S
• Function: Copper metallochaperone essential for the maturation of cytochrome c oxidase subunit II (MT-CO2/COX2). Not required for the synthesis of MT-CO2/COX2 but plays a crucial role in stabilizing MT-CO2/COX2 during its subsequent maturation. Involved in transporting copper to the Cu(A) site on MT-CO2/COX2. Plays an important role in the regulation of copper homeostasis by controlling the abundance and cell membrane localization of copper transporter CTR1.
• Tissue Specificity: Predominantly expressed in tissues characterized by high rates of oxidative phosphorylation (OxPhos), including muscle, heart, and brain.
• Reactome Pathway:
  Respiratory electron transport (R-HSA-611105)
  Cytoprotection by HMOX1 (R-HSA-9707564)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cytochrome-c oxidase deficiency disease	DISK7N3G	Definitive	Autosomal recessive	[1]
Mitochondrial disease	DISKAHA3	Definitive	Autosomal recessive	[2]
Abscess	DISAP982	Strong	Biomarker	[3]
Acute liver failure	DIS5EZKX	Strong	Biomarker	[4]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[5]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[6]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[5]
Liver failure	DISLGEL6	Strong	Genetic Variation	[7]
Mitochondrial complex 4 deficiency, nuclear type 4	DISRGAHM	Strong	Autosomal recessive	[8]
Parasitic infection	DISX9CEW	Strong	Biomarker	[3]
Myasthenia gravis	DISELRCI	moderate	Genetic Variation	[9]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[9]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[9]
Brain disease	DIS6ZC3X	Limited	Biomarker	[10]
Cardiac disease	DISVO1I5	Limited	Biomarker	[10]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[11]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein SCO1 homolog, mitochondrial (SCO1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein SCO1 homolog, mitochondrial (SCO1).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein SCO1 homolog, mitochondrial (SCO1).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein SCO1 homolog, mitochondrial (SCO1).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein SCO1 homolog, mitochondrial (SCO1).	[18]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Protein SCO1 homolog, mitochondrial (SCO1).	[19]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Protein SCO1 homolog, mitochondrial (SCO1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein SCO1 homolog, mitochondrial (SCO1).	[21]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Protein SCO1 homolog, mitochondrial (SCO1).	[22]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein SCO1 homolog, mitochondrial (SCO1).	[17]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Increased frequency of HLA-DR3 and complotype SCO1 in Mexican mestizo children with amoebic abscess of the liver.Parasite Immunol. 1996 Oct;18(10):491-8. doi: 10.1046/j.1365-3024.1996.d01-16.x.
• [4] Unexpected vascular enrichment of SCO1 over SCO2 in mammalian tissues: implications for human mitochondrial disease.Am J Pathol. 2010 Nov;177(5):2541-8. doi: 10.2353/ajpath.2010.100229. Epub 2010 Sep 23.
• [5] Demethyl fruticulin A (SCO-1) causes apoptosis by inducing reactive oxygen species in mitochondria.J Cell Biochem. 2010 Dec 1;111(5):1149-59. doi: 10.1002/jcb.22801.
• [6] DP polymorphism in HLA-A1,-B8,-DR3 extended haplotypes associated with membranoproliferative glomerulonephritis and systemic lupus erythematosus.Pediatr Nephrol. 1993 Jun;7(3):243-6. doi: 10.1007/BF00853205.
• [7] Cytochrome c oxidase deficiency.Am J Med Genet. 2001 Spring;106(1):46-52. doi: 10.1002/ajmg.1378.
• [8] [Remote afterloading high dose rate intracavitary radiotherapy for head and neck cancer (author's transl)]. Nihon Igaku Hoshasen Gakkai Zasshi. 1979 Jan 25;39(1):53-9.
• [9] Autoimmunogenic HLA-DRB1*0301 allele (DR3) may be distinguished at the DRB1 non-coding regions of HLA-B8,DR3,Dw24 and B18,DR3,Dw25 haplotypes.Mol Immunol. 1991 Jan-Feb;28(1-2):189-92. doi: 10.1016/0161-5890(91)90105-s.
• [10] COX19 mediates the transduction of a mitochondrial redox signal from SCO1 that regulates ATP7A-mediated cellular copper efflux.Mol Biol Cell. 2013 Mar;24(6):683-91. doi: 10.1091/mbc.E12-09-0705. Epub 2013 Jan 23.
• [11] Cardiac deficiency of single cytochrome oxidase assembly factor scox induces p53-dependent apoptosis in a Drosophila cardiomyopathy model.Hum Mol Genet. 2015 Jul 1;24(13):3608-22. doi: 10.1093/hmg/ddv106. Epub 2015 Mar 19.
• [12] Synthesis of cytochrome c oxidase 1 (SCO1) inhibits insulin sensitivity by decreasing copper levels in adipocytes.Biochem Biophys Res Commun. 2017 Sep 23;491(3):814-820. doi: 10.1016/j.bbrc.2017.06.124. Epub 2017 Jun 21.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [18] 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.
• [19] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [20] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [21] 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.
• [22] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.