Details of Drug Off-Target (DOT)

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

• DOT Name: Polyglutamine-binding protein 1 (PQBP1)
• Synonyms: PQBP-1; 38 kDa nuclear protein containing a WW domain; Npw38; Polyglutamine tract-binding protein 1
• Gene Name: PQBP1
• Related Disease:
  Bone osteosarcoma
  Hereditary spastic paraplegia
  Microphthalmia
  Osteosarcoma
  Renpenning syndrome
  Alzheimer disease
  Atrial septal defect
  Coffin-Lowry syndrome
  Coronary heart disease
  Epilepsy
  Fatty liver disease
  Intellectual disability
  Intellectual disability, X-linked 19
  Microlissencephaly
  Motor neurone disease
  Trichohepatoenteric syndrome
  X-linked intellectual disability
  Spinocerebellar ataxia type 1
  Hamel cerebro-palato-cardiac syndrome
  X-linked intellectual disability, Golabi-Ito-hall type
  X-linked intellectual disability, Porteous type
  X-linked intellectual disability, Sutherland-Haan type
  Asthma
  Isolated congenital microcephaly
  Nervous system disease
  Parkinson disease
• UniProt ID: PQBP1_HUMAN
• PDB ID: 4BWQ; 4BWS; 4CDO
• Sequence:
  MPLPVALQTRLAKRGILKHLEPEPEEEIIAEDYDDDPVDYEATRLEGLPPSWYKVFDPSC
  GLPYYWNADTDLVSWLSPHDPNSVVTKSAKKLRSSNADAEEKLDRSHDKSDRGHDKSDRS
  HEKLDRGHDKSDRGHDKSDRDRERGYDKVDRERERDRERDRDRGYDKADREEGKERRHHR
  REELAPYPKSKKAVSRKDEELDPMDPSSYSDAPRGTWSTGLPKRNEAKTGADTTAAGPLF
  QQRPYPSPGAVLRANAEASRTKQQD
• Function: Intrinsically disordered protein that acts as a scaffold, and which is involved in different processes, such as pre-mRNA splicing, transcription regulation, innate immunity and neuron development. Interacts with splicing-related factors via the intrinsically disordered region and regulates alternative splicing of target pre-mRNA species. May suppress the ability of POU3F2 to transactivate the DRD1 gene in a POU3F2 dependent manner. Can activate transcription directly or via association with the transcription machinery. May be involved in ATXN1 mutant-induced cell death. The interaction with ATXN1 mutant reduces levels of phosphorylated RNA polymerase II large subunit. Involved in the assembly of cytoplasmic stress granule, possibly by participating in the transport of neuronal RNA granules. Also acts as an innate immune sensor of infection by retroviruses, such as HIV, by detecting the presence of reverse-transcribed DNA in the cytosol. Directly binds retroviral reverse-transcribed DNA in the cytosol and interacts with CGAS, leading to activate the cGAS-STING signaling pathway, triggering type-I interferon production.
• Tissue Specificity: Widely expressed with high level in heart, skeletal muscle, pancreas, spleen, thymus, prostate, ovary, small intestine and peripheral blood leukocytes.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Biomarker	[1]
Hereditary spastic paraplegia	DISGZQV1	Definitive	Biomarker	[2]
Microphthalmia	DISGEBES	Definitive	Genetic Variation	[3]
Osteosarcoma	DISLQ7E2	Definitive	Biomarker	[1]
Renpenning syndrome	DISYK1IP	Definitive	X-linked	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Atrial septal defect	DISJT76B	Strong	Biomarker	[6]
Coffin-Lowry syndrome	DISMTBDA	Strong	Genetic Variation	[7]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[8]
Epilepsy	DISBB28L	Strong	Biomarker	[9]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[10]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[11]
Intellectual disability, X-linked 19	DIS240KZ	Strong	Biomarker	[7]
Microlissencephaly	DISUCKNT	Strong	Biomarker	[6]
Motor neurone disease	DISUHWUI	Strong	Biomarker	[12]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[9]
X-linked intellectual disability	DISYJBY3	Strong	Biomarker	[13]
Spinocerebellar ataxia type 1	DISF7BO2	moderate	Biomarker	[14]
Hamel cerebro-palato-cardiac syndrome	DISL5AZO	Supportive	X-linked	[15]
X-linked intellectual disability, Golabi-Ito-hall type	DISJ2G04	Supportive	X-linked	[15]
X-linked intellectual disability, Porteous type	DISOP6NJ	Supportive	X-linked	[15]
X-linked intellectual disability, Sutherland-Haan type	DIS6YDTU	Supportive	X-linked	[15]
Asthma	DISW9QNS	Limited	Genetic Variation	[16]
Isolated congenital microcephaly	DISUXHZ6	Limited	Biomarker	[17]
Nervous system disease	DISJ7GGT	Limited	Biomarker	[18]
Parkinson disease	DISQVHKL	Limited	Biomarker	[19]

9 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 Polyglutamine-binding protein 1 (PQBP1).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Polyglutamine-binding protein 1 (PQBP1).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Polyglutamine-binding protein 1 (PQBP1).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Polyglutamine-binding protein 1 (PQBP1).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Polyglutamine-binding protein 1 (PQBP1).	[24]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Polyglutamine-binding protein 1 (PQBP1).	[25]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Polyglutamine-binding protein 1 (PQBP1).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Polyglutamine-binding protein 1 (PQBP1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Polyglutamine-binding protein 1 (PQBP1).	[30]

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 increases the methylation of Polyglutamine-binding protein 1 (PQBP1).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Polyglutamine-binding protein 1 (PQBP1).	[29]

References

• [1] High Expression of PQBP1 and Low Expression of PCK2 are Associated with Metastasis and Recurrence of Osteosarcoma and Unfavorable Survival Outcomes of the Patients.J Cancer. 2019 May 12;10(9):2091-2101. doi: 10.7150/jca.28480. eCollection 2019.
• [2] Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation. Nat Genet. 2003 Dec;35(4):313-5. doi: 10.1038/ng1264. Epub 2003 Nov 23.
• [3] Microphthalmos-anophthalmos-coloboma (MAC) spectrum in two brothers with Renpenning syndrome due to a truncating mutation in the polyglutamine tract binding protein 1 (PQBP1) gene.Ophthalmic Genet. 2019 Dec;40(6):534-540. doi: 10.1080/13816810.2019.1686158. Epub 2019 Nov 13.
• [4] 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.
• [5] The intellectual disability gene PQBP1 rescues Alzheimer's disease pathology.Mol Psychiatry. 2018 Oct;23(10):2090-2110. doi: 10.1038/s41380-018-0253-8. Epub 2018 Oct 3.
• [6] Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene. J Med Genet. 2006 Jun;43(6):e30. doi: 10.1136/jmg.2005.037556.
• [7] Regional localization of an X-linked mental retardation gene to Xp21.1-Xp22.13 (MRX38).Am J Med Genet. 1996 Jul 12;64(1):89-96. doi: 10.1002/(SICI)1096-8628(19960712)64:1<89::AID-AJMG16>3.0.CO;2-O.
• [8] Systems Pharmacology Identifies an Arterial Wall Regulatory Gene Network Mediating Coronary Artery Disease Side Effects of Antiretroviral Therapy.Circ Genom Precis Med. 2019 Jun;12(6):e002390. doi: 10.1161/CIRCGEN.118.002390. Epub 2019 May 6.
• [9] Phenotype-genotype correlations in 17 new patients with an Xp11.23p11.22 microduplication and review of the literature.Am J Med Genet A. 2015 Jan;167A(1):111-22. doi: 10.1002/ajmg.a.36807. Epub 2014 Nov 25.
• [10] SIRT1 transcription is decreased in visceral adipose tissue of morbidly obese patients with severe hepatic steatosis.Obes Surg. 2010 May;20(5):633-9. doi: 10.1007/s11695-009-0052-z. Epub 2009 Dec 22.
• [11] Frameshift PQBP-1 mutants K192S(fs*7) and R153S(fs*41) implicated in X-linked intellectual disability form stable dimers.J Struct Biol. 2019 Jun 1;206(3):305-313. doi: 10.1016/j.jsb.2019.04.003. Epub 2019 Apr 2.
• [12] Polyglutamine tract-binding protein-1 dysfunction induces cell death of neurons through mitochondrial stress.J Neurochem. 2005 Nov;95(3):858-70. doi: 10.1111/j.1471-4159.2005.03405.x. Epub 2005 Aug 16.
• [13] A restricted level of PQBP1 is needed for the best longevity of Drosophila.Neurobiol Aging. 2013 Jan;34(1):356.e11-20. doi: 10.1016/j.neurobiolaging.2012.07.015. Epub 2012 Aug 15.
• [14] PQBP-1 transgenic mice show a late-onset motor neuron disease-like phenotype.Hum Mol Genet. 2003 Apr 1;12(7):711-25. doi: 10.1093/hmg/ddg084.
• [15] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [16] Variants in genes coding for glutathione S-transferases and asthma outcomes in children.Pharmacogenomics. 2018 Jun 1;19(8):707-713. doi: 10.2217/pgs-2018-0027. Epub 2018 May 22.
• [17] In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells.Mol Psychiatry. 2015 Apr;20(4):459-71. doi: 10.1038/mp.2014.69. Epub 2014 Jul 29.
• [18] PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth.Genes Dev. 2013 Mar 15;27(6):615-26. doi: 10.1101/gad.212308.112.
• [19] A ratiometric two-photon fluorescent probe reveals reduction in mitochondrial H2S production in Parkinson's disease gene knockout astrocytes.J Am Chem Soc. 2013 Jul 3;135(26):9915-23. doi: 10.1021/ja404004v. Epub 2013 Jun 18.
• [20] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [21] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [22] 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.
• [23] 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.
• [24] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [25] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [26] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] 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.
• [29] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [30] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.