Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV3R4RB)

• DOT Name: Translation initiation factor eIF2B subunit epsilon (EIF2B5)
• Synonyms: eIF2B GDP-GTP exchange factor subunit epsilon
• Gene Name: EIF2B5
• Related Disease:
  Leukoencephalopathy with vanishing white matter 1
  Non-insulin dependent diabetes
  Obsolete leukoencephalopathy with vanishing white matter
  Advanced cancer
  Autoimmune disease
  Crohn disease
  Cutaneous lupus erythematosus
  Dermatitis
  Dermatomyositis
  Fatty liver disease
  Leukoencephalopathy with vanishing white matter
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Multiple sclerosis
  Peripheral neuropathy
  Skin disease
  Systemic lupus erythematosus
  Systemic sclerosis
  Leukodystrophy
  Movement disorder
  Neoplasm
  Obsolete ovarioleukodystrophy
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Nasopharyngeal carcinoma
• UniProt ID: EI2BE_HUMAN
• PDB ID: 3JUI; 6CAJ; 6EZO; 6K71; 6K72; 6O81; 6O85; 6O9Z; 7D43; 7D44; 7D45; 7D46; 7F64; 7F66; 7F67; 7KMF; 7L70; 7L7G; 7RLO; 7TRJ; 7VLK; 8TQO; 8TQZ
• Pfam ID: PF02020
• Sequence:
  MAAPVVAPPGVVVSRANKRSGAGPGGSGGGGARGAEEEPPPPLQAVLVADSFDRRFFPIS
  KDQPRVLLPLANVALIDYTLEFLTATGVQETFVFCCWKAAQIKEHLLKSKWCRPTSLNVV
  RIITSELYRSLGDVLRDVDAKALVRSDFLLVYGDVISNINITRALEEHRLRRKLEKNVSV
  MTMIFKESSPSHPTRCHEDNVVVAVDSTTNRVLHFQKTQGLRRFAFPLSLFQGSSDGVEV
  RYDLLDCHISICSPQVAQLFTDNFDYQTRDDFVRGLLVNEEILGNQIHMHVTAKEYGARV
  SNLHMYSAVCADVIRRWVYPLTPEANFTDSTTQSCTHSRHNIYRGPEVSLGHGSILEENV
  LLGSGTVIGSNCFITNSVIGPGCHIGDNVVLDQTYLWQGVRVAAGAQIHQSLLCDNAEVK
  ERVTLKPRSVLTSQVVVGPNITLPEGSVISLHPPDAEEDEDDGEFSDDSGADQEKDKVKM
  KGYNPAEVGAAGKGYLWKAAGMNMEEEEELQQNLWGLKINMEEESESESEQSMDSEEPDS
  RGGSPQMDDIKVFQNEVLGTLQRGKEENISCDNLVLEINSLKYAYNISLKEVMQVLSHVV
  LEFPLQQMDSPLDSSRYCALLLPLLKAWSPVFRNYIKRAADHLEALAAIEDFFLEHEALG
  ISMAKVLMAFYQLEILAEETILSWFSQRDTTDKGQQLRKNQQLQRFIQWLKEAEEESSED
  D
• Function: Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on eukaryotic initiation factor 2 (eIF2) gamma subunit. Its guanine nucleotide exchange factor activity is repressed when bound to eIF2 complex phosphorylated on the alpha subunit, thereby limiting the amount of methionyl-initiator methionine tRNA available to the ribosome and consequently global translation is repressed.
• KEGG Pathway: Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway: Recycling of eIF2 (R-HSA-72731)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukoencephalopathy with vanishing white matter 1	DIS72ZXN	Definitive	Autosomal recessive	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[2]
Obsolete leukoencephalopathy with vanishing white matter	DISBOYFO	Definitive	Autosomal recessive	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[6]
Cutaneous lupus erythematosus	DISOIX6L	Strong	Biomarker	[5]
Dermatitis	DISY5SZC	Strong	Biomarker	[5]
Dermatomyositis	DIS50C5O	Strong	Genetic Variation	[7]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[8]
Leukoencephalopathy with vanishing white matter	DIS3J8NN	Strong	Biomarker	[9]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[10]
Lung cancer	DISCM4YA	Strong	Biomarker	[11]
Lung carcinoma	DISTR26C	Strong	Biomarker	[11]
Lung neoplasm	DISVARNB	Strong	Biomarker	[11]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[12]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[13]
Skin disease	DISDW8R6	Strong	Biomarker	[14]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[5]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[7]
Leukodystrophy	DISVY1TT	moderate	Biomarker	[15]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[16]
Neoplasm	DISZKGEW	moderate	Biomarker	[17]
Obsolete ovarioleukodystrophy	DIS0K85C	Supportive	Autosomal recessive	[18]
Barrett esophagus	DIS416Y7	Limited	Biomarker	[9]
Breast cancer	DIS7DPX1	Limited	Biomarker	[19]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[19]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[4]
Liver cancer	DISDE4BI	Limited	Altered Expression	[4]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Translation initiation factor eIF2B subunit epsilon (EIF2B5).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Translation initiation factor eIF2B subunit epsilon (EIF2B5).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Translation initiation factor eIF2B subunit epsilon (EIF2B5).	[23]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Translation initiation factor eIF2B subunit epsilon (EIF2B5).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Translation initiation factor eIF2B subunit epsilon (EIF2B5).	[25]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Translation initiation factor eIF2B subunit epsilon (EIF2B5).	[26]

References

• [1] A Japanese girl with an early-infantile onset vanishing white matter disease resembling Cree leukoencephalopathy. Brain Dev. 2015 Jun;37(6):638-42. doi: 10.1016/j.braindev.2014.10.002. Epub 2014 Oct 27.
• [2] A novel TCF7L2 type 2 diabetes SNP identified from fine mapping in African American women.PLoS One. 2017 Mar 2;12(3):e0172577. doi: 10.1371/journal.pone.0172577. eCollection 2017.
• [3] 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.
• [4] High EIF2B5 mRNA expression and its prognostic significance in liver cancer: a study based on the TCGA and GEO database.Cancer Manag Res. 2018 Nov 20;10:6003-6014. doi: 10.2147/CMAR.S185459. eCollection 2018.
• [5] Hypersensitive IFN Responses in Lupus Keratinocytes Reveal Key Mechanistic Determinants in Cutaneous Lupus.J Immunol. 2019 Apr 1;202(7):2121-2130. doi: 10.4049/jimmunol.1800650. Epub 2019 Feb 11.
• [6] Usefulness of confocal laser endomicroscopy for predicting postoperative recurrence in patients with Crohn's disease: apilot study.Gastrointest Endosc. 2019 Jul;90(1):151-157. doi: 10.1016/j.gie.2019.02.030. Epub 2019 Mar 5.
• [7] Prevalence of Pruritus in Cutaneous Lupus Erythematosus: Brief Report of a Multicenter, Multinational Cross-Sectional Study.Biomed Res Int. 2018 Jul 25;2018:3491798. doi: 10.1155/2018/3491798. eCollection 2018.
• [8] Arctic berry extracts target the gut-liver axis to alleviate metabolic endotoxaemia, insulin resistance and hepatic steatosis in diet-induced obese mice.Diabetologia. 2018 Apr;61(4):919-931. doi: 10.1007/s00125-017-4520-z. Epub 2017 Dec 21.
• [9] Analysis of a new begomovirus unveils a composite element conserved in the CP gene promoters of several Geminiviridae genera: Clues to comprehend the complex regulation of late genes.PLoS One. 2019 Jan 23;14(1):e0210485. doi: 10.1371/journal.pone.0210485. eCollection 2019.
• [10] Screening for transcription factors and their regulatory small molecules involved in regulating the functions of CL1-5 cancer cells under the effects of macrophage-conditioned medium.Oncol Rep. 2014 Mar;31(3):1323-33. doi: 10.3892/or.2013.2937. Epub 2013 Dec 20.
• [11] Needle-based confocal laser endomicroscopy for real-time diagnosingand staging of lung cancer.Eur Respir J. 2019 Jun 20;53(6):1801520. doi: 10.1183/13993003.01520-2018. Print 2019 Jun.
• [12] Multiple Sclerosis and EIF2B5: A Paradox or a Missing Link.Adv Exp Med Biol. 2017;958:57-64. doi: 10.1007/978-3-319-47861-6_5.
• [13] Peripheral neuropathy in vanishing white matter disease with a novel EIF2B5 mutation.Neurology. 2006 Jul 25;67(2):353-5. doi: 10.1212/01.wnl.0000225077.40532.a5.
• [14] JAK inhibitor ruxolitinib inhibits the expression of cytokines characteristic of cutaneous lupus erythematosus.Exp Dermatol. 2017 Aug;26(8):728-730. doi: 10.1111/exd.13253. Epub 2017 May 3.
• [15] Eukaryotic initiation factor 2B (eIF2B) GEF activity as a diagnostic tool for EIF2B-related disorders.PLoS One. 2009 Dec 15;4(12):e8318. doi: 10.1371/journal.pone.0008318.
• [16] Vanishing white matter disease in a spanish population.J Cent Nerv Syst Dis. 2014 Jul 13;6:59-68. doi: 10.4137/JCNSD.S13540. eCollection 2014.
• [17] A MYC-GCN2-eIF2 negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer.Nat Cell Biol. 2019 Nov;21(11):1413-1424. doi: 10.1038/s41556-019-0408-0. Epub 2019 Nov 4.
• [18] Childhood Ataxia with Central Nervous System Hypomyelination / Vanishing White Matter. 2003 Feb 20 [updated 2019 Apr 4]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [19] CLE-10 from Carpesium abrotanoides L. Suppresses the Growth of Human Breast Cancer Cells (MDA-MB-231) In Vitro by Inducing Apoptosis and Pro-Death Autophagy Via the PI3K/Akt/mTOR Signaling Pathway.Molecules. 2019 Mar 20;24(6):1091. doi: 10.3390/molecules24061091.
• [20] Probe-based confocal laser endomicroscopy for diagnosis of nasopharyngeal carcinoma in vivo.Laryngoscope. 2019 Apr;129(4):897-902. doi: 10.1002/lary.27450. Epub 2018 Aug 27.
• [21] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] 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.
• [24] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [25] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [26] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.