Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT66MP0F)

• DOT Name: Carboxypeptidase A4 (CPA4)
• Synonyms: EC 3.4.17.-; Carboxypeptidase A3
• Gene Name: CPA4
• UniProt ID: CBPA4_HUMAN
• PDB ID: 2BO9; 2BOA; 2PCU; 4A94; 4BD9
• EC Number: 3.4.17.-
• Pfam ID: PF00246 ; PF02244
• Sequence:
  MRWILFIGALIGSSICGQEKFFGDQVLRINVRNGDEISKLSQLVNSNNLKLNFWKSPSSF
  NRPVDVLVPSVSLQAFKSFLRSQGLEYAVTIEDLQALLDNEDDEMQHNEGQERSSNNFNY
  GAYHSLEAIYHEMDNIAADFPDLARRVKIGHSFENRPMYVLKFSTGKGVRRPAVWLNAGI
  HSREWISQATAIWTARKIVSDYQRDPAITSILEKMDIFLLPVANPDGYVYTQTQNRLWRK
  TRSRNPGSSCIGADPNRNWNASFAGKGASDNPCSEVYHGPHANSEVEVKSVVDFIQKHGN
  FKGFIDLHSYSQLLMYPYGYSVKKAPDAEELDKVARLAAKALASVSGTEYQVGPTCTTVY
  PASGSSIDWAYDNGIKFAFTFELRDTGTYGFLLPANQIIPTAEETWLGLKTIMEHVRDNL
  Y
• Function: Metalloprotease that could be involved in the histone hyperacetylation pathway. Releases a C-terminal amino acid, with preference for -Phe, -Leu, -Ile, -Met, -Tyr and -Val.
• Tissue Specificity: Fetal expression in the adrenal gland, brain, heart, intestine, kidney, liver and lung. Except for fetal brain that shows no imprinting, expression was found preferentially from the maternal allele.

Molecular Interaction Atlas (MIA) of This DOT

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 Carboxypeptidase A4 (CPA4).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Carboxypeptidase A4 (CPA4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Carboxypeptidase A4 (CPA4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Carboxypeptidase A4 (CPA4).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Carboxypeptidase A4 (CPA4).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Carboxypeptidase A4 (CPA4).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Carboxypeptidase A4 (CPA4).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Carboxypeptidase A4 (CPA4).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Carboxypeptidase A4 (CPA4).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Carboxypeptidase A4 (CPA4).	[10]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Carboxypeptidase A4 (CPA4).	[11]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Carboxypeptidase A4 (CPA4).	[12]
Palbociclib	DMD7L94	Approved	Palbociclib increases the expression of Carboxypeptidase A4 (CPA4).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Carboxypeptidase A4 (CPA4).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Carboxypeptidase A4 (CPA4).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Carboxypeptidase A4 (CPA4).	[17]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Carboxypeptidase A4 (CPA4).	[18]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Carboxypeptidase A4 (CPA4).	[19]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Carboxypeptidase A4 (CPA4).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Carboxypeptidase A4 (CPA4).	[14]

References

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• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
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• [6] Unique signatures of stress-induced senescent human astrocytes. Exp Neurol. 2020 Dec;334:113466. doi: 10.1016/j.expneurol.2020.113466. Epub 2020 Sep 17.
• [7] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
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• [11] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [12] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [13] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [16] 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.
• [17] 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.
• [18] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [19] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [20] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.