Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIUY91L)

• DOT Name: Lysosomal Pro-X carboxypeptidase (PRCP)
• Synonyms: EC 3.4.16.2; Angiotensinase C; Lysosomal carboxypeptidase C; Proline carboxypeptidase; Prolylcarboxypeptidase; PRCP
• Gene Name: PRCP
• UniProt ID: PCP_HUMAN
• PDB ID: 3N2Z
• EC Number: 3.4.16.2
• Pfam ID: PF05577
• Sequence:
  MGRRALLLLLLSFLAPWATIALRPALRALGSLHLPTNPTSLPAVAKNYSVLYFQQKVDHF
  GFNTVKTFNQRYLVADKYWKKNGGSILFYTGNEGDIIWFCNNTGFMWDVAEELKAMLVFA
  EHRYYGESLPFGDNSFKDSRHLNFLTSEQALADFAELIKHLKRTIPGAENQPVIAIGGSY
  GGMLAAWFRMKYPHMVVGALAASAPIWQFEDLVPCGVFMKIVTTDFRKSGPHCSESIHRS
  WDAINRLSNTGSGLQWLTGALHLCSPLTSQDIQHLKDWISETWVNLAMVDYPYASNFLQP
  LPAWPIKVVCQYLKNPNVSDSLLLQNIFQALNVYYNYSGQVKCLNISETATSSLGTLGWS
  YQACTEVVMPFCTNGVDDMFEPHSWNLKELSDDCFQQWGVRPRPSWITTMYGGKNISSHT
  NIVFSNGELDPWSGGGVTKDITDTLVAVTISEGAHHLDLRTKNALDPMSVLLARSLEVRH
  MKNWIRDFYDSAGKQH
• Function: Cleaves C-terminal amino acids linked to proline in peptides such as angiotensin II, III and des-Arg9-bradykinin. This cleavage occurs at acidic pH, but enzymatic activity is retained with some substrates at neutral pH.
• Tissue Specificity: Highest levels in placenta, lung and liver. Also present in heart, brain, pancreas and kidney.
• KEGG Pathway:
  Renin-angiotensin system (hsa04614)
  Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gentamicin	DMKINJO	Approved	Lysosomal Pro-X carboxypeptidase (PRCP) increases the Renal function abnormal ADR of Gentamicin.	[13]
Benazepril	DMH1M9B	Approved	Lysosomal Pro-X carboxypeptidase (PRCP) affects the response to substance of Benazepril.	[14]
Afimoxifene	DMFORDT	Phase 2	Lysosomal Pro-X carboxypeptidase (PRCP) decreases the response to substance of Afimoxifene.	[15]

11 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 Lysosomal Pro-X carboxypeptidase (PRCP).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lysosomal Pro-X carboxypeptidase (PRCP).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Lysosomal Pro-X carboxypeptidase (PRCP).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lysosomal Pro-X carboxypeptidase (PRCP).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Lysosomal Pro-X carboxypeptidase (PRCP).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Lysosomal Pro-X carboxypeptidase (PRCP).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lysosomal Pro-X carboxypeptidase (PRCP).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Lysosomal Pro-X carboxypeptidase (PRCP).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Lysosomal Pro-X carboxypeptidase (PRCP).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Lysosomal Pro-X carboxypeptidase (PRCP).	[11]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Lysosomal Pro-X carboxypeptidase (PRCP).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Lysosomal Pro-X carboxypeptidase (PRCP).	[10]

References

• [1] 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.
• [2] 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.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [12] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.
• [13] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [14] E112D polymorphism in the prolylcarboxypeptidase gene is associated with blood pressure response to benazepril in Chinese hypertensive patients. Chin Med J (Engl). 2009 Oct 20;122(20):2461-5.
• [15] Prolylcarboxypeptidase regulates proliferation, autophagy, and resistance to 4-hydroxytamoxifen-induced cytotoxicity in estrogen receptor-positive breast cancer cells. J Biol Chem. 2011 Jan 28;286(4):2864-76. doi: 10.1074/jbc.M110.143271. Epub 2010 Nov 17.