Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYYFE7K)

• DOT Name: Eukaryotic initiation factor 4A-III (EIF4A3)
• Synonyms: eIF-4A-III; eIF4A-III; EC 3.6.4.13; ATP-dependent RNA helicase DDX48; ATP-dependent RNA helicase eIF4A-3; DEAD box protein 48; Eukaryotic initiation factor 4A-like NUK-34; Eukaryotic translation initiation factor 4A isoform 3; Nuclear matrix protein 265; NMP 265; hNMP 265
• Gene Name: EIF4A3
• Related Disease:
  Coronary heart disease
  Gastric neoplasm
  Richieri Costa-Pereira syndrome
  Carcinoma of esophagus
  Clubfoot
  Congenital deformities of limbs
  Esophageal cancer
  Gastric cancer
  Intellectual disability
  Isolated Pierre-Robin syndrome
  Myocardial infarction
  Neoplasm
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Pancreatic tumour
  Stomach cancer
  Acrofacial dysostosis
  Cervical carcinoma
  Choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome
  Hirschsprung disease
  Hepatocellular carcinoma
  Advanced cancer
  Bone osteosarcoma
  Colorectal carcinoma
  Glioblastoma multiforme
  Osteosarcoma
  Squamous cell carcinoma
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
• UniProt ID: IF4A3_HUMAN
• PDB ID: 2HXY; 2HYI; 2J0Q; 2J0S; 2J0U; 2XB2; 3EX7; 4C9B; 5MQF; 5XJC; 5YZG; 6ICZ; 6QDV; 6YVH; 7A5P; 7W59; 7W5A; 7W5B; 7ZNJ; 8C6J
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271
• Sequence:
  MATTATMATSGSARKRLLKEEDMTKVEFETSEEVDVTPTFDTMGLREDLLRGIYAYGFEK
  PSAIQQRAIKQIIKGRDVIAQSQSGTGKTATFSISVLQCLDIQVRETQALILAPTRELAV
  QIQKGLLALGDYMNVQCHACIGGTNVGEDIRKLDYGQHVVAGTPGRVFDMIRRRSLRTRA
  IKMLVLDEADEMLNKGFKEQIYDVYRYLPPATQVVLISATLPHEILEMTNKFMTDPIRIL
  VKRDELTLEGIKQFFVAVEREEWKFDTLCDLYDTLTITQAVIFCNTKRKVDWLTEKMREA
  NFTVSSMHGDMPQKERESIMKEFRSGASRVLISTDVWARGLDVPQVSLIINYDLPNNREL
  YIHRIGRSGRYGRKGVAINFVKNDDIRILRDIEQYYSTQIDEMPMNVADLI
• Function: ATP-dependent RNA helicase. Involved in pre-mRNA splicing as component of the spliceosome. Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). Its RNA-dependent ATPase and RNA-helicase activities are induced by CASC3, but abolished in presence of the MAGOH-RBM8A heterodimer, thereby trapping the ATP-bound EJC core onto spliced mRNA in a stable conformation. The inhibition of ATPase activity by the MAGOH-RBM8A heterodimer increases the RNA-binding affinity of the EJC. Involved in translational enhancement of spliced mRNAs after formation of the 80S ribosome complex. Binds spliced mRNA in sequence-independent manner, 20-24 nucleotides upstream of mRNA exon-exon junctions. Shows higher affinity for single-stranded RNA in an ATP-bound core EJC complex than after the ATP is hydrolyzed. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly. Involved in craniofacial development.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  mR. surveillance pathway (hsa03015)
  Spliceosome (hsa03040)
• Reactome Pathway:
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)
  Deadenylation of mRNA (R-HSA-429947)
  mRNA Splicing - Major Pathway (R-HSA-72163)
  mRNA 3'-end processing (R-HSA-72187)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  M-decay (R-HSA-9820841)
  Z-decay (R-HSA-9820865)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary heart disease	DIS5OIP1	Definitive	Altered Expression	[1]
Gastric neoplasm	DISOKN4Y	Definitive	Altered Expression	[2]
Richieri Costa-Pereira syndrome	DISDQOSK	Definitive	Autosomal recessive	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[4]
Clubfoot	DISLXT4S	Strong	Biomarker	[5]
Congenital deformities of limbs	DISP4N1Q	Strong	Genetic Variation	[6]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[7]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[8]
Intellectual disability	DISMBNXP	Strong	Biomarker	[9]
Isolated Pierre-Robin syndrome	DISVEHG7	Strong	Biomarker	[10]
Myocardial infarction	DIS655KI	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[13]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[14]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[8]
Acrofacial dysostosis	DISNBM5T	moderate	Biomarker	[10]
Cervical carcinoma	DIST4S00	moderate	Biomarker	[15]
Choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome	DISI9JIG	moderate	Biomarker	[10]
Hirschsprung disease	DISUUSM1	moderate	Altered Expression	[16]
Hepatocellular carcinoma	DIS0J828	Disputed	Altered Expression	[17]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[18]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[19]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[18]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[20]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[19]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[21]
Thyroid cancer	DIS3VLDH	Limited	Biomarker	[22]
Thyroid gland carcinoma	DISMNGZ0	Limited	Biomarker	[22]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[22]

5 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 Eukaryotic initiation factor 4A-III (EIF4A3).	[23]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Eukaryotic initiation factor 4A-III (EIF4A3).	[30]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Eukaryotic initiation factor 4A-III (EIF4A3).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Eukaryotic initiation factor 4A-III (EIF4A3).	[32]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Eukaryotic initiation factor 4A-III (EIF4A3).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Eukaryotic initiation factor 4A-III (EIF4A3).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Eukaryotic initiation factor 4A-III (EIF4A3).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic initiation factor 4A-III (EIF4A3).	[26]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Eukaryotic initiation factor 4A-III (EIF4A3).	[27]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Eukaryotic initiation factor 4A-III (EIF4A3).	[28]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Eukaryotic initiation factor 4A-III (EIF4A3).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Eukaryotic initiation factor 4A-III (EIF4A3).	[33]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Eukaryotic initiation factor 4A-III (EIF4A3).	[34]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Eukaryotic initiation factor 4A-III (EIF4A3).	[35]

References

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• [35] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.