Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN5XMLZ)

• DOT Name: Prolyl endopeptidase-like (PREPL)
• Synonyms: EC 3.4.21.-; Prolylendopeptidase-like
• Gene Name: PREPL
• Related Disease:
  Hypotonia-cystinuria syndrome
  Myasthenic syndrome, congenital, 22
• UniProt ID: PPCEL_HUMAN
• PDB ID: 7OBM
• EC Number: 3.4.21.-
• Pfam ID: PF00326 ; PF02897
• Sequence:
  MQQKTKLFLQALKYSIPHLGKCMQKQHLNHYNFADHCYNRIKLKKYHLTKCLQNKPKISE
  LARNIPSRSFSCKDLQPVKQENEKPLPENMDAFEKVRTKLETQPQEEYEIINVEVKHGGF
  VYYQEGCCLVRSKDEEADNDNYEVLFNLEELKLDQPFIDCIRVAPDEKYVAAKIRTEDSE
  ASTCVIIKLSDQPVMEASFPNVSSFEWVKDEEDEDVLFYTFQRNLRCHDVYRATFGDNKR
  NERFYTEKDPSYFVFLYLTKDSRFLTINIMNKTTSEVWLIDGLSPWDPPVLIQKRIHGVL
  YYVEHRDDELYILTNVGEPTEFKLMRTAADTPAIMNWDLFFTMKRNTKVIDLDMFKDHCV
  LFLKHSNLLYVNVIGLADDSVRSLKLPPWACGFIMDTNSDPKNCPFQLCSPIRPPKYYTY
  KFAEGKLFEETGHEDPITKTSRVLRLEAKSKDGKLVPMTVFHKTDSEDLQKKPLLVHVYG
  AYGMDLKMNFRPERRVLVDDGWILAYCHVRGGGELGLQWHADGRLTKKLNGLADLEACIK
  TLHGQGFSQPSLTTLTAFSAGGVLAGALCNSNPELVRAVTLEAPFLDVLNTMMDTTLPLT
  LEELEEWGNPSSDEKHKNYIKRYCPYQNIKPQHYPSIHITAYENDERVPLKGIVSYTEKL
  KEAIAEHAKDTGEGYQTPNIILDIQPGGNHVIEDSHKKITAQIKFLYEELGLDSTSVFED
  LKKYLKF
• Function: Serine peptidase whose precise substrate specificity remains unclear. Does not cleave peptides after a arginine or lysine residue. Regulates trans-Golgi network morphology and sorting by regulating the membrane binding of the AP-1 complex. May play a role in the regulation of synaptic vesicle exocytosis.
• Tissue Specificity: Expressed in pyramidal neurons of the temporal cortex and neocortex (at protein level) . Widely expressed . Expressed at higher level in brain, skeletal muscle, heart and kidney . Expressed at the endplates in the neuromuscular junction .

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypotonia-cystinuria syndrome	DISUPMRI	Strong	Autosomal recessive	[1]
Myasthenic syndrome, congenital, 22	DISROZY1	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Prolyl endopeptidase-like (PREPL).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Prolyl endopeptidase-like (PREPL).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Prolyl endopeptidase-like (PREPL).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Prolyl endopeptidase-like (PREPL).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Prolyl endopeptidase-like (PREPL).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Prolyl endopeptidase-like (PREPL).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Prolyl endopeptidase-like (PREPL).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Prolyl endopeptidase-like (PREPL).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Prolyl endopeptidase-like (PREPL).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Prolyl endopeptidase-like (PREPL).	[12]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Prolyl endopeptidase-like (PREPL).	[13]
Heroin diacetylmorphine	DMDBWHY	Approved	Heroin diacetylmorphine decreases the expression of Prolyl endopeptidase-like (PREPL).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Prolyl endopeptidase-like (PREPL).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Prolyl endopeptidase-like (PREPL).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Prolyl endopeptidase-like (PREPL).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Prolyl endopeptidase-like (PREPL).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Prolyl endopeptidase-like (PREPL).	[19]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Prolyl endopeptidase-like (PREPL).	[20]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Prolyl endopeptidase-like (PREPL).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Prolyl endopeptidase-like (PREPL).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Prolyl endopeptidase-like (PREPL).	[15]

References

• [1] PREPL deficiency with or without cystinuria causes a novel myasthenic syndrome. Neurology. 2014 Apr 8;82(14):1254-60. doi: 10.1212/WNL.0000000000000295. Epub 2014 Mar 7.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [13] Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology. 2006 Oct;31(10):2304-12. doi: 10.1038/sj.npp.1301089. Epub 2006 May 3.
• [14] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [21] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.