Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG6HE7D)

• DOT Name: Translation initiation factor eIF2B subunit gamma (EIF2B3)
• Synonyms: eIF2B GDP-GTP exchange factor subunit gamma
• Gene Name: EIF2B3
• Related Disease:
  Leukoencephalopathy with vanishing white matter
  Leukoencephalopathy with vanishing white matter 1
  Obsolete leukoencephalopathy with vanishing white matter
  Parkinson disease
  Obsolete ovarioleukodystrophy
• UniProt ID: EI2BG_HUMAN
• PDB ID: 6CAJ; 6EZO; 6K71; 6K72; 6O81; 6O85; 6O9Z; 7D43; 7D44; 7D45; 7D46; 7F64; 7F66; 7F67; 7KMF; 7L70; 7L7G; 7RLO; 7TRJ; 7VLK; 8TQO; 8TQZ
• Pfam ID: PF00483
• Sequence:
  MEFQAVVMAVGGGSRMTDLTSSIPKPLLPVGNKPLIWYPLNLLERVGFEEVIVVTTRDVQ
  KALCAEFKMKMKPDIVCIPDDADMGTADSLRYIYPKLKTDVLVLSCDLITDVALHEVVDL
  FRAYDASLAMLMRKGQDSIEPVPGQKGKKKAVEQRDFIGVDSTGKRLLFMANEADLDEEL
  VIKGSILQKHPRIRFHTGLVDAHLYCLKKYIVDFLMENGSITSIRSELIPYLVRKQFSSA
  SSQQGQEEKEEDLKKKELKSLDIYSFIKEANTLNLAPYDACWNACRGDRWEDLSRSQVRC
  YVHIMKEGLCSRVSTLGLYMEANRQVPKLLSALCPEEPPVHSSAQIVSKHLVGVDSLIGP
  ETQIGEKSSIKRSVIGSSCLIKDRVTITNCLLMNSVTVEEGSNIQGSVICNNAVIEKGAD
  IKDCLIGSGQRIEAKAKRVNEVIVGNDQLMEI
• Function: Acts as a component of the translation initiation factor 2B (eIF2B) complex, which catalyzes the exchange of GDP for GTP on the eukaryotic initiation factor 2 (eIF2) complex 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

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukoencephalopathy with vanishing white matter	DIS3J8NN	Strong	Biomarker	[1]
Leukoencephalopathy with vanishing white matter 1	DIS72ZXN	Strong	Autosomal recessive	[2]
Obsolete leukoencephalopathy with vanishing white matter	DISBOYFO	Strong	Autosomal recessive	[3]
Parkinson disease	DISQVHKL	Strong	Biomarker	[4]
Obsolete ovarioleukodystrophy	DIS0K85C	Supportive	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Translation initiation factor eIF2B subunit gamma (EIF2B3).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Translation initiation factor eIF2B subunit gamma (EIF2B3).	[7]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Translation initiation factor eIF2B subunit gamma (EIF2B3).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Translation initiation factor eIF2B subunit gamma (EIF2B3).	[9]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Translation initiation factor eIF2B subunit gamma (EIF2B3).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Translation initiation factor eIF2B subunit gamma (EIF2B3).	[12]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Translation initiation factor eIF2B subunit gamma (EIF2B3).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Translation initiation factor eIF2B subunit gamma (EIF2B3).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Translation initiation factor eIF2B subunit gamma (EIF2B3).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Translation initiation factor eIF2B subunit gamma (EIF2B3).	[18]

3 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 Translation initiation factor eIF2B subunit gamma (EIF2B3).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Translation initiation factor eIF2B subunit gamma (EIF2B3).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Translation initiation factor eIF2B subunit gamma (EIF2B3).	[17]

References

• [1] Postmortem Whole Exome Sequencing Identifies Novel EIF2B3 Mutation With Prenatal Phenotype in 2 Siblings.J Child Neurol. 2017 Sep;32(10):867-870. doi: 10.1177/0883073817712588. Epub 2017 Jun 9.
• [2] Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann Neurol. 2002 Feb;51(2):264-70. doi: 10.1002/ana.10112.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] Investigation of the PARK10 gene in Parkinson disease.Ann Hum Genet. 2007 Sep;71(Pt 5):639-47. doi: 10.1111/j.1469-1809.2007.00353.x. Epub 2007 Mar 27.
• [5] 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.
• [6] 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.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [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] 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.
• [11] 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.
• [12] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [13] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [16] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.