Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLE1JY8)

• DOT Name: eIF-2-alpha kinase GCN2 (EIF2AK4)
• Synonyms: EC 2.7.11.1; Eukaryotic translation initiation factor 2-alpha kinase 4; GCN2-like protein
• Gene Name: EIF2AK4
• Related Disease:
  Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis
  Pulmonary venoocclusive disease 2
  Heritable pulmonary arterial hypertension
  Pulmonary venoocclusive disease
• UniProt ID: E2AK4_HUMAN
• PDB ID: 6N3L; 6N3N; 6N3O; 7E2K; 7E2M; 7QQ6; 7QWK
• EC Number: 2.7.11.1
• Pfam ID: PF12745 ; PF00069 ; PF05773 ; PF13393
• Sequence:
  MAGGRGAPGRGRDEPPESYPQRQDHELQALEAIYGADFQDLRPDACGPVKEPPEINLVLY
  PQGLTGEEVYVKVDLRVKCPPTYPDVVPEIELKNAKGLSNESVNLLKSRLEELAKKHCGE
  VMIFELAYHVQSFLSEHNKPPPKSFHEEMLERRAQEEQQRLLEAKRKEEQEQREILHEIQ
  RRKEEIKEEKKRKEMAKQERLEIASLSNQDHTSKKDPGGHRTAAILHGGSPDFVGNGKHR
  ANSSGRSRRERQYSVCNSEDSPGSCEILYFNMGSPDQLMVHKGKCIGSDEQLGKLVYNAL
  ETATGGFVLLYEWVLQWQKKMGPFLTSQEKEKIDKCKKQIQGTETEFNSLVKLSHPNVVR
  YLAMNLKEQDDSIVVDILVEHISGVSLAAHLSHSGPIPVHQLRRYTAQLLSGLDYLHSNS
  VVHKVLSASNVLVDAEGTVKITDYSISKRLADICKEDVFEQTRVRFSDNALPYKTGKKGD
  VWRLGLLLLSLSQGQECGEYPVTIPSDLPADFQDFLKKCVCLDDKERWSPQQLLKHSFIN
  PQPKMPLVEQSPEDSEGQDYVETVIPSNRLPSAAFFSETQRQFSRYFIEFEELQLLGKGA
  FGAVIKVQNKLDGCCYAVKRIPINPASRQFRRIKGEVTLLSRLHHENIVRYYNAWIERHE
  RPAGPGTPPPDSGPLAKDDRAARGQPASDTDGLDSVEAAAPPPILSSSVEWSTSGERSAS
  ARFPATGPGSSDDEDDDEDEHGGVFSQSFLPASDSESDIIFDNEDENSKSQNQDEDCNEK
  NGCHESEPSVTTEAVHYLYIQMEYCEKSTLRDTIDQGLYRDTVRLWRLFREILDGLAYIH
  EKGMIHRDLKPVNIFLDSDDHVKIGDFGLATDHLAFSADSKQDDQTGDLIKSDPSGHLTG
  MVGTALYVSPEVQGSTKSAYNQKVDLFSLGIIFFEMSYHPMVTASERIFVLNQLRDPTSP
  KFPEDFDDGEHAKQKSVISWLLNHDPAKRPTATELLKSELLPPPQMEESELHEVLHHTLT
  NVDGKAYRTMMAQIFSQRISPAIDYTYDSDILKGNFSIRTAKMQQHVCETIIRIFKRHGA
  VQLCTPLLLPRNRQIYEHNEAALFMDHSGMLVMLPFDLRIPFARYVARNNILNLKRYCIE
  RVFRPRKLDRFHPKELLECAFDIVTSTTNSFLPTAEIIYTIYEIIQEFPALQERNYSIYL
  NHTMLLKAILLHCGIPEDKLSQVYIILYDAVTEKLTRREVEAKFCNLSLSSNSLCRLYKF
  IEQKGDLQDLMPTINSLIKQKTGIAQLVKYGLKDLEEVVGLLKKLGIKLQVLINLGLVYK
  VQQHNGIIFQFVAFIKRRQRAVPEILAAGGRYDLLIPQFRGPQALGPVPTAIGVSIAIDK
  ISAAVLNMEESVTISSCDLLVVSVGQMSMSRAINLTQKLWTAGITAEIMYDWSQSQEELQ
  EYCRHHEITYVALVSDKEGSHVKVKSFEKERQTEKRVLETELVDHVLQKLRTKVTDERNG
  REASDNLAVQNLKGSFSNASGLFEIHGATVVPIVSVLAPEKLSASTRRRYETQVQTRLQT
  SLANLHQKSSEIEILAVDLPKETILQFLSLEWDADEQAFNTTVKQLLSRLPKQRYLKLVC
  DEIYNIKVEKKVSVLFLYSYRDDYYRILF
• Function: Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to low amino acid availability. Plays a role as an activator of the integrated stress response (ISR) required for adaptation to amino acid starvation. EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha into a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, and thus to a reduced overall utilization of amino acids, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming of amino acid biosynthetic gene expression to alleviate nutrient depletion. Binds uncharged tRNAs. Required for the translational induction of protein kinase PRKCH following amino acid starvation. Involved in cell cycle arrest by promoting cyclin D1 mRNA translation repression after the unfolded protein response pathway (UPR) activation or cell cycle inhibitor CDKN1A/p21 mRNA translation activation in response to amino acid deprivation. Plays a role in the consolidation of synaptic plasticity, learning as well as formation of long-term memory. Plays a role in neurite outgrowth inhibition. Plays a proapoptotic role in response to glucose deprivation. Promotes global cellular protein synthesis repression in response to UV irradiation independently of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 MAPK signaling pathways. Plays a role in the antiviral response against alphavirus infection; impairs early viral mRNA translation of the incoming genomic virus RNA, thus preventing alphavirus replication; (Microbial infection) Plays a role in modulating the adaptive immune response to yellow fever virus infection; promotes dendritic cells to initiate autophagy and antigene presentation to both CD4(+) and CD8(+) T-cells under amino acid starvation.
• Tissue Specificity: Widely expressed . Expressed in lung, smooth muscle cells and macrophages .
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Hepatitis C (hsa05160)
  Measles (hsa05162)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway: Response of EIF2AK4 (GCN2) to amino acid deficiency (R-HSA-9633012)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis	DIS2QWBE	Definitive	Autosomal recessive	[1]
Pulmonary venoocclusive disease 2	DISJIUZP	Strong	Autosomal recessive	[2]
Heritable pulmonary arterial hypertension	DISD1Y94	Supportive	Autosomal dominant	[3]
Pulmonary venoocclusive disease	DIS62DX8	Supportive	Autosomal recessive	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[13]
Irinotecan	DMP6SC2	Approved	Irinotecan affects the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[14]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of eIF-2-alpha kinase GCN2 (EIF2AK4).	[22]
Borrelidin	DMBSQTR	Investigative	Borrelidin increases the activity of eIF-2-alpha kinase GCN2 (EIF2AK4).	[23]

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 decreases the phosphorylation of eIF-2-alpha kinase GCN2 (EIF2AK4).	[19]

References

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• [2] The GCN2 eIF2alpha kinase is required for adaptation to amino acid deprivation in mice. Mol Cell Biol. 2002 Oct;22(19):6681-8. doi: 10.1128/MCB.22.19.6681-6688.2002.
• [3] A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies. Clin Genet. 2015 Dec;88(6):579-83. doi: 10.1111/cge.12549. Epub 2015 Jan 7.
• [4] EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet. 2014 Jan;46(1):65-9. doi: 10.1038/ng.2844. Epub 2013 Dec 1.
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• [10] 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.
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• [12] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [13] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [14] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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• [18] 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.
• [19] 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.
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• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Borrelidin, a small molecule nitrile-containing macrolide inhibitor of threonyl-tRNA synthetase, is a potent inducer of apoptosis in acute lymphoblastic leukemia. Invest New Drugs. 2012 Aug;30(4):1361-70. doi: 10.1007/s10637-011-9700-y. Epub 2011 Jun 17.