Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3LFY7S)

• DOT Name: Xaa-Pro dipeptidase (PEPD)
• Synonyms: X-Pro dipeptidase; EC 3.4.13.9; Imidodipeptidase; Peptidase D; Proline dipeptidase; Prolidase
• Gene Name: PEPD
• Related Disease: Prolidase deficiency
• UniProt ID: PEPD_HUMAN
• PDB ID: 2IW2; 2OKN; 5M4G; 5M4J; 5M4L; 5M4Q; 5MBY; 5MBZ; 5MC0; 5MC1; 5MC2; 5MC3; 5MC4; 5MC5; 6H2P; 6H2Q; 6QSB; 6QSC; 6SRE; 6SRF; 6SRG
• EC Number: 3.4.13.9
• Pfam ID: PF05195 ; PF00557
• Sequence:
  MAAATGPSFWLGNETLKVPLALFALNRQRLCERLRKNPAVQAGSIVVLQGGEETQRYCTD
  TGVLFRQESFFHWAFGVTEPGCYGVIDVDTGKSTLFVPRLPASHATWMGKIHSKEHFKEK
  YAVDDVQYVDEIASVLTSQKPSVLLTLRGVNTDSGSVCREASFDGISKFEVNNTILHPEI
  VECRVFKTDMELEVLRYTNKISSEAHREVMKAVKVGMKEYELESLFEHYCYSRGGMRHSS
  YTCICGSGENSAVLHYGHAGAPNDRTIQNGDMCLFDMGGEYYCFASDITCSFPANGKFTA
  DQKAVYEAVLRSSRAVMGAMKPGVWWPDMHRLADRIHLEELAHMGILSGSVDAMVQAHLG
  AVFMPHGLGHFLGIDVHDVGGYPEGVERIDEPGLRSLRTARHLQPGMVLTVEPGIYFIDH
  LLDEALADPARASFLNREVLQRFRGFGGVRIEEDVVVTDSGIELLTCVPRTVEEIEACMA
  GCDKAFTPFSGPK
• Function: Dipeptidase that catalyzes the hydrolysis of dipeptides with a prolyl (Xaa-Pro) or hydroxyprolyl residue in the C-terminal position. The preferred dipeptide substrate is Gly-Pro, but other Xaa-Pro dipeptides, such as Ala-Pro, Met-Pro, Phe-Pro, Val-Pro and Leu-Pro, can be cleaved. Plays an important role in collagen metabolism because the high level of iminoacids in collagen.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prolidase deficiency	DISPUOWK	Definitive	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Isoflurophate	DMBSK7X	Approved	Xaa-Pro dipeptidase (PEPD) decreases the response to substance of Isoflurophate.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Xaa-Pro dipeptidase (PEPD).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Xaa-Pro dipeptidase (PEPD).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Xaa-Pro dipeptidase (PEPD).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Xaa-Pro dipeptidase (PEPD).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Xaa-Pro dipeptidase (PEPD).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Xaa-Pro dipeptidase (PEPD).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Xaa-Pro dipeptidase (PEPD).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the activity of Xaa-Pro dipeptidase (PEPD).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Xaa-Pro dipeptidase (PEPD).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Xaa-Pro dipeptidase (PEPD).	[11]
Aspirin	DM672AH	Approved	Aspirin increases the activity of Xaa-Pro dipeptidase (PEPD).	[12]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the activity of Xaa-Pro dipeptidase (PEPD).	[9]
Gentamicin	DMKINJO	Approved	Gentamicin decreases the activity of Xaa-Pro dipeptidase (PEPD).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Xaa-Pro dipeptidase (PEPD).	[3]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Xaa-Pro dipeptidase (PEPD).	[14]
Phenacetin	DMRQAM0	Withdrawn from market	Phenacetin decreases the activity of Xaa-Pro dipeptidase (PEPD).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Xaa-Pro dipeptidase (PEPD).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Xaa-Pro dipeptidase (PEPD).	[16]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the activity of Xaa-Pro dipeptidase (PEPD).	[17]

References

• [1] Structural organization of the gene for human prolidase (peptidase D) and demonstration of a partial gene deletion in a patient with prolidase deficiency. J Biol Chem. 1990 Jul 5;265(19):11306-11.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [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] Comparison of protective effect of ascorbic acid on redox and endocannabinoid systems interactions in in vitro cultured human skin fibroblasts exposed to UV radiation and hydrogen peroxide. Arch Dermatol Res. 2017 May;309(4):285-303. doi: 10.1007/s00403-017-1729-0. Epub 2017 Mar 11.
• [10] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] Kinetic study of paracetamol on prolidase activity in erythrocytes by capillary electrophoresis with Ru(bpy)(3) (2+) electrochemiluminescence detection. Electrophoresis. 2006 Oct;27(20):4047-51. doi: 10.1002/elps.200600197.
• [13] Melanin potentiates gentamicin-induced inhibition of collagen biosynthesis in human skin fibroblasts. Eur J Pharmacol. 2002 Jun 20;446(1-3):7-13. doi: 10.1016/s0014-2999(02)01793-4.
• [14] 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.
• [15] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Methylparaben-induced decrease in collagen production and viability of cultured human dermal fibroblasts. J Appl Toxicol. 2017 Sep;37(9):1117-1124. doi: 10.1002/jat.3466. Epub 2017 Apr 6.
• [18] Persistent and high-level expression of human liver prolidase in vivo in mice using adenovirus. Chem Biol Interact. 2013 Mar 25;203(1):191-5. doi: 10.1016/j.cbi.2012.08.021. Epub 2012 Sep 12.