Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP3WYFD)

• DOT Name: Aminopeptidase N (ANPEP)
• Synonyms: AP-N; hAPN; EC 3.4.11.2; Alanyl aminopeptidase; Aminopeptidase M; AP-M; Microsomal aminopeptidase; Myeloid plasma membrane glycoprotein CD13; gp150; CD antigen CD13
• Gene Name: ANPEP
• UniProt ID: AMPN_HUMAN
• PDB ID: 4FYQ; 4FYR; 4FYS; 4FYT; 5LHD; 6ATK; 6U7E; 6U7F; 6U7G; 6XWD; 7AEW; 7VPQ
• EC Number: 3.4.11.2
• Pfam ID: PF11838 ; PF01433 ; PF17900
• Sequence:
  MAKGFYISKSLGILGILLGVAAVCTIIALSVVYSQEKNKNANSSPVASTTPSASATTNPA
  SATTLDQSKAWNRYRLPNTLKPDSYRVTLRPYLTPNDRGLYVFKGSSTVRFTCKEATDVI
  IIHSKKLNYTLSQGHRVVLRGVGGSQPPDIDKTELVEPTEYLVVHLKGSLVKDSQYEMDS
  EFEGELADDLAGFYRSEYMEGNVRKVVATTQMQAADARKSFPCFDEPAMKAEFNITLIHP
  KDLTALSNMLPKGPSTPLPEDPNWNVTEFHTTPKMSTYLLAFIVSEFDYVEKQASNGVLI
  RIWARPSAIAAGHGDYALNVTGPILNFFAGHYDTPYPLPKSDQIGLPDFNAGAMENWGLV
  TYRENSLLFDPLSSSSSNKERVVTVIAHELAHQWFGNLVTIEWWNDLWLNEGFASYVEYL
  GADYAEPTWNLKDLMVLNDVYRVMAVDALASSHPLSTPASEINTPAQISELFDAISYSKG
  ASVLRMLSSFLSEDVFKQGLASYLHTFAYQNTIYLNLWDHLQEAVNNRSIQLPTTVRDIM
  NRWTLQMGFPVITVDTSTGTLSQEHFLLDPDSNVTRPSEFNYVWIVPITSIRDGRQQQDY
  WLIDVRAQNDLFSTSGNEWVLLNLNVTGYYRVNYDEENWRKIQTQLQRDHSAIPVINRAQ
  IINDAFNLASAHKVPVTLALNNTLFLIEERQYMPWEAALSSLSYFKLMFDRSEVYGPMKN
  YLKKQVTPLFIHFRNNTNNWREIPENLMDQYSEVNAISTACSNGVPECEEMVSGLFKQWM
  ENPNNNPIHPNLRSTVYCNAIAQGGEEEWDFAWEQFRNATLVNEADKLRAALACSKELWI
  LNRYLSYTLNPDLIRKQDATSTIISITNNVIGQGLVWDFVQSNWKKLFNDYGGGSFSFSN
  LIQAVTRRFSTEYELQQLEQFKKDNEETGFGSGTRALEQALEKTKANIKWVKENKEVVLQ
  WFTENSK
• Function: Broad specificity aminopeptidase which plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. Also involved in the processing of various peptides including peptide hormones, such as angiotensin III and IV, neuropeptides, and chemokines. May also be involved the cleavage of peptides bound to major histocompatibility complex class II molecules of antigen presenting cells. May have a role in angiogenesis and promote cholesterol crystallization. May have a role in amino acid transport by acting as binding partner of amino acid transporter SLC6A19 and regulating its activity; (Microbial infection) Acts as a receptor for human coronavirus 229E/HCoV-229E. In case of human coronavirus 229E (HCoV-229E) infection, serves as receptor for HCoV-229E spike glycoprotein; (Microbial infection) Mediates as well Human cytomegalovirus (HCMV) infection.
• Tissue Specificity: Expressed in epithelial cells of the kidney, intestine, and respiratory tract; granulocytes, monocytes, fibroblasts, endothelial cells, cerebral pericytes at the blood-brain barrier, synaptic membranes of cells in the CNS. Also expressed in endometrial stromal cells, but not in the endometrial glandular cells. Found in the vasculature of tissues that undergo angiogenesis and in malignant gliomas and lymph node metastases from multiple tumor types but not in blood vessels of normal tissues. A soluble form has been found in plasma. It is found to be elevated in plasma and effusions of cancer patients.
• KEGG Pathway:
  Glutathione metabolism (hsa00480)
  Metabolic pathways (hsa01100)
  Renin-angiotensin system (hsa04614)
  Hematopoietic cell lineage (hsa04640)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Metabolism of Angiotensinogen to Angiotensins (R-HSA-2022377)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Aminopeptidase N (ANPEP).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Aminopeptidase N (ANPEP).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Aminopeptidase N (ANPEP).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Aminopeptidase N (ANPEP).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Aminopeptidase N (ANPEP).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Aminopeptidase N (ANPEP).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Aminopeptidase N (ANPEP).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Aminopeptidase N (ANPEP).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Aminopeptidase N (ANPEP).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Aminopeptidase N (ANPEP).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Aminopeptidase N (ANPEP).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Aminopeptidase N (ANPEP).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Aminopeptidase N (ANPEP).	[12]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Aminopeptidase N (ANPEP).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Aminopeptidase N (ANPEP).	[14]
Selenium	DM25CGV	Approved	Selenium increases the expression of Aminopeptidase N (ANPEP).	[15]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Aminopeptidase N (ANPEP).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Aminopeptidase N (ANPEP).	[17]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Aminopeptidase N (ANPEP).	[18]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Aminopeptidase N (ANPEP).	[19]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Aminopeptidase N (ANPEP).	[20]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Aminopeptidase N (ANPEP).	[21]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Aminopeptidase N (ANPEP).	[20]
Fenretinide	DMRD5SP	Phase 3	Fenretinide decreases the activity of Aminopeptidase N (ANPEP).	[23]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Aminopeptidase N (ANPEP).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Aminopeptidase N (ANPEP).	[26]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Gentamicin	DMKINJO	Approved	Gentamicin increases the secretion of Aminopeptidase N (ANPEP).	[22]

References

• [1] Nuclear and Mitochondrial DNA Methylation Patterns Induced by Valproic Acid in Human Hepatocytes. Chem Res Toxicol. 2017 Oct 16;30(10):1847-1854. doi: 10.1021/acs.chemrestox.7b00171. Epub 2017 Sep 13.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [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] Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer. Chem Res Toxicol. 2015 Jun 15;28(6):1144-55. doi: 10.1021/tx500393y. Epub 2015 Jun 3.
• [10] Detection of gene expression alteration of myeloma cells treated with arsenic trioxide. Zhonghua Xue Ye Xue Za Zhi. 2005 Apr;26(4):209-13.
• [11] 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.
• [12] Enhancement of methotrexate nephrotoxicity after cisplatin therapy. Cancer. 1986 Dec 15;58(12):2617-21. doi: 10.1002/1097-0142(19861215)58:12<2617::aid-cncr2820581211>3.0.co;2-b.
• [13] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [14] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [15] 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.
• [16] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [17] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [18] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [19] Aspirin inhibits thrombin action on endothelial cells via up-regulation of aminopeptidase N/CD13 expression. Atherosclerosis. 2005 Nov;183(1):49-55.
• [20] The effects of dasatinib on IgE receptor-dependent activation and histamine release in human basophils. Blood. 2008 Mar 15;111(6):3097-107.
• [21] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [22] Investigations on the potential nephrotoxicity of cefazedone and gentamicin and of their combination, in comparison with the combination of cefazolin and cephalothin with gentamicin. Arzneimittelforschung. 1979;29(2a):449-52.
• [23] The transforming growth factor-beta family members bone morphogenetic protein-2 and macrophage inhibitory cytokine-1 as mediators of the antiangiogenic activity of N-(4-hydroxyphenyl)retinamide. Clin Cancer Res. 2005 Jun 15;11(12):4610-9.
• [24] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [25] 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.
• [26] 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.