Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5WULOX)

• DOT Name: Eukaryotic translation initiation factor 4E type 2 (EIF4E2)
• Synonyms: eIF-4E type 2; eIF4E type 2; Eukaryotic translation initiation factor 4E homologous protein; Eukaryotic translation initiation factor 4E-like 3; eIF4E-like protein 4E-LP; mRNA cap-binding protein 4EHP; h4EHP; mRNA cap-binding protein type 3
• Gene Name: EIF4E2
• UniProt ID: IF4E2_HUMAN
• PDB ID: 2JGB; 2JGC; 5NVK; 5NVL; 5NVM; 5NVN; 5XLN
• Pfam ID: PF01652
• Sequence:
  MNNKFDALKDDDSGDHDQNEENSTQKDGEKEKTERDKNQSSSKRKAVVPGPAEHPLQYNY
  TFWYSRRTPGRPTSSQSYEQNIKQIGTFASVEQFWRFYSHMVRPGDLTGHSDFHLFKEGI
  KPMWEDDANKNGGKWIIRLRKGLASRCWENLILAMLGEQFMVGEEICGAVVSVRFQEDII
  SIWNKTASDQATTARIRDTLRRVLNLPPNTIMEYKTHTDSIKMPGRLGPQRLLFQNLWKP
  RLNVP
• Function: Recognizes and binds the 7-methylguanosine-containing mRNA cap during an early step in the initiation. Acts as a repressor of translation initiation. In contrast to EIF4E, it is unable to bind eIF4G (EIF4G1, EIF4G2 or EIF4G3), suggesting that it acts by competing with EIF4E and block assembly of eIF4F at the cap. In P-bodies, component of a complex that promotes miRNA-mediated translational repression. Involved in virus-induced host response by mediating miRNA MIR34A-induced translational silencing which controls IFNB1 production by a negative feedback mechanism ; Component of the 4EHP-GYF2 complex, a multiprotein complex that acts as a repressor of translation initiation. In association with GIGYF2, assists ribosome-associated quality control (RQC) by sequestering the mRNA cap, blocking ribosome initiation and decreasing the translational load on problematic messages. Part of a pathway that works in parallel to RQC-mediated degradation of the stalled nascent polypeptide. GIGYF2 and EIF4E2 work downstream and independently of ZNF598, which seems to work as a scaffold that can recruit them to faulty mRNA even if alternative recruitment mechanisms may exist ; (Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 infection, the interaction with non-structural protein 2 (nsp2) with GIGYF2 enhances GIGYF2 binding to EIF4E2 and increases repression of translation initiation of genes involved in antiviral innate immune response such as IFNB1.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  HIF-1 sig.ling pathway (hsa04066)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  Longevity regulating pathway (hsa04211)
  Insulin sig.ling pathway (hsa04910)
• Reactome Pathway: ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Eukaryotic translation initiation factor 4E type 2 (EIF4E2) affects the response to substance of Acetaminophen.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Eukaryotic translation initiation factor 4E type 2 (EIF4E2).	[1]

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 Eukaryotic translation initiation factor 4E type 2 (EIF4E2).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Eukaryotic translation initiation factor 4E type 2 (EIF4E2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Eukaryotic translation initiation factor 4E type 2 (EIF4E2).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Eukaryotic translation initiation factor 4E type 2 (EIF4E2).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Eukaryotic translation initiation factor 4E type 2 (EIF4E2).	[6]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Eukaryotic translation initiation factor 4E type 2 (EIF4E2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Eukaryotic translation initiation factor 4E type 2 (EIF4E2).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Eukaryotic translation initiation factor 4E type 2 (EIF4E2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Eukaryotic translation initiation factor 4E type 2 (EIF4E2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Eukaryotic translation initiation factor 4E type 2 (EIF4E2).	[11]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [8] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] 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.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.