Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT975ELW)

• DOT Name: Transcriptional activator protein Pur-alpha (PURA)
• Synonyms: Purine-rich single-stranded DNA-binding protein alpha
• Gene Name: PURA
• Related Disease:
  Acute myelogenous leukaemia
  Childhood myelodysplastic syndrome
  Complex neurodevelopmental disorder
  Intellectual disability, autosomal dominant 40
  Myelodysplastic syndrome
  Alzheimer disease
  Autism
  Carcinoma of esophagus
  Epilepsy
  GLUT1 deficiency syndrome
  Intellectual disability
  Nervous system disease
  Neurodevelopmental disorder
  Prostate neoplasm
  PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation
  Schizophrenia
  Movement disorder
  Amyotrophic lateral sclerosis
• UniProt ID: PURA_HUMAN
• Pfam ID: PF04845
• Sequence:
  MADRDSGSEQGGAALGSGGSLGHPGSGSGSGGGGGGGGGGGGSGGGGGGAPGGLQHETQE
  LASKRVDIQNKRFYLDVKQNAKGRFLKIAEVGAGGNKSRLTLSMSVAVEFRDYLGDFIEH
  YAQLGPSQPPDLAQAQDEPRRALKSEFLVRENRKYYMDLKENQRGRFLRIRQTVNRGPGL
  GSTQGQTIALPAQGLIEFRDALAKLIDDYGVEEEPAELPEGTSLTVDNKRFFFDVGSNKY
  GVFMRVSEVKPTYRNSITVPYKVWAKFGHTFCKYSEEMKKIQEKQREKRAACEQLHQQQQ
  QQQEETAAATLLLQGEEEGEED
• Function: This is a probable transcription activator that specifically binds the purine-rich single strand of the PUR element located upstream of the MYC gene. May play a role in the initiation of DNA replication and in recombination.

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Genetic Variation	[1]
Childhood myelodysplastic syndrome	DISMN80I	Definitive	Genetic Variation	[1]
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[2]
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[3]
Myelodysplastic syndrome	DISYHNUI	Definitive	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Autism	DISV4V1Z	Strong	Genetic Variation	[5]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[6]
Epilepsy	DISBB28L	Strong	Biomarker	[7]
GLUT1 deficiency syndrome	DIS8OXEB	Strong	Genetic Variation	[8]
Intellectual disability	DISMBNXP	Strong	Biomarker	[9]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[1]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[7]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[10]
PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation	DIS168GT	Strong	Autosomal dominant	[11]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[12]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[13]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[14]

11 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 Transcriptional activator protein Pur-alpha (PURA).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transcriptional activator protein Pur-alpha (PURA).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Transcriptional activator protein Pur-alpha (PURA).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Transcriptional activator protein Pur-alpha (PURA).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Transcriptional activator protein Pur-alpha (PURA).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Transcriptional activator protein Pur-alpha (PURA).	[20]
Marinol	DM70IK5	Approved	Marinol increases the expression of Transcriptional activator protein Pur-alpha (PURA).	[21]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Transcriptional activator protein Pur-alpha (PURA).	[22]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Transcriptional activator protein Pur-alpha (PURA).	[23]
Celastrol	DMWQIJX	Preclinical	Celastrol decreases the expression of Transcriptional activator protein Pur-alpha (PURA).	[25]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Transcriptional activator protein Pur-alpha (PURA).	[27]

2 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 decreases the methylation of Transcriptional activator protein Pur-alpha (PURA).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Transcriptional activator protein Pur-alpha (PURA).	[26]

References

• [1] PURA, the gene encoding Pur-alpha, member of an ancient nucleic acid-binding protein family with mammalian neurological functions.Gene. 2018 Feb 15;643:133-143. doi: 10.1016/j.gene.2017.12.004. Epub 2017 Dec 6.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] A novel de novo mutation in the PURA gene associated with a new clinical finding: large brainstem. J Genet. 2020;99:7.
• [4] Negative regulation of AbetaPP gene expression by pur-alpha.J Alzheimers Dis. 2008 Sep;15(1):71-82. doi: 10.3233/jad-2008-15106.
• [5] Expanding the neurodevelopmental phenotype of PURA syndrome.Am J Med Genet A. 2018 Jan;176(1):56-67. doi: 10.1002/ajmg.a.38521. Epub 2017 Nov 17.
• [6] miR-144 functions as an oncomiR in KYSE-410 human esophageal carcinoma cell line in vitro and targets PURA.Neoplasma. 2018;65(4):542-551. doi: 10.4149/neo_2018_170814N535.
• [7] De novo variants in neurodevelopmental disorders with epilepsy.Nat Genet. 2018 Jul;50(7):1048-1053. doi: 10.1038/s41588-018-0143-7. Epub 2018 Jun 25.
• [8] A frame-shift deletion in the PURA gene associates with a new clinical finding: Hypoglycorrhachia. Is GLUT1 a new PURA target?.Mol Genet Metab. 2018 Mar;123(3):331-336. doi: 10.1016/j.ymgme.2017.12.436. Epub 2018 Jan 2.
• [9] Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability. J Med Genet. 2014 Dec;51(12):806-13. doi: 10.1136/jmedgenet-2014-102798. Epub 2014 Oct 23.
• [10] Androgen receptor overexpression in prostate cancer linked to Pur alpha loss from a novel repressor complex.Cancer Res. 2008 Apr 15;68(8):2678-88. doi: 10.1158/0008-5472.CAN-07-6017.
• [11] Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome. Am J Hum Genet. 2014 Nov 6;95(5):579-83. doi: 10.1016/j.ajhg.2014.09.014. Epub 2014 Oct 16.
• [12] Prefrontal cortex shotgun proteome analysis reveals altered calcium homeostasis and immune system imbalance in schizophrenia.Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):151-63. doi: 10.1007/s00406-008-0847-2. Epub 2009 Jan 22.
• [13] PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature.J Med Genet. 2018 Feb;55(2):104-113. doi: 10.1136/jmedgenet-2017-104946. Epub 2017 Nov 2.
• [14] The roles of intrinsic disorder-based liquid-liquid phase transitions in the "Dr. Jekyll-Mr. Hyde" behavior of proteins involved in amyotrophic lateral sclerosis and frontotemporal lobar degeneration.Autophagy. 2017;13(12):2115-2162. doi: 10.1080/15548627.2017.1384889. Epub 2017 Dec 17.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] 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.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [20] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [21] 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.
• [22] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [23] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [24] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [25] Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell. 2006 Oct;10(4):321-30.
• [26] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [27] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.