Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCA5C2A)

• DOT Name: Glutamyl aminopeptidase (ENPEP)
• Synonyms: EAP; EC 3.4.11.7; Aminopeptidase A; AP-A; Differentiation antigen gp160; CD antigen CD249
• Gene Name: ENPEP
• UniProt ID: AMPE_HUMAN
• PDB ID: 4KX7; 4KX8; 4KX9; 4KXA; 4KXB; 4KXC; 4KXD
• EC Number: 3.4.11.7
• Pfam ID: PF11838 ; PF01433 ; PF17900
• Sequence:
  MNFAEREGSKRYCIQTKHVAILCAVVVGVGLIVGLAVGLTRSCDSSGDGGPGTAPAPSHL
  PSSTASPSGPPAQDQDICPASEDESGQWKNFRLPDFVNPVHYDLHVKPLLEEDTYTGTVS
  ISINLSAPTRYLWLHLRETRITRLPELKRPSGDQVQVRRCFEYKKQEYVVVEAEEELTPS
  SGDGLYLLTMEFAGWLNGSLVGFYRTTYTENGQVKSIVATDHEPTDARKSFPCFDEPNKK
  ATYTISITHPKEYGALSNMPVAKEESVDDKWTRTTFEKSVPMSTYLVCFAVHQFDSVKRI
  SNSGKPLTIYVQPEQKHTAEYAANITKSVFDYFEEYFAMNYSLPKLDKIAIPDFGTGAME
  NWGLITYRETNLLYDPKESASSNQQRVATVVAHELVHQWFGNIVTMDWWEDLWLNEGFAS
  FFEFLGVNHAETDWQMRDQMLLEDVLPVQEDDSLMSSHPIIVTVTTPDEITSVFDGISYS
  KGSSILRMLEDWIKPENFQKGCQMYLEKYQFKNAKTSDFWAALEEASRLPVKEVMDTWTR
  QMGYPVLNVNGVKNITQKRFLLDPRANPSQPPSDLGYTWNIPVKWTEDNITSSVLFNRSE
  KEGITLNSSNPSGNAFLKINPDHIGFYRVNYEVATWDSIATALSLNHKTFSSADRASLID
  DAFALARAQLLDYKVALNLTKYLKREENFLPWQRVISAVTYIISMFEDDKELYPMIEEYF
  QGQVKPIADSLGWNDAGDHVTKLLRSSVLGFACKMGDREALNNASSLFEQWLNGTVSLPV
  NLRLLVYRYGMQNSGNEISWNYTLEQYQKTSLAQEKEKLLYGLASVKNVTLLSRYLDLLK
  DTNLIKTQDVFTVIRYISYNSYGKNMAWNWIQLNWDYLVNRYTLNNRNLGRIVTIAEPFN
  TELQLWQMESFFAKYPQAGAGEKPREQVLETVKNNIEWLKQHRNTIREWFFNLLESG
• Function: Regulates central hypertension through its calcium-modulated preference to cleave N-terminal acidic residues from peptides such as angiotensin II.
• Tissue Specificity: Expressed in choriocarcinoma cancer cell lines (at protein level) . Expressed by epithelial cells of the proximal tubule cells and the glomerulus of the nephron. Also found in a variety of other tissues.
• KEGG Pathway: Renin-angiotensin system (hsa04614)
• Reactome Pathway: Metabolism of Angiotensinogen to Angiotensins (R-HSA-2022377)
• BioCyc Pathway: MetaCyc:HS06560-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 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 Glutamyl aminopeptidase (ENPEP).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Glutamyl aminopeptidase (ENPEP).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Glutamyl aminopeptidase (ENPEP).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Glutamyl aminopeptidase (ENPEP).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Glutamyl aminopeptidase (ENPEP).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Glutamyl aminopeptidase (ENPEP).	[6]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Glutamyl aminopeptidase (ENPEP).	[7]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Glutamyl aminopeptidase (ENPEP).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glutamyl aminopeptidase (ENPEP).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glutamyl aminopeptidase (ENPEP).	[11]

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 decreases the methylation of Glutamyl aminopeptidase (ENPEP).	[10]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [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] 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.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [8] 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.
• [9] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [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.