Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX258QE)

• DOT Name: Acylamino-acid-releasing enzyme (APEH)
• Synonyms: AARE; EC 3.4.19.1; Acyl-peptide hydrolase; APH; Acylaminoacyl-peptidase; Oxidized protein hydrolase; OPH
• Gene Name: APEH
• UniProt ID: ACPH_HUMAN
• EC Number: 3.4.19.1
• Pfam ID: PF19283 ; PF00326
• Sequence:
  MERQVLLSEPEEAAALYRGLSRQPALSAACLGPEVTTQYGGQYRTVHTEWTQRDLERMEN
  IRFCRQYLVFHDGDSVVFAGPAGNSVETRGELLSRESPSGTMKAVLRKAGGTGPGEEKQF
  LEVWEKNRKLKSFNLSALEKHGPVYEDDCFGCLSWSHSETHLLYVAEKKRPKAESFFQTK
  ALDVSASDDEIARLKKPDQAIKGDQFVFYEDWGENMVSKSIPVLCVLDVESGNISVLEGV
  PENVSPGQAFWAPGDAGVVFVGWWHEPFRLGIRFCTNRRSALYYVDLIGGKCELLSDDSL
  AVSSPRLSPDQCRIVYLQYPSLIPHHQCSQLCLYDWYTKVTSVVVDVVPRQLGENFSGIY
  CSLLPLGCWSADSQRVVFDSAQRSRQDLFAVDTQVGTVTSLTAGGSGGSWKLLTIDQDLM
  VAQFSTPSLPPTLKVGFLPSAGKEQSVLWVSLEEAEPIPDIHWGIRVLQPPPEQENVQYA
  GLDFEAILLQPGSPPDKTQVPMVVMPHGGPHSSFVTAWMLFPAMLCKMGFAVLLVNYRGS
  TGFGQDSILSLPGNVGHQDVKDVQFAVEQVLQEEHFDASHVALMGGSHGGFISCHLIGQY
  PETYRACVARNPVINIASMLGSTDIPDWCVVEAGFPFSSDCLPDLSVWAEMLDKSPIRYI
  PQVKTPLLLMLGQEDRRVPFKQGMEYYRALKTRNVPVRLLLYPKSTHALSEVEVESDSFM
  NAVLWLRTHLGS
• Function: This enzyme catalyzes the hydrolysis of the N-terminal peptide bond of an N-acetylated peptide to generate an N-acetylated amino acid and a peptide with a free N-terminus. It preferentially cleaves off Ac-Ala, Ac-Met and Ac-Ser. Also, involved in the degradation of oxidized and glycated proteins.
• Tissue Specificity: Expressed in erythrocytes (at protein level).
• Reactome Pathway:
  Eukaryotic Translation Termination (R-HSA-72764)
  Neutrophil degranulation (R-HSA-6798695)
• BioCyc Pathway: MetaCyc:HS08997-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Acylamino-acid-releasing enzyme (APEH) decreases the response to substance of Hydrogen peroxide.	[19]
Mitomycin	DMH0ZJE	Approved	Acylamino-acid-releasing enzyme (APEH) affects the response to substance of Mitomycin.	[20]
Paraquat	DMR8O3X	Investigative	Acylamino-acid-releasing enzyme (APEH) decreases the response to substance of Paraquat.	[19]

17 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 Acylamino-acid-releasing enzyme (APEH).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Acylamino-acid-releasing enzyme (APEH).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Acylamino-acid-releasing enzyme (APEH).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Acylamino-acid-releasing enzyme (APEH).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Acylamino-acid-releasing enzyme (APEH).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Acylamino-acid-releasing enzyme (APEH).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Acylamino-acid-releasing enzyme (APEH).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Acylamino-acid-releasing enzyme (APEH).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Acylamino-acid-releasing enzyme (APEH).	[9]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Acylamino-acid-releasing enzyme (APEH).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Acylamino-acid-releasing enzyme (APEH).	[11]
Carbapenem	DMXZU73	Phase 4	Carbapenem decreases the activity of Acylamino-acid-releasing enzyme (APEH).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Acylamino-acid-releasing enzyme (APEH).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Acylamino-acid-releasing enzyme (APEH).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Acylamino-acid-releasing enzyme (APEH).	[16]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Acylamino-acid-releasing enzyme (APEH).	[17]
Chlorphrifos oxon	DMGBT68	Investigative	Chlorphrifos oxon decreases the activity of Acylamino-acid-releasing enzyme (APEH).	[18]

1 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 decreases the phosphorylation of Acylamino-acid-releasing enzyme (APEH).	[13]

References

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• [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] 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.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [8] 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.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Identification of valproic acid glucuronide hydrolase as a key enzyme for the interaction of valproic acid with carbapenem antibiotics. Drug Metab Dispos. 2010 Sep;38(9):1538-44. doi: 10.1124/dmd.110.032938. Epub 2010 Jun 15.
• [13] 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.
• [14] 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.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [17] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [18] Blood acylpeptide hydrolase activity is a sensitive marker for exposure to some organophosphate toxicants. Toxicol Sci. 2005 Aug;86(2):291-9. doi: 10.1093/toxsci/kfi195. Epub 2005 May 11.
• [19] Overexpression of oxidized protein hydrolase protects COS-7 cells from oxidative stress-induced inhibition of cell growth and survival. Biochem Biophys Res Commun. 2003 May 16;304(4):766-71. doi: 10.1016/s0006-291x(03)00657-0.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.