Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIE5OAD)

• DOT Name: Peptidyl-prolyl cis-trans isomerase E (PPIE)
• Synonyms: PPIase E; EC 5.2.1.8; Cyclophilin E; Cyclophilin-33; Rotamase E
• Gene Name: PPIE
• Related Disease:
  Barrett esophagus
  Bipolar disorder
  Familial multiple trichoepithelioma
  Influenza
• UniProt ID: PPIE_HUMAN
• PDB ID: 1ZMF; 2CQB; 2KU7; 2KYX; 2R99; 3LPY; 3MDF; 3UCH; 5MQF; 5YZG; 5Z56; 5Z57; 6FF7; 6ICZ; 6ID0; 6ID1; 7A5P; 7ABI; 7W59; 7W5A; 7W5B; 7ZEV; 7ZEW; 7ZEX; 7ZEY; 7ZEZ; 8C6J; 8CH6
• EC Number: 5.2.1.8
• Pfam ID: PF00160 ; PF00076
• Sequence:
  MATTKRVLYVGGLAEEVDDKVLHAAFIPFGDITDIQIPLDYETEKHRGFAFVEFELAEDA
  AAAIDNMNESELFGRTIRVNLAKPMRIKEGSSRPVWSDDDWLKKFSGKTLEENKEEEGSE
  PPKAETQEGEPIAKKARSNPQVYMDIKIGNKPAGRIQMLLRSDVVPMTAENFRCLCTHEK
  GFGFKGSSFHRIIPQFMCQGGDFTNHNGTGGKSIYGKKFDDENFILKHTGPGLLSMANSG
  PNTNGSQFFLTCDKTDWLDGKHVVFGEVTEGLDVLRQIEAQGSKDGKPKQKVIIADCGEY
  V
• Function: Involved in pre-mRNA splicing as component of the spliceosome. Combines RNA-binding and PPIase activities. Binds mRNA and has a preference for single-stranded RNA molecules with poly-A and poly-U stretches, suggesting it binds to the poly(A)-region in the 3'-UTR of mRNA molecules. Catalyzes the cis-trans isomerization of proline imidic peptide bonds in proteins. Inhibits KMT2A activity; this requires proline isomerase activity.
• Tissue Specificity: Found in all the examined tissues including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway:
  Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827)
  Dual incision in TC-NER (R-HSA-6782135)
  Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210)
  Neutrophil degranulation (R-HSA-6798695)
  mRNA Splicing - Major Pathway (R-HSA-72163)
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Barrett esophagus	DIS416Y7	Strong	Genetic Variation	[1]
Bipolar disorder	DISAM7J2	Strong	Posttranslational Modification	[2]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Genetic Variation	[1]
Influenza	DIS3PNU3	Strong	Biomarker	[3]

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 E (PPIE).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Peptidyl-prolyl cis-trans isomerase E (PPIE).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Peptidyl-prolyl cis-trans isomerase E (PPIE).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peptidyl-prolyl cis-trans isomerase E (PPIE).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Peptidyl-prolyl cis-trans isomerase E (PPIE).	[8]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Peptidyl-prolyl cis-trans isomerase E (PPIE).	[6]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Peptidyl-prolyl cis-trans isomerase E (PPIE).	[11]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Peptidyl-prolyl cis-trans isomerase E (PPIE).	[12]
PP-242	DM2348V	Investigative	PP-242 increases the expression of Peptidyl-prolyl cis-trans isomerase E (PPIE).	[13]

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 affects the methylation of Peptidyl-prolyl cis-trans isomerase E (PPIE).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Peptidyl-prolyl cis-trans isomerase E (PPIE).	[10]

References

• [1] Next-generation sequencing of endoscopic biopsies identifies ARID1A as a tumor-suppressor gene in Barrett's esophagus.Oncogene. 2014 Jan 16;33(3):347-57. doi: 10.1038/onc.2012.586. Epub 2013 Jan 14.
• [2] Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins.Mol Psychiatry. 2008 Apr;13(4):429-41. doi: 10.1038/sj.mp.4002001. Epub 2007 May 1.
• [3] Cyclophilin E functions as a negative regulator to influenza virus replication by impairing the formation of the viral ribonucleoprotein complex.PLoS One. 2011;6(8):e22625. doi: 10.1371/journal.pone.0022625. Epub 2011 Aug 24.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Analysis of the in vitro synergistic effect of 5-fluorouracil and cisplatin on cervical carcinoma cells. Int J Gynecol Cancer. 2006 May-Jun;16(3):1321-9.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] 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.
• [13] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.