Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMTBX6N)

• DOT Name: Eukaryotic initiation factor 4A-I (EIF4A1)
• Synonyms: eIF-4A-I; eIF4A-I; EC 3.6.4.13; ATP-dependent RNA helicase eIF4A-1
• Gene Name: EIF4A1
• Related Disease:
  T-cell acute lymphoblastic leukaemia
  Adult lymphoma
  Advanced cancer
  Alzheimer disease
  B-cell lymphoma
  B-cell neoplasm
  Breast cancer
  Breast neoplasm
  Cervical cancer
  Cervical carcinoma
  Chikungunya virus infection
  Colonic neoplasm
  Colorectal carcinoma
  Estrogen-receptor positive breast cancer
  Hepatocellular carcinoma
  HIV infectious disease
  Immunodeficiency
  Influenza
  Leukemia
  Lymphoma
  Malignant peripheral nerve sheath tumor
  Matthew-Wood syndrome
  Pancreatic cancer
  Pediatric lymphoma
  Carcinoma
  Melanoma
  Meningioma
  Breast carcinoma
  Pancreatic ductal carcinoma
  Patent ductus arteriosus
  Neoplasm
  Neurodevelopmental disorder
  Non-small-cell lung cancer
  Squamous cell carcinoma
• UniProt ID: IF4A1_HUMAN
• PDB ID: 2G9N; 2ZU6; 3EIQ; 5ZBZ; 5ZC9; 6ZMW; 7PPZ; 7PQ0; 8HUJ
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF00271
• Sequence:
  MSASQDSRSRDNGPDGMEPEGVIESNWNEIVDSFDDMNLSESLLRGIYAYGFEKPSAIQQ
  RAILPCIKGYDVIAQAQSGTGKTATFAISILQQIELDLKATQALVLAPTRELAQQIQKVV
  MALGDYMGASCHACIGGTNVRAEVQKLQMEAPHIIVGTPGRVFDMLNRRYLSPKYIKMFV
  LDEADEMLSRGFKDQIYDIFQKLNSNTQVVLLSATMPSDVLEVTKKFMRDPIRILVKKEE
  LTLEGIRQFYINVEREEWKLDTLCDLYETLTITQAVIFINTRRKVDWLTEKMHARDFTVS
  AMHGDMDQKERDVIMREFRSGSSRVLITTDLLARGIDVQQVSLVINYDLPTNRENYIHRI
  GRGGRFGRKGVAINMVTEEDKRTLRDIETFYNTSIEEMPLNVADLI
• Function: ATP-dependent RNA helicase which is a subunit of the eIF4F complex involved in cap recognition and is required for mRNA binding to ribosome. In the current model of translation initiation, eIF4A unwinds RNA secondary structures in the 5'-UTR of mRNAs which is necessary to allow efficient binding of the small ribosomal subunit, and subsequent scanning for the initiator codon.
• Reactome Pathway:
  L13a-mediated translational silencing of Ceruloplasmin expression (R-HSA-156827)
  Deadenylation of mRNA (R-HSA-429947)
  Translation initiation complex formation (R-HSA-72649)
  Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S (R-HSA-72662)
  Ribosomal scanning and start codon recognition (R-HSA-72702)
  GTP hydrolysis and joining of the 60S ribosomal subunit (R-HSA-72706)
  M-decay (R-HSA-9820841)
  Z-decay (R-HSA-9820865)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Biomarker	[1]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[2]
B-cell neoplasm	DISVY326	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Cervical cancer	DISFSHPF	Strong	Biomarker	[7]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[7]
Chikungunya virus infection	DISDXEHY	Strong	Biomarker	[8]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[11]
HIV infectious disease	DISO97HC	Strong	Biomarker	[12]
Immunodeficiency	DIS093I0	Strong	Biomarker	[9]
Influenza	DIS3PNU3	Strong	Biomarker	[13]
Leukemia	DISNAKFL	Strong	Biomarker	[14]
Lymphoma	DISN6V4S	Strong	Biomarker	[2]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Biomarker	[15]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[16]
Pancreatic cancer	DISJC981	Strong	Biomarker	[17]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	moderate	Altered Expression	[18]
Melanoma	DIS1RRCY	moderate	Biomarker	[19]
Meningioma	DISPT4TG	moderate	Biomarker	[20]
Breast carcinoma	DIS2UE88	Disputed	Biomarker	[6]
Pancreatic ductal carcinoma	DIS26F9Q	Disputed	Biomarker	[21]
Patent ductus arteriosus	DIS9P8YS	Disputed	Biomarker	[21]
Neoplasm	DISZKGEW	Limited	Biomarker	[22]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[23]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Genetic Variation	[24]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[25]

18 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 initiation factor 4A-I (EIF4A1).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[30]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[31]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[33]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[34]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[35]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[36]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[37]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[34]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[38]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[39]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[42]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[43]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[44]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Eukaryotic initiation factor 4A-I (EIF4A1).	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Eukaryotic initiation factor 4A-I (EIF4A1).	[27]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Eukaryotic initiation factor 4A-I (EIF4A1).	[41]

4 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the degradation of Eukaryotic initiation factor 4A-I (EIF4A1).	[32]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the degradation of Eukaryotic initiation factor 4A-I (EIF4A1).	[32]
Paraquat	DMR8O3X	Investigative	Paraquat increases the degradation of Eukaryotic initiation factor 4A-I (EIF4A1).	[32]
D-glucose	DMMG2TO	Investigative	D-glucose increases the degradation of Eukaryotic initiation factor 4A-I (EIF4A1).	[32]

References

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