Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSJZBB5)

• DOT Name: Prolyl endopeptidase (PREP)
• Synonyms: PE; EC 3.4.21.26; Post-proline cleaving enzyme
• Gene Name: PREP
• UniProt ID: PPCE_HUMAN
• PDB ID: 3DDU
• EC Number: 3.4.21.26
• Pfam ID: PF00326 ; PF02897
• Sequence:
  MLSLQYPDVYRDETAVQDYHGHKICDPYAWLEDPDSEQTKAFVEAQNKITVPFLEQCPIR
  GLYKERMTELYDYPKYSCHFKKGKRYFYFYNTGLQNQRVLYVQDSLEGEARVFLDPNILS
  DDGTVALRGYAFSEDGEYFAYGLSASGSDWVTIKFMKVDGAKELPDVLERVKFSCMAWTH
  DGKGMFYNSYPQQDGKSDGTETSTNLHQKLYYHVLGTDQSEDILCAEFPDEPKWMGGAEL
  SDDGRYVLLSIREGCDPVNRLWYCDLQQESSGIAGILKWVKLIDNFEGEYDYVTNEGTVF
  TFKTNRQSPNYRVINIDFRDPEESKWKVLVPEHEKDVLEWIACVRSNFLVLCYLHDVKNI
  LQLHDLTTGALLKTFPLDVGSIVGYSGQKKDTEIFYQFTSFLSPGIIYHCDLTKEELEPR
  VFREVTVKGIDASDYQTVQIFYPSKDGTKIPMFIVHKKGIKLDGSHPAFLYGYGGFNISI
  TPNYSVSRLIFVRHMGGILAVANIRGGGEYGETWHKGGILANKQNCFDDFQCAAEYLIKE
  GYTSPKRLTINGGSNGGLLVAACANQRPDLFGCVIAQVGVMDMLKFHKYTIGHAWTTDYG
  CSDSKQHFEWLVKYSPLHNVKLPEADDIQYPSMLLLTADHDDRVVPLHSLKFIATLQYIV
  GRSRKQSNPLLIHVDTKAGHGAGKPTAKVIEEVSDMFAFIARCLNVDWIP
• Function: Cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long.
• KEGG Pathway: Renin-angiotensin system (hsa04614)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Prolyl endopeptidase (PREP) affects the response to substance of Acetaminophen.	[12]

13 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 Prolyl endopeptidase (PREP).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Prolyl endopeptidase (PREP).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Prolyl endopeptidase (PREP).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Prolyl endopeptidase (PREP).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital decreases the expression of Prolyl endopeptidase (PREP).	[5]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Prolyl endopeptidase (PREP).	[6]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Prolyl endopeptidase (PREP).	[7]
JTP-4819	DMI0UJS	Discontinued in Phase 2	JTP-4819 decreases the activity of Prolyl endopeptidase (PREP).	[3]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Prolyl endopeptidase (PREP).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Prolyl endopeptidase (PREP).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Prolyl endopeptidase (PREP).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Prolyl endopeptidase (PREP).	[11]
Z-Pro-Prolinal	DM43O2U	Investigative	Z-Pro-Prolinal decreases the activity of Prolyl endopeptidase (PREP).	[3]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] Prolyl endopeptidase is involved in cellular signalling in human neuroblastoma SH-SY5Y cells. Neurosignals. 2011;19(2):97-109. doi: 10.1159/000326342. Epub 2011 Apr 10.
• [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] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [6] 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.
• [7] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [8] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [9] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [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] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.