Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTRUJBV)

• DTT Name: Eukaryotic translation initiation factor 2-alpha kinase 1 (EIF2AK1)
• Synonyms: PRO1362; KIAA1369; Hemin-sensitive initiation factor 2-alpha kinase; Heme-regulated inhibitor; Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase; HRI
• Gene Name: EIF2AK1
• DTT Type: Literature-reported target; [1]
• UniProt ID: E2AK1_HUMAN
• TTD ID: T02439
• EC Number: EC 2.7.11.1
• Sequence:
  MQGGNSGVRKREEEGDGAGAVAAPPAIDFPAEGPDPEYDESDVPAEIQVLKEPLQQPTFP
  FAVANQLLLVSLLEHLSHVHEPNPLRSRQVFKLLCQTFIKMGLLSSFTCSDEFSSLRLHH
  NRAITHLMRSAKERVRQDPCEDISRIQKIRSREVALEAQTSRYLNEFEELAILGKGGYGR
  VYKVRNKLDGQYYAIKKILIKGATKTVCMKVLREVKVLAGLQHPNIVGYHTAWIEHVHVI
  QPRADRAAIELPSLEVLSDQEEDREQCGVKNDESSSSSIIFAEPTPEKEKRFGESDTENQ
  NNKSVKYTTNLVIRESGELESTLELQENGLAGLSASSIVEQQLPLRRNSHLEESFTSTEE
  SSEENVNFLGQTEAQYHLMLHIQMQLCELSLWDWIVERNKRGREYVDESACPYVMANVAT
  KIFQELVEGVFYIHNMGIVHRDLKPRNIFLHGPDQQVKIGDFGLACTDILQKNTDWTNRN
  GKRTPTHTSRVGTCLYASPEQLEGSEYDAKSDMYSLGVVLLELFQPFGTEMERAEVLTGL
  RTGQLPESLRKRCPVQAKYIQHLTRRNSSQRPSAIQLLQSELFQNSGNVNLTLQMKIIEQ
  EKEIAELKKQLNLLSQDKGVRDDGKDGGVG
• Function: Inhibits protein synthesis at the translation initiation level, in response to various stress conditions, including oxidative stress, heme deficiency, osmotic shock and heat shock. Exerts its function through the phosphorylation of EIF2S1 at 'Ser-48' and 'Ser-51', thus preventing its recycling. Binds hemin forming a 1:1 complex through a cysteine thiolate and histidine nitrogenous coordination. This binding occurs with moderate affinity, allowing it to sense the heme concentration within the cell. 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. Thus plays an essential protective role for RBC survival in anemias of iron deficiency. Similarly, in hepatocytes, involved in heme-mediated translational control of CYP2B and CYP3A and possibly other hepatic P450 cytochromes. May also contain ER stress during acute heme-deficient conditions (By similarity).
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  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 DTT

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID19854648C27	DMEGPBS	Discovery agent	N.A.	Investigative	[1]

References

• [1] Discovery of the first known small-molecule inhibitors of heme-regulated eukaryotic initiation factor 2alpha (HRI) kinase. Bioorg Med Chem Lett. 2009 Dec 1;19(23):6548-51.