Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUIVL1C)

• DOT Name: Dipeptidyl peptidase 3 (DPP3)
• Synonyms: EC 3.4.14.4; Dipeptidyl aminopeptidase III; Dipeptidyl arylamidase III; Dipeptidyl peptidase III; DPP III; Enkephalinase B
• Gene Name: DPP3
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Glioblastoma multiforme
  Neoplasm
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Congestive heart failure
  Estrogen-receptor positive breast cancer
• UniProt ID: DPP3_HUMAN
• PDB ID: 3FVY; 3T6B; 3T6J; 5E2Q; 5E33; 5E3A; 5E3C; 5EGY; 5EHH; 7OUP
• EC Number: 3.4.14.4
• Pfam ID: PF03571
• Sequence:
  MADTQYILPNDIGVSSLDCREAFRLLSPTERLYAYHLSRAAWYGGLAVLLQTSPEAPYIY
  ALLSRLFRAQDPDQLRQHALAEGLTEEEYQAFLVYAAGVYSNMGNYKSFGDTKFVPNLPK
  EKLERVILGSEAAQQHPEEVRGLWQTCGELMFSLEPRLRHLGLGKEGITTYFSGNCTMED
  AKLAQDFLDSQNLSAYNTRLFKEVDGEGKPYYEVRLASVLGSEPSLDSEVTSKLKSYEFR
  GSPFQVTRGDYAPILQKVVEQLEKAKAYAANSHQGQMLAQYIESFTQGSIEAHKRGSRFW
  IQDKGPIVESYIGFIESYRDPFGSRGEFEGFVAVVNKAMSAKFERLVASAEQLLKELPWP
  PTFEKDKFLTPDFTSLDVLTFAGSGIPAGINIPNYDDLRQTEGFKNVSLGNVLAVAYATQ
  REKLTFLEEDDKDLYILWKGPSFDVQVGLHELLGHGSGKLFVQDEKGAFNFDQETVINPE
  TGEQIQSWYRSGETWDSKFSTIASSYEECRAESVGLYLCLHPQVLEIFGFEGADAEDVIY
  VNWLNMVRAGLLALEFYTPEAFNWRQAHMQARFVILRVLLEAGEGLVTITPTTGSDGRPD
  ARVRLDRSKIRSVGKPALERFLRRLQVLKSTGDVAGGRALYEGYATVTDAPPECFLTLRD
  TVLLRKESRKLIVQPNTRLEGSDVQLLEYEASAAGLIRSFSERFPEDGPELEEILTQLAT
  ADARFWKGPSEAPSGQA
• Function: Cleaves and degrades bioactive peptides, including angiotensin, Leu-enkephalin and Met-enkephalin. Also cleaves Arg-Arg-beta-naphthylamide (in vitro).
• Tissue Specificity: Detected in placenta (at protein level) . Detected in erythrocytes (at protein level) .
• Reactome Pathway:
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Definitive	Altered Expression	[1]
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Cardiac failure	DISDC067	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[4]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Dipeptidyl peptidase 3 (DPP3) decreases the response to substance of Hydrogen peroxide.	[14]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Leucine-enkephalin	DMT2CZK	Investigative	Dipeptidyl peptidase 3 (DPP3) increases the cleavage of Leucine-enkephalin.	[15]

8 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 Dipeptidyl peptidase 3 (DPP3).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dipeptidyl peptidase 3 (DPP3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dipeptidyl peptidase 3 (DPP3).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Dipeptidyl peptidase 3 (DPP3).	[8]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Dipeptidyl peptidase 3 (DPP3).	[9]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Dipeptidyl peptidase 3 (DPP3).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Dipeptidyl peptidase 3 (DPP3).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dipeptidyl peptidase 3 (DPP3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dipeptidyl peptidase 3 (DPP3).	[11]

References

• [1] Transcription factor C/EBP- mediates downregulation of dipeptidyl-peptidase III expression by interleukin-6 in human glioblastoma cells.FEBS J. 2014 Mar;281(6):1629-41. doi: 10.1111/febs.12728. Epub 2014 Feb 17.
• [2] NRF2 Induction Supporting Breast Cancer Cell Survival Is Enabled by Oxidative Stress-Induced DPP3-KEAP1 Interaction.Cancer Res. 2017 Jun 1;77(11):2881-2892. doi: 10.1158/0008-5472.CAN-16-2204. Epub 2017 Apr 17.
• [3] Proteomic analysis of ubiquitin ligase KEAP1 reveals associated proteins that inhibit NRF2 ubiquitination.Cancer Res. 2013 Apr 1;73(7):2199-210. doi: 10.1158/0008-5472.CAN-12-4400. Epub 2013 Feb 4.
• [4] Circulating dipeptidyl peptidase 3 is a myocardial depressant factor: dipeptidyl peptidase 3 inhibition rapidly and sustainably improves haemodynamics.Eur J Heart Fail. 2020 Feb;22(2):290-299. doi: 10.1002/ejhf.1601. Epub 2019 Aug 31.
• [5] 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.
• [6] 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.
• [7] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [8] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [9] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [10] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] A genomic screen for activators of the antioxidant response element. Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5205-10. doi: 10.1073/pnas.0700898104. Epub 2007 Mar 12.
• [15] Identification of dipeptidyl peptidase III in human neutrophils. Biochem Biophys Res Commun. 2000 Jul 5;273(2):393-7. doi: 10.1006/bbrc.2000.2827.