Details of Drug Off-Target (DOT)

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

• DOT Name: Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA)
• Synonyms: PKR-associated protein X; PKR-associating protein X; Protein activator of the interferon-induced protein kinase; Protein kinase, interferon-inducible double-stranded RNA-dependent activator
• Gene Name: PRKRA
• Related Disease:
  Alzheimer disease
  Arterial disorder
  Atopic dermatitis
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Craniosynostosis
  Dystonia
  Dystonia 12
  Dystonia 16
  Epithelial ovarian cancer
  Hereditary spastic paraplegia 11
  Intellectual disability
  Mental disorder
  Multiple sclerosis
  Neoplasm
  Neurodegeneration with brain iron accumulation
  Neurodegeneration with brain iron accumulation 5
  Ovarian cancer
  Ovarian neoplasm
  Parkinsonism-dystonia, infantile
  Psoriasis
  Segmental dystonia
  Movement disorder
  Peripheral arterial disease
  Advanced cancer
  Autoimmune disease
  Autosomal recessive juvenile Parkinson disease 2
  Encephalitis
  Focal dystonia
  Juvenile-onset Parkinson disease
  Adenocarcinoma
  Ebola virus infection
  Herpes simplex infection
  Minimally invasive lung adenocarcinoma
  Parkinson disease
  Parkinsonian disorder
  Squamous cell carcinoma
  X-linked dystonia-parkinsonism
• UniProt ID: PRKRA_HUMAN
• PDB ID: 2DIX
• Pfam ID: PF00035
• Sequence:
  MSQSRHRAEAPPLEREDSGTFSLGKMITAKPGKTPIQVLHEYGMKTKNIPVYECERSDVQ
  IHVPTFTFRVTVGDITCTGEGTSKKLAKHRAAEAAINILKANASICFAVPDPLMPDPSKQ
  PKNQLNPIGSLQELAIHHGWRLPEYTLSQEGGPAHKREYTTICRLESFMETGKGASKKQA
  KRNAAEKFLAKFSNISPENHISLTNVVGHSLGCTWHSLRNSPGEKINLLKRSLLSIPNTD
  YIQLLSEIAKEQGFNITYLDIDELSANGQYQCLAELSTSPITVCHGSGISCGNAQSDAAH
  NALQYLKIIAERK
• Function: Activates EIF2AK2/PKR in the absence of double-stranded RNA (dsRNA), leading to phosphorylation of EIF2S1/EFI2-alpha and inhibition of translation and induction of apoptosis. Required for siRNA production by DICER1 and for subsequent siRNA-mediated post-transcriptional gene silencing. Does not seem to be required for processing of pre-miRNA to miRNA by DICER1. Promotes UBC9-p53/TP53 association and sumoylation and phosphorylation of p53/TP53 at 'Lys-386' at 'Ser-392' respectively and enhances its activity in a EIF2AK2/PKR-dependent manner.
• Reactome Pathway:
  Small interfering RNA (siRNA) biogenesis (R-HSA-426486)
  PKR-mediated signaling (R-HSA-9833482)
  MicroRNA (miRNA) biogenesis (R-HSA-203927)

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Biomarker	[1]
Arterial disorder	DISLG4XS	Strong	Genetic Variation	[2]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[3]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[5]
Craniosynostosis	DIS6J405	Strong	Altered Expression	[6]
Dystonia	DISJLFGW	Strong	Biomarker	[7]
Dystonia 12	DISNX38R	Strong	Genetic Variation	[8]
Dystonia 16	DISJY7JE	Strong	Autosomal recessive	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[10]
Hereditary spastic paraplegia 11	DIS8K8V4	Strong	Genetic Variation	[8]
Intellectual disability	DISMBNXP	Strong	Biomarker	[11]
Mental disorder	DIS3J5R8	Strong	Biomarker	[12]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Neurodegeneration with brain iron accumulation	DISRK4DZ	Strong	Genetic Variation	[8]
Neurodegeneration with brain iron accumulation 5	DISW9SFJ	Strong	Genetic Variation	[8]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[10]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[10]
Parkinsonism-dystonia, infantile	DISUX01X	Strong	Genetic Variation	[15]
Psoriasis	DIS59VMN	Strong	Genetic Variation	[3]
Segmental dystonia	DISOACMU	Strong	Genetic Variation	[16]
Movement disorder	DISOJJ2D	moderate	Genetic Variation	[17]
Peripheral arterial disease	DIS78WFB	moderate	Biomarker	[18]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[19]
Autoimmune disease	DISORMTM	Disputed	Biomarker	[19]
Autosomal recessive juvenile Parkinson disease 2	DISNSTD1	Disputed	Biomarker	[20]
Encephalitis	DISLD1RL	Disputed	Biomarker	[19]
Focal dystonia	DIS26D7O	Disputed	Biomarker	[20]
Juvenile-onset Parkinson disease	DISNT5BI	Disputed	Biomarker	[20]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[21]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[22]
Herpes simplex infection	DISL1SAV	Limited	Biomarker	[22]
Minimally invasive lung adenocarcinoma	DIS4W83X	Limited	Altered Expression	[21]
Parkinson disease	DISQVHKL	Limited	Biomarker	[23]
Parkinsonian disorder	DISHGY45	Limited	Biomarker	[7]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[21]
X-linked dystonia-parkinsonism	DIS5TT9O	Limited	Biomarker	[8]

10 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 Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[28]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[30]
Marinol	DM70IK5	Approved	Marinol increases the expression of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[33]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[35]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Interferon-inducible double-stranded RNA-dependent protein kinase activator A (PRKRA).	[35]

References

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