Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4NCVY1)

• DOT Name: Translation initiation factor eIF2B subunit alpha (EIF2B1)
• Synonyms: eIF2B GDP-GTP exchange factor subunit alpha
• Gene Name: EIF2B1
• Related Disease:
  Leishmaniasis
  Brain disease
  Breast cancer
  Breast carcinoma
  Cerebellar ataxia
  Diffuse systemic sclerosis
  Leukoencephalopathy with vanishing white matter 1
  Lung adenocarcinoma
  Obsolete leukoencephalopathy with vanishing white matter
  Scleroderma
  Systemic sclerosis
  Female hypogonadism
  Obsolete ovarioleukodystrophy
  Advanced cancer
  Melanoma
  Neoplasm
  Nervous system disease
  Parkinson disease
• UniProt ID: EI2BA_HUMAN
• PDB ID: 3ECS; 6CAJ; 6EZO; 6K71; 6K72; 6O81; 6O85; 6O9Z; 7D43; 7D44; 7D45; 7D46; 7F64; 7F66; 7F67; 7KMA; 7KMF; 7L70; 7L7G; 7RLO; 7TRJ; 7VLK; 8TQZ
• Pfam ID: PF01008
• Sequence:
  MDDKELIEYFKSQMKEDPDMASAVAAIRTLLEFLKRDKGETIQGLRANLTSAIETLCGVD
  SSVAVSSGGELFLRFISLASLEYSDYSKCKKIMIERGELFLRRISLSRNKIADLCHTFIK
  DGATILTHAYSRVVLRVLEAAVAAKKRFSVYVTESQPDLSGKKMAKALCHLNVPVTVVLD
  AAVGYIMEKADLVIVGAEGVVENGGIINKIGTNQMAVCAKAQNKPFYVVAESFKFVRLFP
  LNQQDVPDKFKYKADTLKVAQTGQDLKEEHPWVDYTAPSLITLLFTDLGVLTPSAVSDEL
  IKLYL
• 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

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leishmaniasis	DISABTW7	Definitive	Biomarker	[1]
Brain disease	DIS6ZC3X	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[4]
Diffuse systemic sclerosis	DISYF5LP	Strong	Biomarker	[5]
Leukoencephalopathy with vanishing white matter 1	DIS72ZXN	Strong	Autosomal recessive	[6]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[7]
Obsolete leukoencephalopathy with vanishing white matter	DISBOYFO	Strong	Autosomal recessive	[8]
Scleroderma	DISVQ342	Strong	Biomarker	[5]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[5]
Female hypogonadism	DISWASB4	moderate	Biomarker	[9]
Obsolete ovarioleukodystrophy	DIS0K85C	Supportive	Autosomal recessive	[10]
Advanced cancer	DISAT1Z9	Disputed	Altered Expression	[11]
Melanoma	DIS1RRCY	Limited	Biomarker	[12]
Neoplasm	DISZKGEW	Limited	Biomarker	[13]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[14]
Parkinson disease	DISQVHKL	Limited	Biomarker	[15]

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 Translation initiation factor eIF2B subunit alpha (EIF2B1).	[16]

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 Translation initiation factor eIF2B subunit alpha (EIF2B1).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Translation initiation factor eIF2B subunit alpha (EIF2B1).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Translation initiation factor eIF2B subunit alpha (EIF2B1).	[19]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Translation initiation factor eIF2B subunit alpha (EIF2B1).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Translation initiation factor eIF2B subunit alpha (EIF2B1).	[21]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Translation initiation factor eIF2B subunit alpha (EIF2B1).	[22]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Translation initiation factor eIF2B subunit alpha (EIF2B1).	[23]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Translation initiation factor eIF2B subunit alpha (EIF2B1).	[22]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of Translation initiation factor eIF2B subunit alpha (EIF2B1).	[24]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of Translation initiation factor eIF2B subunit alpha (EIF2B1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Translation initiation factor eIF2B subunit alpha (EIF2B1).	[26]

References

• [1] Analysis of the Antigenic and Prophylactic Properties of the Leishmania Translation Initiation Factors eIF2 and eIF2B in Natural and Experimental Leishmaniasis.Front Cell Infect Microbiol. 2018 Apr 5;8:112. doi: 10.3389/fcimb.2018.00112. eCollection 2018.
• [2] Mutations causing childhood ataxia with central nervous system hypomyelination reduce eukaryotic initiation factor 2B complex formation and activity.Mol Cell Biol. 2004 Mar;24(6):2352-63. doi: 10.1128/MCB.24.6.2352-2363.2004.
• [3] The PI3K/Akt/GSK-3/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility.Cancer Biol Med. 2019 Feb;16(1):38-54. doi: 10.20892/j.issn.2095-3941.2018.0253.
• [4] Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases.Brain. 2009 Aug;132(Pt 8):2161-9. doi: 10.1093/brain/awp171.
• [5] Presence of anti-eukaryotic initiation factor-2B, anti-RuvBL1/2 and anti-synthetase antibodies in patients with anti-nuclear antibody negative systemic sclerosis.Rheumatology (Oxford). 2018 Apr 1;57(4):712-717. doi: 10.1093/rheumatology/kex458.
• [6] 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.
• [7] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [8] 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.
• [9] The latest on leukodystrophies.Curr Opin Neurol. 2004 Apr;17(2):187-92. doi: 10.1097/00019052-200404000-00017.
• [10] 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.
• [11] Novel mechanisms of eIF2B action and regulation by eIF2 phosphorylation.Nucleic Acids Res. 2017 Nov 16;45(20):11962-11979. doi: 10.1093/nar/gkx845.
• [12] Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma.Genes Dev. 2017 Jan 1;31(1):18-33. doi: 10.1101/gad.290940.116. Epub 2017 Jan 17.
• [13] 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.
• [14] eIF2B: recent structural and functional insights into a key regulator of translation.Biochem Soc Trans. 2015 Dec;43(6):1234-40. doi: 10.1042/BST20150164.
• [15] Identification of risk and age-at-onset genes on chromosome 1p in Parkinson disease.Am J Hum Genet. 2005 Aug;77(2):252-64. doi: 10.1086/432588. Epub 2005 Jun 28.
• [16] 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.
• [17] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27.
• [20] Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab Anim Res. 2011 Jun;27(2):99-107. doi: 10.5625/lar.2011.27.2.99. Epub 2011 Jun 22.
• [21] 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.
• [22] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [23] 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.
• [24] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [25] Gene expression alteration during redox-dependent enhancement of arsenic cytotoxicity by emodin in HeLa cells. Cell Res. 2005 Jul;15(7):511-22.
• [26] 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.