Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2OBJUK)

• DOT Name: Polypyrimidine tract-binding protein 1 (PTBP1)
• Synonyms: PTB; 57 kDa RNA-binding protein PPTB-1; Heterogeneous nuclear ribonucleoprotein I; hnRNP I
• Gene Name: PTBP1
• UniProt ID: PTBP1_HUMAN
• PDB ID: 1QM9; 1SJQ; 1SJR; 2AD9; 2ADB; 2ADC; 2EVZ; 2N3O; 3ZZY; 3ZZZ; 8BGF; 8BWF
• Pfam ID: PF00076 ; PF13893 ; PF11835
• Sequence:
  MDGIVPDIAVGTKRGSDELFSTCVTNGPFIMSSNSASAANGNDSKKFKGDSRSAGVPSRV
  IHIRKLPIDVTEGEVISLGLPFGKVTNLLMLKGKNQAFIEMNTEEAANTMVNYYTSVTPV
  LRGQPIYIQFSNHKELKTDSSPNQARAQAALQAVNSVQSGNLALAASAAAVDAGMAMAGQ
  SPVLRIIVENLFYPVTLDVLHQIFSKFGTVLKIITFTKNNQFQALLQYADPVSAQHAKLS
  LDGQNIYNACCTLRIDFSKLTSLNVKYNNDKSRDYTRPDLPSGDSQPSLDQTMAAAFGAP
  GIISASPYAGAGFPPTFAIPQAAGLSVPNVHGALAPLAIPSAAAAAAAAGRIAIPGLAGA
  GNSVLLVSNLNPERVTPQSLFILFGVYGDVQRVKILFNKKENALVQMADGNQAQLAMSHL
  NGHKLHGKPIRITLSKHQNVQLPREGQEDQGLTKDYGNSPLHRFKKPGSKNFQNIFPPSA
  TLHLSNIPPSVSEEDLKVLFSSNGGVVKGFKFFQKDRKMALIQMGSVEEAVQALIDLHNH
  DLGENHHLRVSFSKSTI
• Function: Plays a role in pre-mRNA splicing and in the regulation of alternative splicing events. Activates exon skipping of its own pre-mRNA during muscle cell differentiation. Binds to the polypyrimidine tract of introns. May promote RNA looping when bound to two separate polypyrimidine tracts in the same pre-mRNA. May promote the binding of U2 snRNP to pre-mRNA. Cooperates with RAVER1 to modulate switching between mutually exclusive exons during maturation of the TPM1 pre-mRNA. Represses the splicing of MAPT/Tau exon 10. Binds to polypyrimidine-rich controlling element (PCE) of CFTR and promotes exon skipping of CFTR exon 9, thereby antagonizing TIA1 and its role in exon inclusion of CFTR exon 9. Plays a role in the splicing of pyruvate kinase PKM by binding repressively to a polypyrimidine tract flanking PKM exon 9, inhibiting exon 9 inclusion and resulting in exon 10 inclusion and production of the PKM M2 isoform. In case of infection by picornaviruses, binds to the viral internal ribosome entry site (IRES) and stimulates the IRES-mediated translation.
• Reactome Pathway:
  mRNA Splicing - Major Pathway (R-HSA-72163)
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  FGFR2 alternative splicing (R-HSA-6803529)

Molecular Interaction Atlas (MIA) of This DOT

3 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 Polypyrimidine tract-binding protein 1 (PTBP1).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Polypyrimidine tract-binding protein 1 (PTBP1).	[5]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Polypyrimidine tract-binding protein 1 (PTBP1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Polypyrimidine tract-binding protein 1 (PTBP1).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Polypyrimidine tract-binding protein 1 (PTBP1).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Polypyrimidine tract-binding protein 1 (PTBP1).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Polypyrimidine tract-binding protein 1 (PTBP1).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Polypyrimidine tract-binding protein 1 (PTBP1).	[7]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Polypyrimidine tract-binding protein 1 (PTBP1).	[8]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Polypyrimidine tract-binding protein 1 (PTBP1).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Polypyrimidine tract-binding protein 1 (PTBP1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Polypyrimidine tract-binding protein 1 (PTBP1).	[11]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Polypyrimidine tract-binding protein 1 (PTBP1).	[3]
AM251	DMTAWHL	Investigative	AM251 decreases the expression of Polypyrimidine tract-binding protein 1 (PTBP1).	[13]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [3] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [4] 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.
• [5] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [8] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [9] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [12] 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.
• [13] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.