Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQQMHM1)

• DOT Name: Translation initiation factor eIF2B subunit beta (EIF2B2)
• Synonyms: S20I15; S20III15; eIF2B GDP-GTP exchange factor subunit beta
• Gene Name: EIF2B2
• Related Disease:
  Leishmaniasis
  Obsolete leukoencephalopathy with vanishing white matter
  Brain disease
  Breast cancer
  Breast carcinoma
  Cerebellar ataxia
  Diffuse systemic sclerosis
  Leukoencephalopathy with vanishing white matter 1
  Neurodevelopmental disorder
  Scleroderma
  Systemic sclerosis
  Adrenocortical insufficiency
  Adrenoleukodystrophy
  Female hypogonadism
  Obsolete ovarioleukodystrophy
  Advanced cancer
  Melanoma
  Neoplasm
  Nervous system disease
  Parkinson disease
• UniProt ID: EI2BB_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: PF01008
• Sequence:
  MPGSAAKGSELSERIESFVETLKRGGGPRSSEEMARETLGLLRQIITDHRWSNAGELMEL
  IRREGRRMTAAQPSETTVGNMVRRVLKIIREEYGRLHGRSDESDQQESLHKLLTSGGLNE
  DFSFHYAQLQSNIIEAINELLVELEGTMENIAAQALEHIHSNEVIMTIGFSRTVEAFLKE
  AARKRKFHVIVAECAPFCQGHEMAVNLSKAGIETTVMTDAAIFAVMSRVNKVIIGTKTIL
  ANGALRAVTGTHTLALAAKHHSTPLIVCAPMFKLSPQFPNEEDSFHKFVAPEEVLPFTEG
  DILEKVSVHCPVFDYVPPELITLFISNIGGNAPSYIYRLMSELYHPDDHVL
• 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

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leishmaniasis	DISABTW7	Definitive	Biomarker	[1]
Obsolete leukoencephalopathy with vanishing white matter	DISBOYFO	Definitive	Autosomal recessive	[2]
Brain disease	DIS6ZC3X	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[5]
Diffuse systemic sclerosis	DISYF5LP	Strong	Biomarker	[6]
Leukoencephalopathy with vanishing white matter 1	DIS72ZXN	Strong	Autosomal recessive	[2]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[7]
Scleroderma	DISVQ342	Strong	Biomarker	[6]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[6]
Adrenocortical insufficiency	DISZ0CPT	moderate	Genetic Variation	[8]
Adrenoleukodystrophy	DISTUD1F	moderate	Genetic Variation	[8]
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]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Translation initiation factor eIF2B subunit beta (EIF2B2).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Translation initiation factor eIF2B subunit beta (EIF2B2).	[17]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Translation initiation factor eIF2B subunit beta (EIF2B2).	[18]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Translation initiation factor eIF2B subunit beta (EIF2B2).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Translation initiation factor eIF2B subunit beta (EIF2B2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Translation initiation factor eIF2B subunit beta (EIF2B2).	[21]

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] Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet. 2001 Dec;29(4):383-8. doi: 10.1038/ng764.
• [3] 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.
• [4] 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.
• [5] Childhood ataxia with CNS hypomyelination/vanishing white matter disease--a common leukodystrophy caused by abnormal control of protein synthesis.Mol Genet Metab. 2006 May;88(1):7-15. doi: 10.1016/j.ymgme.2005.10.019. Epub 2006 Jan 18.
• [6] 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.
• [7] Identification of novel genetic causes of Rett syndrome-like phenotypes. J Med Genet. 2016 Mar;53(3):190-9. doi: 10.1136/jmedgenet-2015-103568. Epub 2016 Jan 6.
• [8] Vanishing white matter disease caused by EIF2B2 mutation with the presentation of an adrenoleukodystrophy phenotype.Gene. 2012 Apr 1;496(2):141-3. doi: 10.1016/j.gene.2011.12.047. Epub 2012 Jan 17.
• [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] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [17] 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.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] Proteomic analysis of antiproliferative effects by treatment of 5-fluorouracil in cervical cancer cells. DNA Cell Biol. 2004 Nov;23(11):769-76.
• [20] 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.
• [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.