Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN0NXX2)

• DOT Name: Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1)
• Synonyms: EC 2.7.11.1; Heme-controlled repressor; HCR; Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase; Heme-regulated inhibitor; hHRI; Hemin-sensitive initiation factor 2-alpha kinase
• Gene Name: EIF2AK1
• Related Disease: Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome
• UniProt ID: E2AK1_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MQGGNSGVRKREEEGDGAGAVAAPPAIDFPAEGPDPEYDESDVPAEIQVLKEPLQQPTFP
  FAVANQLLLVSLLEHLSHVHEPNPLRSRQVFKLLCQTFIKMGLLSSFTCSDEFSSLRLHH
  NRAITHLMRSAKERVRQDPCEDISRIQKIRSREVALEAQTSRYLNEFEELAILGKGGYGR
  VYKVRNKLDGQYYAIKKILIKGATKTVCMKVLREVKVLAGLQHPNIVGYHTAWIEHVHVI
  QPRADRAAIELPSLEVLSDQEEDREQCGVKNDESSSSSIIFAEPTPEKEKRFGESDTENQ
  NNKSVKYTTNLVIRESGELESTLELQENGLAGLSASSIVEQQLPLRRNSHLEESFTSTEE
  SSEENVNFLGQTEAQYHLMLHIQMQLCELSLWDWIVERNKRGREYVDESACPYVMANVAT
  KIFQELVEGVFYIHNMGIVHRDLKPRNIFLHGPDQQVKIGDFGLACTDILQKNTDWTNRN
  GKRTPTHTSRVGTCLYASPEQLEGSEYDAKSDMYSLGVVLLELFQPFGTEMERAEVLTGL
  RTGQLPESLRKRCPVQAKYIQHLTRRNSSQRPSAIQLLQSELFQNSGNVNLTLQMKIIEQ
  EKEIAELKKQLNLLSQDKGVRDDGKDGGVG
• Function: Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions. Key activator of the integrated stress response (ISR) required for adaptation to various stress, such as heme deficiency, oxidative stress, osmotic shock, mitochondrial dysfunction and heat shock. EIF2S1/eIF-2-alpha phosphorylation in response to stress converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, leading to a global attenuation of cap-dependent translation, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4, and hence allowing ATF4-mediated reprogramming. Acts as a key sensor of heme-deficiency: in normal conditions, binds hemin via a cysteine thiolate and histidine nitrogenous coordination, leading to inhibit the protein kinase activity. This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell: heme depletion relieves inhibition and stimulates kinase activity, activating the ISR. Thanks to this unique heme-sensing capacity, plays a crucial role to shut off protein synthesis during acute heme-deficient conditions. In red blood cells (RBCs), controls hemoglobin synthesis ensuring a coordinated regulation of the synthesis of its heme and globin moieties. It thereby plays an essential protective role for RBC survival in anemias of iron deficiency. Iron deficiency also triggers activation by full-length DELE1. Also activates the ISR in response to mitochondrial dysHRI/EIF2AK1 protein kinase activity is activated upon binding to the processed form of DELE1 (S-DELE1), thereby promoting the ATF4-mediated reprogramming.
• KEGG Pathway:
  Hepatitis C (hsa05160)
  Measles (hsa05162)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway: Response of EIF2AK1 (HRI) to heme deficiency (R-HSA-9648895)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome	DISD6SHO	Limited	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1) affects the response to substance of Josamycin.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1).	[5]
Marinol	DM70IK5	Approved	Marinol increases the expression of Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1).	[6]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1).	[5]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1).	[7]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1).	[9]

References

• [1] Case of 7p22.1 Microduplication Detected by Whole Genome Microarray (REVEAL) in Workup of Child Diagnosed with Autism. Case Rep Genet. 2015;2015:212436. doi: 10.1155/2015/212436. Epub 2015 Mar 29.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [6] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [7] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [8] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [9] 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.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.