Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBMZW2O)

• DOT Name: Dipeptidyl peptidase 9 (DPP9)
• Synonyms: DP9; EC 3.4.14.5; Dipeptidyl peptidase IV-related protein 2; DPRP-2; Dipeptidyl peptidase IX; DPP IX; Dipeptidyl peptidase-like protein 9; DPLP9
• Gene Name: DPP9
• Related Disease: Hatipoglu immunodeficiency syndrome
• UniProt ID: DPP9_HUMAN
• PDB ID: 6EOQ; 6EOR; 6QZV; 6X6A; 6X6C; 7A3F; 7JKQ; 7JN7; 7SVL; 7SVN; 7ZXS
• EC Number: 3.4.14.5
• Pfam ID: PF19520 ; PF00930 ; PF00326
• Sequence:
  MATTGTPTADRGDAAATDDPAARFQVQKHSWDGLRSIIHGSRKYSGLIVNKAPHDFQFVQ
  KTDESGPHSHRLYYLGMPYGSRENSLLYSEIPKKVRKEALLLLSWKQMLDHFQATPHHGV
  YSREEELLRERKRLGVFGITSYDFHSESGLFLFQASNSLFHCRDGGKNGFMVSPMKPLEI
  KTQCSGPRMDPKICPADPAFFSFINNSDLWVANIETGEERRLTFCHQGLSNVLDDPKSAG
  VATFVIQEEFDRFTGYWWCPTASWEGSEGLKTLRILYEEVDESEVEVIHVPSPALEERKT
  DSYRYPRTGSKNPKIALKLAEFQTDSQGKIVSTQEKELVQPFSSLFPKVEYIARAGWTRD
  GKYAWAMFLDRPQQWLQLVLLPPALFIPSTENEEQRLASARAVPRNVQPYVVYEEVTNVW
  INVHDIFYPFPQSEGEDELCFLRANECKTGFCHLYKVTAVLKSQGYDWSEPFSPGEDEFK
  CPIKEEIALTSGEWEVLARHGSKIWVNEETKLVYFQGTKDTPLEHHLYVVSYEAAGEIVR
  LTTPGFSHSCSMSQNFDMFVSHYSSVSTPPCVHVYKLSGPDDDPLHKQPRFWASMMEAAS
  CPPDYVPPEIFHFHTRSDVRLYGMIYKPHALQPGKKHPTVLFVYGGPQVQLVNNSFKGIK
  YLRLNTLASLGYAVVVIDGRGSCQRGLRFEGALKNQMGQVEIEDQVEGLQFVAEKYGFID
  LSRVAIHGWSYGGFLSLMGLIHKPQVFKVAIAGAPVTVWMAYDTGYTERYMDVPENNQHG
  YEAGSVALHVEKLPNEPNRLLILHGFLDENVHFFHTNFLVSQLIRAGKPYQLQIYPNERH
  SIRCPESGEHYEVTLLHFLQEYL
• Function: Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2. Acts as a key inhibitor of caspase-1-dependent monocyte and macrophage pyroptosis in resting cells by preventing activation of NLRP1 and CARD8. Sequesters the cleaved C-terminal part of NLRP1 and CARD8, which respectively constitute the active part of the NLRP1 and CARD8 inflammasomes, in a ternary complex, thereby preventing their oligomerization and activation. The dipeptidyl peptidase activity is required to suppress NLRP1 and CARD8; however, neither NLRP1 nor CARD8 are bona fide substrates of DPP9, suggesting the existence of substrate(s) required for NLRP1 and CARD8 inhibition.
• Tissue Specificity: Ubiquitously expressed, with highest levels in liver, heart and muscle, and lowest levels in brain.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hatipoglu immunodeficiency syndrome	DISDL1RW	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Dipeptidyl peptidase 9 (DPP9).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dipeptidyl peptidase 9 (DPP9).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dipeptidyl peptidase 9 (DPP9).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dipeptidyl peptidase 9 (DPP9).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dipeptidyl peptidase 9 (DPP9).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Dipeptidyl peptidase 9 (DPP9).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dipeptidyl peptidase 9 (DPP9).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Dipeptidyl peptidase 9 (DPP9).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Dipeptidyl peptidase 9 (DPP9).	[10]
Ibuprofen	DM8VCBE	Approved	Ibuprofen increases the expression of Dipeptidyl peptidase 9 (DPP9).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Dipeptidyl peptidase 9 (DPP9).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dipeptidyl peptidase 9 (DPP9).	[13]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Dipeptidyl peptidase 9 (DPP9).	[14]

2 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 Dipeptidyl peptidase 9 (DPP9).	[8]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Dipeptidyl peptidase 9 (DPP9).	[12]

References

• [1] Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017 Feb 23;542(7642):433-438. doi: 10.1038/nature21062. Epub 2017 Jan 25.
• [2] 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.
• [3] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [4] 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.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [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] 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.
• [9] 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.
• [10] 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.
• [11] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [12] 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.
• [13] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [14] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.