Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTM5SX1)

• DOT Name: Translation initiation factor eIF2B subunit delta (EIF2B4)
• Synonyms: eIF2B GDP-GTP exchange factor subunit delta
• Gene Name: EIF2B4
• Related Disease:
  Leishmaniasis
  Leukoencephalopathy with vanishing white matter 1
  Brain disease
  Breast cancer
  Breast carcinoma
  Cerebellar ataxia
  Diffuse systemic sclerosis
  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: EI2BD_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:
  MAAVAVAVREDSGSGMKAELPPGPGAVGREMTKEEKLQLRKEKKQQKKKRKEEKGAEPET
  GSAVSAAQCQVGPTRELPESGIQLGTPREKVPAGRSKAELRAERRAKQEAERALKQARKG
  EQGGPPPKASPSTAGETPSGVKRLPEYPQVDDLLLRRLVKKPERQQVPTRKDYGSKVSLF
  SHLPQYSRQNSLTQFMSIPSSVIHPAMVRLGLQYSQGLVSGSNARCIALLRALQQVIQDY
  TTPPNEELSRDLVNKLKPYMSFLTQCRPLSASMHNAIKFLNKEITSVGSSKREEEAKSEL
  RAAIDRYVQEKIVLAAQAISRFAYQKISNGDVILVYGCSSLVSRILQEAWTEGRRFRVVV
  VDSRPWLEGRHTLRSLVHAGVPASYLLIPAASYVLPEVSKVLLGAHALLANGSVMSRVGT
  AQLALVARAHNVPVLVCCETYKFCERVQTDAFVSNELDDPDDLQCKRGEHVALANWQNHA
  SLRLLNLVYDVTPPELVDLVITELGMIPCSSVPVVLRVKSSDQ
• 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]
Leukoencephalopathy with vanishing white matter 1	DIS72ZXN	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]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[7]
Obsolete leukoencephalopathy with vanishing white matter	DISBOYFO	Strong	Autosomal recessive	[8]
Scleroderma	DISVQ342	Strong	Biomarker	[6]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[6]
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]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Translation initiation factor eIF2B subunit delta (EIF2B4).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Translation initiation factor eIF2B subunit delta (EIF2B4).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Translation initiation factor eIF2B subunit delta (EIF2B4).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Translation initiation factor eIF2B subunit delta (EIF2B4).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Translation initiation factor eIF2B subunit delta (EIF2B4).	[20]

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] Vanishing white matter disease: the first reported chinese patient. J Child Neurol. 2008 Jun;23(6):710-4. doi: 10.1177/0883073808314154.
• [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] 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.
• [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] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.