Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOKXPL3)

• DOT Name: Leucyl-cystinyl aminopeptidase (LNPEP)
• Synonyms: Cystinyl aminopeptidase; EC 3.4.11.3; Insulin-regulated membrane aminopeptidase; Insulin-responsive aminopeptidase; IRAP; Oxytocinase; OTase; Placental leucine aminopeptidase; P-LAP
• Gene Name: LNPEP
• UniProt ID: LCAP_HUMAN
• PDB ID: 4P8Q; 4PJ6; 4Z7I; 5C97; 5JHQ; 5MJ6; 7ZYF
• EC Number: 3.4.11.3
• Pfam ID: PF11838 ; PF01433 ; PF17900
• Sequence:
  MEPFTNDRLQLPRNMIENSMFEEEPDVVDLAKEPCLHPLEPDEVEYEPRGSRLLVRGLGE
  HEMEEDEEDYESSAKLLGMSFMNRSSGLRNSATGYRQSPDGACSVPSARTMVVCAFVIVV
  AVSVIMVIYLLPRCTFTKEGCHKKNQSIGLIQPFATNGKLFPWAQIRLPTAVVPLRYELS
  LHPNLTSMTFRGSVTISVQALQVTWNIILHSTGHNISRVTFMSAVSSQEKQAEILEYAYH
  GQIAIVAPEALLAGHNYTLKIEYSANISSSYYGFYGFSYTDESNEKKYFAATQFEPLAAR
  SAFPCFDEPAFKATFIIKIIRDEQYTALSNMPKKSSVVLDDGLVQDEFSESVKMSTYLVA
  FIVGEMKNLSQDVNGTLVSIYAVPEKIGQVHYALETTVKLLEFFQNYFEIQYPLKKLDLV
  AIPDFEAGAMENWGLLTFREETLLYDSNTSSMADRKLVTKIIAHELAHQWFGNLVTMKWW
  NDLWLNEGFATFMEYFSLEKIFKELSSYEDFLDARFKTMKKDSLNSSHPISSSVQSSEQI
  EEMFDSLSYFKGSSLLLMLKTYLSEDVFQHAVVLYLHNHSYASIQSDDLWDSFNEVTNQT
  LDVKRMMKTWTLQKGFPLVTVQKKGKELFIQQERFFLNMKPEIQPSDTSYLWHIPLSYVT
  EGRNYSKYQSVSLLDKKSGVINLTEEVLWVKVNINMNGYYIVHYADDDWEALIHQLKINP
  YVLSDKDRANLINNIFELAGLGKVPLKRAFDLINYLGNENHTAPITEALFQTDLIYNLLE
  KLGYMDLASRLVTRVFKLLQNQIQQQTWTDEGTPSMRELRSALLEFACTHNLGNCSTTAM
  KLFDDWMASNGTQSLPTDVMTTVFKVGAKTDKGWSFLLGKYISIGSEAEKNKILEALASS
  EDVRKLYWLMKSSLNGDNFRTQKLSFIIRTVGRHFPGHLLAWDFVKENWNKLVQKFPLGS
  YTIQNIVAGSTYLFSTKTHLSEVQAFFENQSEATFRLRCVQEALEVIQLNIQWMEKNLKS
  LTWWL
• Function: Release of an N-terminal amino acid, cleaves before cysteine, leucine as well as other amino acids. Degrades peptide hormones such as oxytocin, vasopressin and angiotensin III, and plays a role in maintaining homeostasis during pregnancy. May be involved in the inactivation of neuronal peptides in the brain. Cleaves Met-enkephalin and dynorphin. Binds angiotensin IV and may be the angiotensin IV receptor in the brain.
• Tissue Specificity: Highly expressed in placenta, heart, kidney and small intestine. Detected at lower levels in neuronal cells in the brain, in skeletal muscle, spleen, liver, testes and colon.
• KEGG Pathway: Renin-angiotensin system (hsa04614)
• Reactome Pathway:
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)
  Antigen processing (R-HSA-983168)
  Endosomal/Vacuolar pathway (R-HSA-1236977)

Molecular Interaction Atlas (MIA) of This DOT

14 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 Leucyl-cystinyl aminopeptidase (LNPEP).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[4]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[11]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[17]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Leucyl-cystinyl aminopeptidase (LNPEP).	[18]

4 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 Leucyl-cystinyl aminopeptidase (LNPEP).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Leucyl-cystinyl aminopeptidase (LNPEP).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Leucyl-cystinyl aminopeptidase (LNPEP).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Leucyl-cystinyl aminopeptidase (LNPEP).	[15]

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] 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] 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] 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.
• [6] 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.
• [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] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.