Details of Drug Off-Target (DOT)

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

• DOT Name: Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4)
• Synonyms: PPIase; EC 5.2.1.8; Cyclophilin-like protein PPIL4; Rotamase PPIL4
• Gene Name: PPIL4
• Related Disease:
  Abscess
  Gastric disease
  Parkinson disease
  Rheumatoid arthritis
• UniProt ID: PPIL4_HUMAN
• PDB ID: 7QTT; 8CH6
• EC Number: 5.2.1.8
• Pfam ID: PF00160 ; PF00076
• Sequence:
  MAVLLETTLGDVVIDLYTEERPRACLNFLKLCKIKYYNYCLIHNVQRDFIIQTGDPTGTG
  RGGESIFGQLYGDQASFFEAEKVPRIKHKKKGTVSMVNNGSDQHGSQFLITTGENLDYLD
  GVHTVFGEVTEGMDIIKKINETFVDKDFVPYQDIRINHTVILDDPFDDPPDLLIPDRSPE
  PTREQLDSGRIGADEEIDDFKGRSAEEVEEIKAEKEAKTQAILLEMVGDLPDADIKPPEN
  VLFVCKLNPVTTDEDLEIIFSRFGPIRSCEVIRDWKTGESLCYAFIEFEKEEDCEKAFFK
  MDNVLIDDRRIHVDFSQSVAKVKWKGKGGKYTKSDFKEYEKEQDKPPNLVLKDKVKPKQD
  TKYDLILDEQAEDSKSSHSHTSKKHKKKTHHCSEEKEDEDYMPIKNTNQDIYREMGFGHY
  EEEESCWEKQKSEKRDRTQNRSRSRSRERDGHYSNSHKSKYQTDLYERERSKKRDRSRSP
  KKSKDKEKSKYR
• Function: PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
• Tissue Specificity: Abundantly expressed in kidney but has a ubiquitously low expression pattern in other adult tissues.
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Abscess	DISAP982	Strong	Biomarker	[1]
Gastric disease	DISNZNTG	Strong	Biomarker	[2]
Parkinson disease	DISQVHKL	Strong	Biomarker	[3]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[4]

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 Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4).	[12]

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] 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.
• [3] 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.
• [4] Genetic influences on susceptibility to rheumatoid arthritis in African-Americans.Hum Mol Genet. 2019 Mar 1;28(5):858-874. doi: 10.1093/hmg/ddy395.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.