Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT72S99B)

• DOT Name: Endoplasmic reticulum aminopeptidase 1 (ERAP1)
• Synonyms: EC 3.4.11.-; ARTS-1; Adipocyte-derived leucine aminopeptidase; A-LAP; Aminopeptidase PILS; Puromycin-insensitive leucyl-specific aminopeptidase; PILS-AP; Type 1 tumor necrosis factor receptor shedding aminopeptidase regulator
• Gene Name: ERAP1
• UniProt ID: ERAP1_HUMAN
• PDB ID: 2YD0; 3MDJ; 3QNF; 3RJO; 5J5E; 6M8P; 6MGQ; 6Q4R; 6RQX; 6RYF; 6T6R; 7MWB; 7MWC; 7Z28
• EC Number: 3.4.11.-
• Pfam ID: PF11838 ; PF01433 ; PF17900
• Sequence:
  MVFLPLKWSLATMSFLLSSLLALLTVSTPSWCQSTEASPKRSDGTPFPWNKIRLPEYVIP
  VHYDLLIHANLTTLTFWGTTKVEITASQPTSTIILHSHHLQISRATLRKGAGERLSEEPL
  QVLEHPRQEQIALLAPEPLLVGLPYTVVIHYAGNLSETFHGFYKSTYRTKEGELRILAST
  QFEPTAARMAFPCFDEPAFKASFSIKIRREPRHLAISNMPLVKSVTVAEGLIEDHFDVTV
  KMSTYLVAFIISDFESVSKITKSGVKVSVYAVPDKINQADYALDAAVTLLEFYEDYFSIP
  YPLPKQDLAAIPDFQSGAMENWGLTTYRESALLFDAEKSSASSKLGITMTVAHELAHQWF
  GNLVTMEWWNDLWLNEGFAKFMEFVSVSVTHPELKVGDYFFGKCFDAMEVDALNSSHPVS
  TPVENPAQIREMFDDVSYDKGACILNMLREYLSADAFKSGIVQYLQKHSYKNTKNEDLWD
  SMASICPTDGVKGMDGFCSRSQHSSSSSHWHQEGVDVKTMMNTWTLQKGFPLITITVRGR
  NVHMKQEHYMKGSDGAPDTGYLWHVPLTFITSKSDMVHRFLLKTKTDVLILPEEVEWIKF
  NVGMNGYYIVHYEDDGWDSLTGLLKGTHTAVSSNDRASLINNAFQLVSIGKLSIEKALDL
  SLYLKHETEIMPVFQGLNELIPMYKLMEKRDMNEVETQFKAFLIRLLRDLIDKQTWTDEG
  SVSERMLRSQLLLLACVHNYQPCVQRAEGYFRKWKESNGNLSLPVDVTLAVFAVGAQSTE
  GWDFLYSKYQFSLSSTEKSQIEFALCRTQNKEKLQWLLDESFKGDKIKTQEFPQILTLIG
  RNPVGYPLAWQFLRKNWNKLVQKFELGSSSIAHMVMGTTNQFSTRTRLEEVKGFFSSLKE
  NGSQLRCVQQTIETIEENIGWMDKNFDKIRVWLQSEKLERM
• Function: Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides. Peptide trimming is essential to customize longer precursor peptides to fit them to the correct length required for presentation on MHC class I molecules. Strongly prefers substrates 9-16 residues long. Rapidly degrades 13-mer to a 9-mer and then stops. Preferentially hydrolyzes the residue Leu and peptides with a hydrophobic C-terminus, while it has weak activity toward peptides with charged C-terminus. May play a role in the inactivation of peptide hormones. May be involved in the regulation of blood pressure through the inactivation of angiotensin II and/or the generation of bradykinin in the kidney.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: Antigen Presentation (R-HSA-983170)

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
Irbesartan	DMTP1DC	Investigative	Endoplasmic reticulum aminopeptidase 1 (ERAP1) affects the response to substance of Irbesartan.	[14]

16 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 Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[8]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[9]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[9]
Haloperidol	DM96SE0	Approved	Haloperidol decreases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Endoplasmic reticulum aminopeptidase 1 (ERAP1).	[13]

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] 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.
• [4] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] 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.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [10] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [14] Adipocyte-derived leucine aminopeptidase genotype and response to antihypertensive therapy. BMC Cardiovasc Disord. 2003 Sep 18;3:11. doi: 10.1186/1471-2261-3-11. Epub 2003 Sep 18.