Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT91OVAU)

DOT Name Tripeptidyl-peptidase 2 (TPP2)
Synonyms TPP-2; EC 3.4.14.10; Tripeptidyl aminopeptidase; Tripeptidyl-peptidase II; TPP-II
Gene Name TPP2
Related Disease
Immunodeficiency 78 with autoimmunity and developmental delay ( )
Autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome ( )
UniProt ID
TPP2_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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EC Number
3.4.14.10
Pfam ID
PF00082 ; PF12580 ; PF12583 ; PF21316 ; PF21223
Sequence
MATAATEEPFPFHGLLPKKETGAASFLCRYPEYDGRGVLIAVLDTGVDPGAPGMQVTTDG
KPKIVDIIDTTGSGDVNTATEVEPKDGEIVGLSGRVLKIPASWTNPSGKYHIGIKNGYDF
YPKALKERIQKERKEKIWDPVHRVALAEACRKQEEFDVANNGSSQANKLIKEELQSQVEL
LNSFEKKYSDPGPVYDCLVWHDGEVWRACIDSNEDGDLSKSTVLRNYKEAQEYGSFGTAE
MLNYSVNIYDDGNLLSIVTSGGAHGTHVASIAAGHFPEEPERNGVAPGAQILSIKIGDTR
LSTMETGTGLIRAMIEVINHKCDLVNYSYGEATHWPNSGRICEVINEAVWKHNIIYVSSA
GNNGPCLSTVGCPGGTTSSVIGVGAYVSPDMMVAEYSLREKLPANQYTWSSRGPSADGAL
GVSISAPGGAIASVPNWTLRGTQLMNGTSMSSPNACGGIALILSGLKANNIDYTVHSVRR
ALENTAVKADNIEVFAQGHGIIQVDKAYDYLVQNTSFANKLGFTVTVGNNRGIYLRDPVQ
VAAPSDHGVGIEPVFPENTENSEKISLQLHLALTSNSSWVQCPSHLELMNQCRHINIRVD
PRGLREGLHYTEVCGYDIASPNAGPLFRVPITAVIAAKVNESSHYDLAFTDVHFKPGQIR
RHFIEVPEGATWAEVTVCSCSSEVSAKFVLHAVQLVKQRAYRSHEFYKFCSLPEKGTLTE
AFPVLGGKAIEFCIARWWASLSDVNIDYTISFHGIVCTAPQLNIHASEGINRFDVQSSLK
YEDLAPCITLKNWVQTLRPVSAKTKPLGSRDVLPNNRQLYEMVLTYNFHQPKSGEVTPSC
PLLCELLYESEFDSQLWIIFDQNKRQMGSGDAYPHQYSLKLEKGDYTIRLQIRHEQISDL
ERLKDLPFIVSHRLSNTLSLDIHENHSFALLGKKKSSNLTLPPKYNQPFFVTSLPDDKIP
KGAGPGCYLAGSLTLSKTELGKKADVIPVHYYLIPPPTKTKNGSKDKEKDSEKEKDLKEE
FTEALRDLKIQWMTKLDSSDIYNELKETYPNYLPLYVARLHQLDAEKERMKRLNEIVDAA
NAVISHIDQTALAVYIAMKTDPRPDAATIKNDMDKQKSTLVDALCRKGCALADHLLHTQA
QDGAISTDAEGKEEEGESPLDSLAETFWETTKWTDLFDNKVLTFAYKHALVNKMYGRGLK
FATKLVEEKPTKENWKNCIQLMKLLGWTHCASFTENWLPIMYPPDYCVF
Function
Cytosolic tripeptidyl-peptidase that releases N-terminal tripeptides from polypeptides and is a component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway. It plays an important role in intracellular amino acid homeostasis. Stimulates adipogenesis.
Reactome Pathway
Antigen processing (R-HSA-983168 )

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Immunodeficiency 78 with autoimmunity and developmental delay DISWXASJ Strong Autosomal recessive [1]
Autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome DISIWQV8 Supportive Autosomal recessive [2]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
8 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Tripeptidyl-peptidase 2 (TPP2). [3]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Tripeptidyl-peptidase 2 (TPP2). [4]
Testosterone DM7HUNW Approved Testosterone decreases the expression of Tripeptidyl-peptidase 2 (TPP2). [5]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of Tripeptidyl-peptidase 2 (TPP2). [8]
Geldanamycin DMS7TC5 Discontinued in Phase 2 Geldanamycin increases the expression of Tripeptidyl-peptidase 2 (TPP2). [9]
Torcetrapib DMDHYM7 Discontinued in Phase 2 Torcetrapib increases the expression of Tripeptidyl-peptidase 2 (TPP2). [10]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Tripeptidyl-peptidase 2 (TPP2). [11]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of Tripeptidyl-peptidase 2 (TPP2). [12]
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⏷ Show the Full List of 8 Drug(s)
4 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT
Drug Name Drug ID Highest Status Interaction REF
Fluorouracil DMUM7HZ Approved Fluorouracil affects the localization of Tripeptidyl-peptidase 2 (TPP2). [6]
Etoposide DMNH3PG Approved Etoposide affects the localization of Tripeptidyl-peptidase 2 (TPP2). [6]
Hydroxyurea DMOQVU9 Approved Hydroxyurea affects the localization of Tripeptidyl-peptidase 2 (TPP2). [6]
DNCB DMDTVYC Phase 2 DNCB affects the binding of Tripeptidyl-peptidase 2 (TPP2). [7]
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References

1 Activation of cellular death programs associated with immunosenescence-like phenotype in TPPII knockout mice. Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5177-82. doi: 10.1073/pnas.0801413105. Epub 2008 Mar 24.
2 Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency. Blood. 2015 Jan 29;125(5):753-61. doi: 10.1182/blood-2014-08-593202. Epub 2014 Nov 20.
3 Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
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 The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
6 MAP kinase-signaling controls nuclear translocation of tripeptidyl-peptidase II in response to DNA damage and oxidative stress. Biochem Biophys Res Commun. 2010 Aug 27;399(3):324-30. doi: 10.1016/j.bbrc.2010.06.133. Epub 2010 Jul 17.
7 Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
8 Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
9 Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
10 Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
11 Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
12 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.