Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTARRES9)

• DOT Name: Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3)
• Synonyms: EC 3.6.5.3; Eukaryotic translation initiation factor 2 subunit gamma X; eIF2-gamma X; eIF2gX
• Gene Name: EIF2S3
• Related Disease:
  Cognitive impairment
  MEHMO syndrome
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Chagas disease
  Colorectal carcinoma
  Epilepsy
  Familial adenomatous polyposis
  Fatty liver disease
  Hypoglycemia
  Hypogonadism
  Intellectual disability
  Isolated congenital microcephaly
  Leukoencephalopathy with vanishing white matter
  Liposarcoma
  Liver cirrhosis
  Non-small-cell lung cancer
  Obesity
  Pituitary gland disorder
  Schizophrenia
  Trichohepatoenteric syndrome
  Type-1/2 diabetes
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Myotonic dystrophy type 2
  Wolcott-Rallison syndrome
  Hypopituitarism
• UniProt ID: IF2G_HUMAN
• PDB ID: 6FEC; 6K71; 6K72; 6O81; 6O85; 6YBV; 6ZMW; 6ZP4; 7A09; 7D43; 7F66; 7F67; 7QP6; 7QP7; 8PHD; 8PHV; 8PPL
• EC Number: 3.6.5.3
• Pfam ID: PF09173 ; PF00009 ; PF03144
• Sequence:
  MAGGEAGVTLGQPHLSRQDLTTLDVTKLTPLSHEVISRQATINIGTIGHVAHGKSTVVKA
  ISGVHTVRFKNELERNITIKLGYANAKIYKLDDPSCPRPECYRSCGSSTPDEFPTDIPGT
  KGNFKLVRHVSFVDCPGHDILMATMLNGAAVMDAALLLIAGNESCPQPQTSEHLAAIEIM
  KLKHILILQNKIDLVKESQAKEQYEQILAFVQGTVAEGAPIIPISAQLKYNIEVVCEYIV
  KKIPVPPRDFTSEPRLIVIRSFDVNKPGCEVDDLKGGVAGGSILKGVLKVGQEIEVRPGI
  VSKDSEGKLMCKPIFSKIVSLFAEHNDLQYAAPGGLIGVGTKIDPTLCRADRMVGQVLGA
  VGALPEIFTELEISYFLLRRLLGVRTEGDKKAAKVQKLSKNEVLMVNIGSLSTGGRVSAV
  KADLGKIVLTNPVCTEVGEKIALSRRVEKHWRLIGWGQIRRGVTIKPTVDDD
• Function: Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. This complex binds to a 40S ribosomal subunit, followed by mRNA binding to form the 43S pre-initiation complex (43S PIC). Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF2 and release of an eIF2-GDP binary complex. In order for eIF2 to recycle and catalyze another round of initiation, the GDP bound to eIF2 must exchange with GTP by way of a reaction catalyzed by eIF-2B.
• Tissue Specificity: Expressed in testis, brain, liver and muscle.
• Reactome Pathway:
  PERK regulates gene expression (R-HSA-381042)
  ABC-family proteins mediated transport (R-HSA-382556)
  Translation initiation complex formation (R-HSA-72649)
  Formation of the ternary complex, and subsequently, the 43S complex (R-HSA-72695)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  Recycling of eIF2 (R-HSA-72731)
  Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012)
  Response of EIF2AK1 (HRI) to heme deficiency (R-HSA-9648895)
  PKR-mediated signaling (R-HSA-9833482)
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cognitive impairment	DISH2ERD	Definitive	Posttranslational Modification	[1]
MEHMO syndrome	DISPH301	Definitive	Autosomal dominant	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[6]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[6]
Chagas disease	DIS8KNVF	Strong	Posttranslational Modification	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Epilepsy	DISBB28L	Strong	Biomarker	[9]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[10]
Fatty liver disease	DIS485QZ	Strong	Genetic Variation	[11]
Hypoglycemia	DISRCKR7	Strong	Genetic Variation	[12]
Hypogonadism	DISICMNI	Strong	Biomarker	[9]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[9]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[12]
Leukoencephalopathy with vanishing white matter	DIS3J8NN	Strong	Posttranslational Modification	[13]
Liposarcoma	DIS8IZVM	Strong	Biomarker	[14]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[15]
Obesity	DIS47Y1K	Strong	Biomarker	[16]
Pituitary gland disorder	DIS7XB48	Strong	Biomarker	[12]
Schizophrenia	DISSRV2N	Strong	Biomarker	[17]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[9]
Type-1/2 diabetes	DISIUHAP	Strong	X-linked	[18]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Biomarker	[19]
Liver cancer	DISDE4BI	moderate	Biomarker	[19]
Myotonic dystrophy type 2	DIS5ZWF1	moderate	Altered Expression	[20]
Wolcott-Rallison syndrome	DISKVKXN	moderate	Genetic Variation	[21]
Hypopituitarism	DIS1QT3G	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3).	[24]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3).	[25]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3).	[26]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3).	[26]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3).	[28]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Eukaryotic translation initiation factor 2 subunit 3 (EIF2S3).	[27]

References

• [1] Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.Science. 2018 Mar 30;359(6383):eaaq0939. doi: 10.1126/science.aaq0939.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Integrated Stress Response Activity Marks Stem Cells in Normal Hematopoiesis and Leukemia.Cell Rep. 2018 Oct 30;25(5):1109-1117.e5. doi: 10.1016/j.celrep.2018.10.021.
• [4] Translational control: the cancer connection.Int J Biochem Cell Biol. 1999 Jan;31(1):1-23. doi: 10.1016/s1357-2725(98)00127-7.
• [5] Double stranded RNA activated EIF2 alpha kinase (EIF2AK2; PKR) is associated with Alzheimer's disease.Neurobiol Aging. 2008 Aug;29(8):1160-6. doi: 10.1016/j.neurobiolaging.2007.02.023. Epub 2007 Apr 8.
• [6] Increased susceptibility of breast cancer cells to stress mediated inhibition of protein synthesis.Cancer Res. 2008 Jun 15;68(12):4862-74. doi: 10.1158/0008-5472.CAN-08-0074.
• [7] Identification of di-substituted ureas that prevent growth of trypanosomes through inhibition of translation initiation.Sci Rep. 2018 Mar 20;8(1):4857. doi: 10.1038/s41598-018-23259-9.
• [8] The Immunome of Colon Cancer: Functional In Silico Analysis of Antigenic Proteins Deduced from IgG Microarray Profiling.Genomics Proteomics Bioinformatics. 2018 Feb;16(1):73-84. doi: 10.1016/j.gpb.2017.10.002. Epub 2018 Mar 2.
• [9] EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO. Hum Mutat. 2017 Apr;38(4):409-425. doi: 10.1002/humu.23170. Epub 2017 Jan 23.
• [10] Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures.Theranostics. 2016 Jul 18;6(11):1792-809. doi: 10.7150/thno.14584. eCollection 2016.
• [11] Multi-SNP analysis of GWAS data identifies pathways associated with nonalcoholic fatty liver disease.PLoS One. 2013 Jul 19;8(7):e65982. doi: 10.1371/journal.pone.0065982. Print 2013.
• [12] Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation.EBioMedicine. 2019 Apr;42:470-480. doi: 10.1016/j.ebiom.2019.03.013. Epub 2019 Mar 14.
• [13] Bergmann glia translocation: a new disease marker for vanishing white matter identifies therapeutic effects of Guanabenz treatment.Neuropathol Appl Neurobiol. 2018 Jun;44(4):391-403. doi: 10.1111/nan.12411. Epub 2017 Aug 1.
• [14] FUS-DDIT3 prevents the development of adipocytic precursors in liposarcoma by repressing PPARgamma and C/EBPalpha and activating eIF4E.PLoS One. 2008 Jul 2;3(7):e2569. doi: 10.1371/journal.pone.0002569.
• [15] eIF2, a subunit of translation-initiation factor EIF2, is a potential therapeutic target for non-small cell lung cancer.Cancer Sci. 2018 Jun;109(6):1843-1852. doi: 10.1111/cas.13602. Epub 2018 May 25.
• [16] Dietary Intake of Curcumin Improves eIF2 Signaling and Reduces Lipid Levels in the White Adipose Tissue of Obese Mice.Sci Rep. 2018 Jun 13;8(1):9081. doi: 10.1038/s41598-018-27105-w.
• [17] Thalamic transcriptome screening in three psychiatric states.J Hum Genet. 2009 Nov;54(11):665-75. doi: 10.1038/jhg.2009.93. Epub 2009 Oct 16.
• [18] 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.
• [19] The role of CUGBP1 in age-dependent changes of liver functions.Ageing Res Rev. 2012 Sep;11(4):442-9. doi: 10.1016/j.arr.2012.02.007. Epub 2012 Mar 14.
• [20] Expression of RNA CCUG repeats dysregulates translation and degradation of proteins in myotonic dystrophy 2 patients.Am J Pathol. 2009 Aug;175(2):748-62. doi: 10.2353/ajpath.2009.090047. Epub 2009 Jul 9.
• [21] Endoplasmic reticulum stress and the development of diabetes: a review.Diabetes. 2002 Dec;51 Suppl 3:S455-61. doi: 10.2337/diabetes.51.2007.s455.
• [22] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [23] 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.
• [24] DNA microarray analysis of changes in gene expression induced by 1,25-dihydroxyvitamin D3 in human promyelocytic leukemia HL-60 cells. Biomed Res. 2006 Jun;27(3):99-109. doi: 10.2220/biomedres.27.99.
• [25] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [26] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [27] 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.
• [28] 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.
• [29] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.