Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM5ZD8Y)

• DOT Name: Elongation factor 1-delta (EEF1D)
• Synonyms: EF-1-delta; Antigen NY-CO-4
• Gene Name: EEF1D
• Related Disease:
  Intellectual disability
  Advanced cancer
  Bone osteosarcoma
  Breast neoplasm
  Carcinoma of esophagus
  Hepatocellular carcinoma
  Medulloblastoma
  Neoplasm
  Osteosarcoma
  Spinal muscular atrophy
  Squamous cell carcinoma
  Neurodevelopmental disorder
• UniProt ID: EF1D_HUMAN
• PDB ID: 2MVM; 2MVN; 2N51; 5JPO
• Pfam ID: PF10587 ; PF00736
• Sequence:
  MATNFLAHEKIWFDKFKYDDAERRFYEQMNGPVAGASRQENGASVILRDIARARENIQKS
  LAGSSGPGASSGTSGDHGELVVRIASLEVENQSLRGVVQELQQAISKLEARLNVLEKSSP
  GHRATAPQTQHVSPMRQVEPPAKKPATPAEDDEDDDIDLFGSDNEEEDKEAAQLREERLR
  QYAEKKAKKPALVAKSSILLDVKPWDDETDMAQLEACVRSIQLDGLVWGASKLVPVGYGI
  RKLQIQCVVEDDKVGTDLLEEEITKFEEHVQSVDIAAFNKI
• Function: [Isoform 1]: EF-1-beta and EF-1-delta stimulate the exchange of GDP bound to EF-1-alpha to GTP, regenerating EF-1-alpha for another round of transfer of aminoacyl-tRNAs to the ribosome.; [Isoform 2]: Regulates induction of heat-shock-responsive genes through association with heat shock transcription factors and direct DNA-binding at heat shock promoter elements (HSE).
• Tissue Specificity: Isoform 2 is specifically expressed in brain, cerebellum and testis.
• Reactome Pathway: Eukaryotic Translation Elongation (R-HSA-156842)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Spinal muscular atrophy	DISTLKOB	Strong	Genetic Variation	[7]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[8]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[9]

3 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 Elongation factor 1-delta (EEF1D).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Elongation factor 1-delta (EEF1D).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Elongation factor 1-delta (EEF1D).	[23]

14 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 Elongation factor 1-delta (EEF1D).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Elongation factor 1-delta (EEF1D).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Elongation factor 1-delta (EEF1D).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Elongation factor 1-delta (EEF1D).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Elongation factor 1-delta (EEF1D).	[15]
Selenium	DM25CGV	Approved	Selenium increases the expression of Elongation factor 1-delta (EEF1D).	[16]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Elongation factor 1-delta (EEF1D).	[17]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Elongation factor 1-delta (EEF1D).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Elongation factor 1-delta (EEF1D).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Elongation factor 1-delta (EEF1D).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of Elongation factor 1-delta (EEF1D).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Elongation factor 1-delta (EEF1D).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Elongation factor 1-delta (EEF1D).	[24]
Z-Pro-Prolinal	DM43O2U	Investigative	Z-Pro-Prolinal increases the expression of Elongation factor 1-delta (EEF1D).	[25]

References

• [1] Biallelic loss of EEF1D function links heat shock response pathway to autosomal recessive intellectual disability.J Hum Genet. 2019 May;64(5):421-426. doi: 10.1038/s10038-019-0570-z. Epub 2019 Feb 21.
• [2] EEF1D overexpression promotes osteosarcoma cell proliferation by facilitating Akt-mTOR and Akt-bad signaling.J Exp Clin Cancer Res. 2018 Mar 6;37(1):50. doi: 10.1186/s13046-018-0715-5.
• [3] BMP-6 promotes E-cadherin expression through repressing deltaEF1 in breast cancer cells.BMC Cancer. 2007 Nov 13;7:211. doi: 10.1186/1471-2407-7-211.
• [4] Clinical significance of elongation factor-1 delta mRNA expression in oesophageal carcinoma.Br J Cancer. 2004 Jul 19;91(2):282-6. doi: 10.1038/sj.bjc.6601941.
• [5] Alterations in Eukaryotic Elongation Factor complex proteins (EEF1s) in cancer and their implications in epigenetic regulation.Life Sci. 2019 Dec 1;238:116977. doi: 10.1016/j.lfs.2019.116977. Epub 2019 Oct 19.
• [6] Medulloblastoma outcome is adversely associated with overexpression of EEF1D, RPL30, and RPS20 on the long arm of chromosome 8.BMC Cancer. 2006 Sep 12;6:223. doi: 10.1186/1471-2407-6-223.
• [7] The role of copy number variation in susceptibility to amyotrophic lateral sclerosis: genome-wide association study and comparison with published loci.PLoS One. 2009 Dec 4;4(12):e8175. doi: 10.1371/journal.pone.0008175.
• [8] EEF1D modulates proliferation and epithelial-mesenchymal transition in oral squamous cell carcinoma.Clin Sci (Lond). 2016 May 1;130(10):785-99. doi: 10.1042/CS20150646. Epub 2016 Jan 28.
• [9] The role of translation elongation factor eEF1 subunits in neurodevelopmental disorders.Hum Mutat. 2019 Feb;40(2):131-141. doi: 10.1002/humu.23677. Epub 2018 Nov 23.
• [10] 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.
• [11] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] 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.
• [14] 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.
• [15] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [16] 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.
• [17] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [18] 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.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [21] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [22] 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.
• [23] 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.
• [24] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [25] Prolyl endopeptidase is involved in cellular signalling in human neuroblastoma SH-SY5Y cells. Neurosignals. 2011;19(2):97-109. doi: 10.1159/000326342. Epub 2011 Apr 10.