Details of Drug Off-Target (DOT)

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

• DOT Name: Endoplasmic reticulum aminopeptidase 2 (ERAP2)
• Synonyms: EC 3.4.11.-; Leukocyte-derived arginine aminopeptidase; L-RAP
• Gene Name: ERAP2
• UniProt ID: ERAP2_HUMAN
• PDB ID: 3SE6; 4E36; 4JBS; 5AB0; 5AB2; 5CU5; 5J6S; 5K1V; 6EA4; 7NSK; 7NUP; 7P7P; 7PFS; 7SH0
• EC Number: 3.4.11.-
• Pfam ID: PF11838 ; PF01433 ; PF17900
• Sequence:
  MFHSSAMVNSHRKPMFNIHRGFYCLTAILPQICICSQFSVPSSYHFTEDPGAFPVATNGE
  RFPWQELRLPSVVIPLHYDLFVHPNLTSLDFVASEKIEVLVSNATQFIILHSKDLEITNA
  TLQSEEDSRYMKPGKELKVLSYPAHEQIALLVPEKLTPHLKYYVAMDFQAKLGDGFEGFY
  KSTYRTLGGETRILAVTDFEPTQARMAFPCFDEPLFKANFSIKIRRESRHIALSNMPKVK
  TIELEGGLLEDHFETTVKMSTYLVAYIVCDFHSLSGFTSSGVKVSIYASPDKRNQTHYAL
  QASLKLLDFYEKYFDIYYPLSKLDLIAIPDFAPGAMENWGLITYRETSLLFDPKTSSASD
  KLWVTRVIAHELAHQWFGNLVTMEWWNDIWLKEGFAKYMELIAVNATYPELQFDDYFLNV
  CFEVITKDSLNSSRPISKPAETPTQIQEMFDEVSYNKGACILNMLKDFLGEEKFQKGIIQ
  YLKKFSYRNAKNDDLWSSLSNSCLESDFTSGGVCHSDPKMTSNMLAFLGENAEVKEMMTT
  WTLQKGIPLLVVKQDGCSLRLQQERFLQGVFQEDPEWRALQERYLWHIPLTYSTSSSNVI
  HRHILKSKTDTLDLPEKTSWVKFNVDSNGYYIVHYEGHGWDQLITQLNQNHTLLRPKDRV
  GLIHDVFQLVGAGRLTLDKALDMTYYLQHETSSPALLEGLSYLESFYHMMDRRNISDISE
  NLKRYLLQYFKPVIDRQSWSDKGSVWDRMLRSALLKLACDLNHAPCIQKAAELFSQWMES
  SGKLNIPTDVLKIVYSVGAQTTAGWNYLLEQYELSMSSAEQNKILYALSTSKHQEKLLKL
  IELGMEGKVIKTQNLAALLHAIARRPKGQQLAWDFVRENWTHLLKKFDLGSYDIRMIISG
  TTAHFSSKDKLQEVKLFFESLEAQGSHLDIFQTVLETITKNIKWLEKNLPTLRTWLMVNT
• 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. Preferentially hydrolyzes the basic residues Arg and Lys.
• Tissue Specificity: Ubiquitously expressed. Highly expressed in spleen and leukocytes.
• Reactome Pathway: Antigen Presentation (R-HSA-983170)

Molecular Interaction Atlas (MIA) of This DOT

18 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 2 (ERAP2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[9]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[10]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[11]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[12]
Capecitabine	DMTS85L	Approved	Capecitabine decreases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[11]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Endoplasmic reticulum aminopeptidase 2 (ERAP2).	[17]

References

• [1] 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.
• [2] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] 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.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [13] Gene expression responses reflecting 5-FU-induced toxicity: Comparison between patient colon tissue and 3D human colon organoids. Toxicol Lett. 2022 Dec 1;371:17-24. doi: 10.1016/j.toxlet.2022.09.013. Epub 2022 Sep 29.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [17] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.