Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS5S837)

• DOT Name: Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1)
• Synonyms: PPIase; EC 5.2.1.8; Rotamase PPIL1
• Gene Name: PPIL1
• Related Disease:
  Abscess
  Alzheimer disease
  Gastric cancer
  Gastric disease
  Glioma
  Hepatitis C virus infection
  Parkinson disease
  Pontocerebellar hypoplasia, type 14
  Stomach cancer
  Vibrio cholerae infection
  Hepatocellular carcinoma
  Advanced cancer
  Diphtheria
• UniProt ID: PPIL1_HUMAN
• PDB ID: 1XWN; 2K7N; 2X7K; 5MQF; 5XJC; 5YZG; 5Z56; 5Z57; 6FF4; 6FF7; 6ICZ; 6ID0; 6ID1; 6QDV; 6ZYM; 7QTT; 7W59; 7W5A; 7W5B; 8C6J; 8CH6
• EC Number: 5.2.1.8
• Pfam ID: PF00160
• Sequence:
  MAAIPPDSWQPPNVYLETSMGIIVLELYWKHAPKTCKNFAELARRGYYNGTKFHRIIKDF
  MIQGGDPTGTGRGGASIYGKQFEDELHPDLKFTGAGILAMANAGPDTNGSQFFVTLAPTQ
  WLDGKHTIFGRVCQGIGMVNRVGMVETNSQDRPVDDVKIIKAYPSG
• Function: Involved in pre-mRNA splicing as component of the spliceosome. PPIases accelerate the folding of proteins. Catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Catalyzes prolyl peptide bond isomerization in CDC40/PRP17. Plays an important role in embryonic brain development; this function is independent of its isomerase activity.
• Tissue Specificity: Ubiquitous, with the most abundant expression in heart and skeletal muscle.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Abscess	DISAP982	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Gastric disease	DISNZNTG	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[6]
Parkinson disease	DISQVHKL	Strong	Biomarker	[7]
Pontocerebellar hypoplasia, type 14	DIS2XQ03	Strong	Autosomal recessive	[8]
Stomach cancer	DISKIJSX	Strong	Biomarker	[3]
Vibrio cholerae infection	DISW7E3U	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[10]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[11]
Diphtheria	DISZWM55	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[16]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[24]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[25]
Butanoic acid	DMTAJP7	Investigative	Butanoic acid decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[26]
Apicidin	DM83WVF	Investigative	Apicidin decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Peptidyl-prolyl cis-trans isomerase-like 1 (PPIL1).	[20]

References

• [1] Novel Regulation of Alpha-Toxin and the Phenol-Soluble Modulins by Peptidyl-Prolyl cis/trans Isomerase Enzymes in Staphylococcus aureus.Toxins (Basel). 2019 Jun 16;11(6):343. doi: 10.3390/toxins11060343.
• [2] Pin1 facilitates isoproterenolinduced cardiac fibrosis and collagen deposition by promoting oxidative stress and activating the MEK1/2ERK1/2 signal transduction pathway in rats.Int J Mol Med. 2018 Mar;41(3):1573-1583. doi: 10.3892/ijmm.2017.3354. Epub 2017 Dec 29.
• [3] Subtractive hybridization analysis of gastric diseases-associated Helicobacter pylori identifies peptidyl-prolyl isomerase as a potential marker for gastric cancer.FEMS Microbiol Lett. 2011 Jul;320(2):103-9. doi: 10.1111/j.1574-6968.2011.02296.x. Epub 2011 May 13.
• [4] Differential Proteomic Analysis Reveals Protein Networks and Pathways that May Contribute to Helicobacter pylori FKBP-Type PPIase-Associated Gastric Diseases.Proteomics Clin Appl. 2018 May;12(3):e1700127. doi: 10.1002/prca.201700127. Epub 2017 Dec 5.
• [5] Cyclophilin J is a novel peptidyl-prolyl isomerase and target for repressing the growth of hepatocellular carcinoma.PLoS One. 2015 May 28;10(5):e0127668. doi: 10.1371/journal.pone.0127668. eCollection 2015.
• [6] Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase.Mol Cell. 2005 Jul 1;19(1):111-22. doi: 10.1016/j.molcel.2005.05.014.
• [7] The Molecular Basis of the Interaction of CyclophilinA with -Synuclein.Angew Chem Int Ed Engl. 2020 Mar 27;59(14):5643-5646. doi: 10.1002/anie.201914878. Epub 2020 Jan 29.
• [8] Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly. Neuron. 2021 Jan 20;109(2):241-256.e9. doi: 10.1016/j.neuron.2020.10.035. Epub 2020 Nov 20.
• [9] Host Cell Chaperones Hsp70/Hsp90 and Peptidyl-Prolyl Cis/Trans Isomerases Are Required for the Membrane Translocation of Bacterial ADP-Ribosylating Toxins.Curr Top Microbiol Immunol. 2017;406:163-198. doi: 10.1007/82_2016_14.
• [10] miR-874-3p is down-regulated in hepatocellular carcinoma and negatively regulates PIN1 expression.Oncotarget. 2017 Feb 14;8(7):11343-11355. doi: 10.18632/oncotarget.14526.
• [11] Acetonitrile-assisted enzymatic digestion can facilitate the bottom-up identification of proteins of cancer origin.Anal Biochem. 2019 Apr 1;570:1-4. doi: 10.1016/j.ab.2019.01.004. Epub 2019 Jan 17.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [16] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] 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.
• [21] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [22] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [23] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [24] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [25] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [26] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.