Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT40Z0OV)

• DOT Name: Eukaryotic elongation factor 2 kinase (EEF2K)
• Synonyms: eEF-2 kinase; eEF-2K; EC 2.7.11.20; Calcium/calmodulin-dependent eukaryotic elongation factor 2 kinase
• Gene Name: EEF2K
• UniProt ID: EF2K_HUMAN
• PDB ID: 5J8H; 5KS5; 6NX4; 7SHQ; 8FNY; 8FO6; 8GM4; 8GM5
• EC Number: 2.7.11.20
• Pfam ID: PF02816
• Sequence:
  MADEDLIFRLEGVDGGQSPRAGHDGDSDGDSDDEEGYFICPITDDPSSNQNVNSKVNKYY
  SNLTKSERYSSSGSPANSFHFKEAWKHAIQKAKHMPDPWAEFHLEDIATERATRHRYNAV
  TGEWLDDEVLIKMASQPFGRGAMRECFRTKKLSNFLHAQQWKGASNYVAKRYIEPVDRDV
  YFEDVRLQMEAKLWGEEYNRHKPPKQVDIMQMCIIELKDRPGKPLFHLEHYIEGKYIKYN
  SNSGFVRDDNIRLTPQAFSHFTFERSGHQLIVVDIQGVGDLYTDPQIHTETGTDFGDGNL
  GVRGMALFFYSHACNRICESMGLAPFDLSPRERDAVNQNTKLLQSAKTILRGTEEKCGSP
  QVRTLSGSRPPLLRPLSENSGDENMSDVTFDSLPSSPSSATPHSQKLDHLHWPVFSDLDN
  MASRDHDHLDNHRESENSGDSGYPSEKRGELDDPEPREHGHSYSNRKYESDEDSLGSSGR
  VCVEKWNLLNSSRLHLPRASAVALEVQRLNALDLEKKIGKSILGKVHLAMVRYHEGGRFC
  EKGEEWDQESAVFHLEHAANLGELEAIVGLGLMYSQLPHHILADVSLKETEENKTKGFDY
  LLKAAEAGDRQSMILVARAFDSGQNLSPDRCQDWLEALHWYNTALEMTDCDEGGEYDGMQ
  DEPRYMMLAREAEMLFTGGYGLEKDPQRSGDLYTQAAEAAMEAMKGRLANQYYQKAEEAW
  AQMEE
• Function: Threonine kinase that regulates protein synthesis by controlling the rate of peptide chain elongation. Upon activation by a variety of upstream kinases including AMPK or TRPM7, phosphorylates the elongation factor EEF2 at a single site, renders it unable to bind ribosomes and thus inactive. In turn, the rate of protein synthesis is reduced.
• KEGG Pathway:
  AMPK sig.ling pathway (hsa04152)
  Oxytocin sig.ling pathway (hsa04921)
• Reactome Pathway: mTORC1-mediated signalling (R-HSA-166208)

Molecular Interaction Atlas (MIA) of This DOT

11 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 Eukaryotic elongation factor 2 kinase (EEF2K).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Eukaryotic elongation factor 2 kinase (EEF2K).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Eukaryotic elongation factor 2 kinase (EEF2K).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Eukaryotic elongation factor 2 kinase (EEF2K).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Eukaryotic elongation factor 2 kinase (EEF2K).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Eukaryotic elongation factor 2 kinase (EEF2K).	[7]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Eukaryotic elongation factor 2 kinase (EEF2K).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Eukaryotic elongation factor 2 kinase (EEF2K).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Eukaryotic elongation factor 2 kinase (EEF2K).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Eukaryotic elongation factor 2 kinase (EEF2K).	[14]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Eukaryotic elongation factor 2 kinase (EEF2K).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Eukaryotic elongation factor 2 kinase (EEF2K).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Eukaryotic elongation factor 2 kinase (EEF2K).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Eukaryotic elongation factor 2 kinase (EEF2K).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Eukaryotic elongation factor 2 kinase (EEF2K).	[12]

References

• [1] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [2] 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.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] 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.
• [5] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [8] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [9] 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.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] 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.
• [12] 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.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.