Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD2Y7LU)

• DOT Name: Xaa-Arg dipeptidase (PM20D2)
• Synonyms: EC 3.4.13.4; Beta-Ala-Lys dipeptidase
• Gene Name: PM20D2
• UniProt ID: P20D2_HUMAN
• PDB ID: 7YH4
• EC Number: 3.4.13.4
• Pfam ID: PF07687 ; PF01546
• Sequence:
  MRPGGERPVEGGACNGRSELELLKLRSAECIDEAAERLGALSRAIWSQPELAYEEHHAHR
  VLTHFFEREPPAASWAVQPHYQLPTAFRAEWEPPEARAPSATPRPLHLGFLCEYDALPGI
  GHACGHNLIAEVGAAAALGVRGALEGLPRPPPPVKVVVLGTPAEEDGGGKIDLIEAGAFT
  NLDVVFMAHPSQENAAYLPDMAEHDVTVKYYGKASHSASYPWEGLNALDAAVLAYNNLSV
  FRQQMKPTWRVHGIIKNGGVKPNIIPSYSELIYYFRAPSMKELQVLTKKAEDCFRAAALA
  SGCTVEIKGGAHDYYNVLPNKSLWKAYMENGRKLGIEFISEDTMLNGPSGSTDFGNVSFV
  VPGIHPYFHIGSNALNHTEQYTEAAGSQEAQFYTLRTAKALAMTALDVIFKPELLEGIRE
  DFKLKLQEEQFVNAVE
• Function: Catalyzes the peptide bond hydrolysis in dipeptides having basic amino acids lysine, ornithine or arginine at C-terminus. Postulated to function in a metabolite repair mechanism by eliminating alternate dipeptide by-products formed during carnosine synthesis.

Molecular Interaction Atlas (MIA) of This DOT

1 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 Xaa-Arg dipeptidase (PM20D2).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Xaa-Arg dipeptidase (PM20D2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Xaa-Arg dipeptidase (PM20D2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Xaa-Arg dipeptidase (PM20D2).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Xaa-Arg dipeptidase (PM20D2).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Xaa-Arg dipeptidase (PM20D2).	[6]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Xaa-Arg dipeptidase (PM20D2).	[7]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Xaa-Arg dipeptidase (PM20D2).	[8]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Xaa-Arg dipeptidase (PM20D2).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Xaa-Arg dipeptidase (PM20D2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Xaa-Arg dipeptidase (PM20D2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Xaa-Arg dipeptidase (PM20D2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Xaa-Arg dipeptidase (PM20D2).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Xaa-Arg dipeptidase (PM20D2).	[7]

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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] 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.
• [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] 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.
• [7] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [8] 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.
• [9] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] 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.
• [12] 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.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.