Details of Drug Off-Target (DOT)

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

• DOT Name: Protein SCO2 homolog, mitochondrial (SCO2)
• Gene Name: SCO2
• Related Disease:
  Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1
  Leigh syndrome
  Adenocarcinoma
  Adenoma
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast neoplasm
  Carcinoma
  Cardiomyopathy
  Cervical carcinoma
  Clear cell renal carcinoma
  Colon carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Cytochrome-c oxidase deficiency disease
  Dystonia
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Idiopathic cardiomyopathy
  Influenza
  Melanoma
  Metabolic disorder
  Mitochondrial disease
  Mitochondrial DNA depletion syndrome 1
  Mitochondrial neurogastrointestinal encephalomyopathy
  Myopia 6
  Nasopharyngeal carcinoma
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Ptosis
  Rectal carcinoma
  Rheumatoid arthritis
  Spinal muscular atrophy
  Squamous cell carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Dilated cardiomyopathy
  Myopia
  Pancreatic cancer
  Autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect
  Colon cancer
  Lactic acidosis
  Leukodystrophy
  Mitochondrial encephalomyopathy
  Respiratory failure
• UniProt ID: SCO2_HUMAN
• PDB ID: 2RLI
• Pfam ID: PF02630
• Sequence:
  MLLLTRSPTAWHRLSQLKPRVLPGTLGGQALHLRSWLLSRQGPAETGGQGQPQGPGLRTR
  LLITGLFGAGLGGAWLALRAEKERLQQQKRTEALRQAAVGQGDFHLLDHRGRARCKADFR
  GQWVLMYFGFTHCPDICPDELEKLVQVVRQLEAEPGLPPVQPVFITVDPERDDVEAMARY
  VQDFHPRLLGLTGSTKQVAQASHSYRVYYNAGPKDEDQDYIVDHSIAIYLLNPDGLFTDY
  YGRSRSAEQISDSVRRHMAAFRSVLS
• Function: Copper metallochaperone essential for the synthesis and maturation of cytochrome c oxidase subunit II (MT-CO2/COX2). Involved in transporting copper to the Cu(A) site on MT-CO2/COX2. Also acts as a thiol-disulfide oxidoreductase to regulate the redox state of the cysteines in SCO1 during maturation of MT-CO2/COX2.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Central carbon metabolism in cancer (hsa05230)
• 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

52 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1	DISPCNGL	Definitive	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Adenoma	DIS78ZEV	Strong	Altered Expression	[4]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[5]
Bladder cancer	DISUHNM0	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[7]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[8]
Carcinoma	DISH9F1N	Strong	Altered Expression	[9]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[10]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[11]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[12]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[13]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[14]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[15]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Genetic Variation	[16]
Dystonia	DISJLFGW	Strong	Biomarker	[17]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[18]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[19]
Gastric cancer	DISXGOUK	Strong	Biomarker	[20]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[21]
Glioma	DIS5RPEH	Strong	Biomarker	[21]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[22]
Idiopathic cardiomyopathy	DISUGBZL	Strong	Biomarker	[23]
Influenza	DIS3PNU3	Strong	Biomarker	[24]
Melanoma	DIS1RRCY	Strong	Biomarker	[25]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[26]
Mitochondrial disease	DISKAHA3	Strong	Biomarker	[27]
Mitochondrial DNA depletion syndrome 1	DISZ48YF	Strong	CausalMutation	[28]
Mitochondrial neurogastrointestinal encephalomyopathy	DIS5HV4H	Strong	Genetic Variation	[29]
Myopia 6	DIS1ZT40	Strong	Autosomal dominant	[30]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Altered Expression	[31]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[32]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[18]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[18]
Ptosis	DISJZNIY	Strong	Genetic Variation	[33]
Rectal carcinoma	DIS8FRR7	Strong	Biomarker	[34]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[35]
Spinal muscular atrophy	DISTLKOB	Strong	Genetic Variation	[36]
Squamous cell carcinoma	DISQVIFL	Strong	Posttranslational Modification	[37]
Stomach cancer	DISKIJSX	Strong	Biomarker	[20]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
Dilated cardiomyopathy	DISX608J	moderate	Genetic Variation	[38]
Myopia	DISK5S60	moderate	Biomarker	[39]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[40]
Autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect	DIS993DX	Supportive	Autosomal recessive	[41]
Colon cancer	DISVC52G	Limited	Biomarker	[13]
Lactic acidosis	DISZI1ZK	Limited	Genetic Variation	[36]
Leukodystrophy	DISVY1TT	Limited	Genetic Variation	[42]
Mitochondrial encephalomyopathy	DISA6PTN	Limited	Biomarker	[43]
Respiratory failure	DISVMYJO	Limited	Genetic Variation	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Protein SCO2 homolog, mitochondrial (SCO2).	[44]

11 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 SCO2 homolog, mitochondrial (SCO2).	[45]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein SCO2 homolog, mitochondrial (SCO2).	[46]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein SCO2 homolog, mitochondrial (SCO2).	[47]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein SCO2 homolog, mitochondrial (SCO2).	[48]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein SCO2 homolog, mitochondrial (SCO2).	[49]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein SCO2 homolog, mitochondrial (SCO2).	[46]
Selenium	DM25CGV	Approved	Selenium increases the expression of Protein SCO2 homolog, mitochondrial (SCO2).	[50]
Bezafibrate	DMZDCS0	Approved	Bezafibrate increases the activity of Protein SCO2 homolog, mitochondrial (SCO2).	[51]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein SCO2 homolog, mitochondrial (SCO2).	[52]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein SCO2 homolog, mitochondrial (SCO2).	[53]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Protein SCO2 homolog, mitochondrial (SCO2).	[54]

References

• [1] Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency. Hum Mol Genet. 2000 Mar 22;9(5):795-801. doi: 10.1093/hmg/9.5.795.
• [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] Tumor-related gene expression levels in pulmonary pleomorphic carcinoma.J Cardiothorac Surg. 2015 Jun 3;10:79. doi: 10.1186/s13019-015-0282-1.
• [4] Concurrent expression of angiogenic growth factors and neovascularization during tumourigenesis in colorectal carcinoma patients.Acta Oncol. 2001;40(5):622-8. doi: 10.1080/028418601750444178.
• [5] Identification of 1,2,4-triazoles as new thymidine phosphorylase inhibitors: Future anti-tumor drugs.Bioorg Chem. 2019 Apr;85:209-220. doi: 10.1016/j.bioorg.2019.01.005. Epub 2019 Jan 4.
• [6] Expression of the fluoropyrimidine-metabolizing enzymes in bladder cancers as measured by the Danenberg tumor profile.Oncol Res. 2009;18(4):153-62. doi: 10.3727/096504009790217371.
• [7] Synthesis, thymidine phosphorylase inhibitory and computational study of novel 1,3,4-oxadiazole-2-thione derivatives as potential anticancer agents.Comput Biol Chem. 2018 Oct;76:151-160. doi: 10.1016/j.compbiolchem.2018.05.013. Epub 2018 May 16.
• [8] Increased sensitivity to the prodrug 5'-deoxy-5-fluorouridine and modulation of 5-fluoro-2'-deoxyuridine sensitivity in MCF-7 cells transfected with thymidine phosphorylase.Br J Cancer. 1995 Sep;72(3):669-75. doi: 10.1038/bjc.1995.392.
• [9] Thymidine phosphorylase-mediated angiogenesis regulated by thymidine phosphorylase inhibitor in human ovarian cancer cells in vivo.Int J Oncol. 2003 May;22(5):961-7.
• [10] 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.
• [11] No relationship between thymidine phosphorylase (TP, PD-ECGF) expression and hypoxia in carcinoma of the cervix.Br J Cancer. 2006 Jan 16;94(1):115-20. doi: 10.1038/sj.bjc.6602882.
• [12] Non-Coding Micro RNAs and Hypoxia-Inducible Factors Are Selenium Targets for Development of a Mechanism-Based Combination Strategy in Clear-Cell Renal Cell Carcinoma-Bench-to-Bedside Therapy.Int J Mol Sci. 2018 Oct 29;19(11):3378. doi: 10.3390/ijms19113378.
• [13] Platelet-derived endothelial cell growth factor mediates Rho-associated coiled-coil domain kinase messenger RNA expression and promotes cell motility.Ann Surg Oncol. 2003 Jun;10(5):582-7. doi: 10.1245/aso.2003.08.020.
• [14] Determination of thymidine phosphorylase expression level facilitates recurrence risk stratification in stage II/III colorectal cancer following adjuvant chemotherapy with oral fluoropyrimidines.Oncol Lett. 2019 Jun;17(6):5267-5274. doi: 10.3892/ol.2019.10181. Epub 2019 Mar 21.
• [15] Molecular factors of 5-fluorouracil metabolism in colorectal cancer: analysis of primary tumor and lymph node metastasis.Int J Oncol. 2006 Feb;28(2):527-33. doi: 10.3892/ijo.28.2.527.
• [16] Exome-based search for recurrent disease-causing alleles in Russian population.Eur J Med Genet. 2019 Jul;62(7):103656. doi: 10.1016/j.ejmg.2019.04.013. Epub 2019 Apr 24.
• [17] Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module.J Biol Chem. 2017 May 12;292(19):7774-7783. doi: 10.1074/jbc.M117.778514. Epub 2017 Mar 22.
• [18] 4-Methylumbelliferone inhibits ovarian cancer growth by suppressing thymidine phosphorylase expression.J Ovarian Res. 2014 Oct 11;7:94. doi: 10.1186/s13048-014-0094-2.
• [19] Thymidine phosphorylase and angiogenesis in early stage esophageal squamous cell carcinoma.Esophagus. 2018 Jan;15(1):19-26. doi: 10.1007/s10388-017-0588-2. Epub 2017 Jul 24.
• [20] Impact of intratumoral expression levels of fluoropyrimidine-metabolizing enzymes on treatment outcomes of adjuvant S-1 therapy in gastric cancer.PLoS One. 2015 Mar 20;10(3):e0120324. doi: 10.1371/journal.pone.0120324. eCollection 2015.
• [21] Interferons upregulate thymidine phosphorylase expression via JAK-STAT-dependent transcriptional activation and mRNA stabilization in human glioblastoma cells. J Neurooncol. 2005 May;72(3):217-23. doi: 10.1007/s11060-004-3012-4.
• [22] Thymidine phosphorylase promotes malignant progression in hepatocellular carcinoma through pentose Warburg effect.Cell Death Dis. 2019 Jan 17;10(2):43. doi: 10.1038/s41419-018-1282-6.
• [23] Retrospective, multicentric study of 180 children with cytochrome C oxidase deficiency.Pediatr Res. 2006 Jan;59(1):21-6. doi: 10.1203/01.pdr.0000190572.68191.13. Epub 2005 Dec 2.
• [24] A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2.PLoS One. 2013;8(1):e52198. doi: 10.1371/journal.pone.0052198. Epub 2013 Jan 9.
• [25] Decreased expression of thymidine phosphorylase/platelet-derived endothelial cell growth factor in basal cell carcinomas.Exp Dermatol. 2008 Nov;17(11):908-15. doi: 10.1111/j.1600-0625.2008.00718.x. Epub 2008 Mar 12.
• [26] Discovery profiling and bioinformatics analysis of serum microRNA in Mitochondrial NeuroGastroIntestinal Encephalomyopathy (MNGIE).Nucleosides Nucleotides Nucleic Acids. 2018;37(11):618-629. doi: 10.1080/15257770.2018.1492138. Epub 2018 Dec 27.
• [27] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [28] Clinical and genetic spectrum of mitochondrial neurogastrointestinal encephalomyopathy. Brain. 2011 Nov;134(Pt 11):3326-32. doi: 10.1093/brain/awr245. Epub 2011 Sep 20.
• [29] Anesthetic Considerations for Liver Transplantation in a Patient with Mitochondrial Neurogastrointestinal Encephalopathy Syndrome.Cureus. 2019 Jun 29;11(6):e5038. doi: 10.7759/cureus.5038.
• [30] Mutations in SCO2 are associated with autosomal-dominant high-grade myopia. Am J Hum Genet. 2013 May 2;92(5):820-6. doi: 10.1016/j.ajhg.2013.04.005.
• [31] Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells.Oncogene. 2009 Apr 30;28(17):1904-15. doi: 10.1038/onc.2009.55. Epub 2009 Mar 30.
• [32] Inhibition of thymidine phosphorylase expression by Hsp90 inhibitor potentiates the cytotoxic effect of salinomycin in human non-small-cell lung cancer cells. Toxicology. 2019 Apr 1;417:54-63.
• [33] Transient clinical improvement of a mitochondrial neurogastrointestinal encephalomyopathy-like syndrome after allogeneic haematopoietic stem cell transplantation.BMJ Case Rep. 2017 Aug 1;2017:bcr2016218276. doi: 10.1136/bcr-2016-218276.
• [34] Pretreatment expression of 13 molecular markers as a predictor of tumor responses after neoadjuvant chemoradiation in rectal cancer.Ann Surg. 2014 Mar;259(3):508-15. doi: 10.1097/SLA.0b013e31829b3916.
• [35] Caught in a Trap? Proteomic Analysis of Neutrophil Extracellular Traps in Rheumatoid Arthritis and Systemic Lupus Erythematosus.Front Immunol. 2019 Mar 11;10:423. doi: 10.3389/fimmu.2019.00423. eCollection 2019.
• [36] A homozygous mutation in the SCO2 gene causes a spinal muscular atrophy like presentation with stridor and respiratory insufficiency.Eur J Paediatr Neurol. 2010 May;14(3):253-60. doi: 10.1016/j.ejpn.2009.09.008. Epub 2009 Oct 29.
• [37] 5-Aza-2-deoxycytidine Enhances the Sensitivity of 5-Fluorouracil by Demethylation of the Thymidine Phosphorylase Promoter.Anticancer Res. 2019 Aug;39(8):4129-4136. doi: 10.21873/anticanres.13571.
• [38] A novel mutation in the SCO2 gene in a neonate with early-onset cardioencephalomyopathy.Pediatr Neurol. 2010 Mar;42(3):227-30. doi: 10.1016/j.pediatrneurol.2009.10.004.
• [39] Association between SCO2 mutation and extreme myopia in Japanese patients.Jpn J Ophthalmol. 2016 Jul;60(4):319-25. doi: 10.1007/s10384-016-0442-4. Epub 2016 Apr 6.
• [40] Phase II study of capecitabine with concomitant radiotherapy for patients with locally advanced pancreatic cancer: up-regulation of thymidine phosphorylase.Cancer J. 2007 Jul-Aug;13(4):247-56. doi: 10.1097/PPO.0b013e31813c12b8.
• [41] SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency. Brain. 2018 Mar 1;141(3):662-672. doi: 10.1093/brain/awx369.
• [42] Disorders of nuclear-mitochondrial intergenomic signaling.Gene. 2005 Jul 18;354:162-8. doi: 10.1016/j.gene.2005.03.025.
• [43] 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.
• [44] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [45] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [46] Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells. Nat Commun. 2018 Aug 9;9(1):3069. doi: 10.1038/s41467-018-05402-2.
• [47] 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.
• [48] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [49] 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.
• [50] 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.
• [51] Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with SCO2 mutations. Orphanet J Rare Dis. 2012 Apr 19;7:21. doi: 10.1186/1750-1172-7-21.
• [52] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [53] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [54] 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.