Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2LQ771)

• DOT Name: Tripeptidyl-peptidase 1 (TPP1)
• Synonyms: TPP-1; EC 3.4.14.9; Cell growth-inhibiting gene 1 protein; Lysosomal pepstatin-insensitive protease; LPIC; Tripeptidyl aminopeptidase; Tripeptidyl-peptidase I; TPP-I
• Gene Name: TPP1
• Related Disease:
  Neuronal ceroid lipofuscinosis
  Neuronal ceroid lipofuscinosis 2
  Autosomal recessive spinocerebellar ataxia 7
• UniProt ID: TPP1_HUMAN
• PDB ID: 3EDY; 3EE6
• EC Number: 3.4.14.9
• Pfam ID: PF00082 ; PF09286
• Sequence:
  MGLQACLLGLFALILSGKCSYSPEPDQRRTLPPGWVSLGRADPEEELSLTFALRQQNVER
  LSELVQAVSDPSSPQYGKYLTLENVADLVRPSPLTLHTVQKWLLAAGAQKCHSVITQDFL
  TCWLSIRQAELLLPGAEFHHYVGGPTETHVVRSPHPYQLPQALAPHVDFVGGLHRFPPTS
  SLRQRPEPQVTGTVGLHLGVTPSVIRKRYNLTSQDVGSGTSNNSQACAQFLEQYFHDSDL
  AQFMRLFGGNFAHQASVARVVGQQGRGRAGIEASLDVQYLMSAGANISTWVYSSPGRHEG
  QEPFLQWLMLLSNESALPHVHTVSYGDDEDSLSSAYIQRVNTELMKAAARGLTLLFASGD
  SGAGCWSVSGRHQFRPTFPASSPYVTTVGGTSFQEPFLITNEIVDYISGGGFSNVFPRPS
  YQEEAVTKFLSSSPHLPPSSYFNASGRAYPDVAALSDGYWVVSNRVPIPWVSGTSASTPV
  FGGILSLINEHRILSGRPPLGFLNPRLYQQHGAGLFDVTRGCHESCLDEEVEGQGFCSGP
  GWDPVTGWGTPNFPALLKTLLNP
• Function: Lysosomal serine protease with tripeptidyl-peptidase I activity. May act as a non-specific lysosomal peptidase which generates tripeptides from the breakdown products produced by lysosomal proteinases. Requires substrates with an unsubstituted N-terminus.
• Tissue Specificity: Detected in all tissues examined with highest levels in heart and placenta and relatively similar levels in other tissues.
• KEGG Pathway: Lysosome (hsa04142)
• Reactome Pathway: XBP1(S) activates chaperone genes (R-HSA-381038)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuronal ceroid lipofuscinosis	DIS9A4K4	Definitive	Autosomal recessive	[1]
Neuronal ceroid lipofuscinosis 2	DISKPI4X	Definitive	Autosomal recessive	[1]
Autosomal recessive spinocerebellar ataxia 7	DIS8JTK7	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Tripeptidyl-peptidase 1 (TPP1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tripeptidyl-peptidase 1 (TPP1).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tripeptidyl-peptidase 1 (TPP1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Tripeptidyl-peptidase 1 (TPP1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tripeptidyl-peptidase 1 (TPP1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Tripeptidyl-peptidase 1 (TPP1).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tripeptidyl-peptidase 1 (TPP1).	[7]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tripeptidyl-peptidase 1 (TPP1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tripeptidyl-peptidase 1 (TPP1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Tripeptidyl-peptidase 1 (TPP1).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Tripeptidyl-peptidase 1 (TPP1).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Tripeptidyl-peptidase 1 (TPP1).	[6]
Selenium	DM25CGV	Approved	Selenium increases the expression of Tripeptidyl-peptidase 1 (TPP1).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Tripeptidyl-peptidase 1 (TPP1).	[13]
Gentamicin	DMKINJO	Approved	Gentamicin increases the expression of Tripeptidyl-peptidase 1 (TPP1).	[14]
LY2835219	DM93VBZ	Approved	LY2835219 increases the expression of Tripeptidyl-peptidase 1 (TPP1).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Tripeptidyl-peptidase 1 (TPP1).	[12]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Tripeptidyl-peptidase 1 (TPP1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tripeptidyl-peptidase 1 (TPP1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Tripeptidyl-peptidase 1 (TPP1).	[20]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of Tripeptidyl-peptidase 1 (TPP1).	[21]
PP-242	DM2348V	Investigative	PP-242 increases the expression of Tripeptidyl-peptidase 1 (TPP1).	[22]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease). Hum Mutat. 2013 May;34(5):706-13. doi: 10.1002/humu.22292. Epub 2013 Mar 11.
• [3] 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.
• [4] 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.
• [5] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [6] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [7] 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.
• [8] 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.
• [9] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [10] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] 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.
• [13] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [14] Aminoglycoside-mediated suppression of nonsense mutations in late infantile neuronal ceroid lipofuscinosis. Eur J Paediatr Neurol. 2001;5 Suppl A:57-62. doi: 10.1053/ejpn.2000.0436.
• [15] Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. Oncotarget. 2017 Jul 4;8(27):43678-43691. doi: 10.18632/oncotarget.18435.
• [16] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [22] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.