Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXNTV79)

• DOT Name: Carboxypeptidase E (CPE)
• Synonyms: CPE; EC 3.4.17.10; Carboxypeptidase H; CPH; Enkephalin convertase; Prohormone-processing carboxypeptidase
• Gene Name: CPE
• Related Disease: BDV syndrome
• UniProt ID: CBPE_HUMAN
• EC Number: 3.4.17.10
• Pfam ID: PF13620 ; PF00246
• Sequence:
  MAGRGGSALLALCGALAACGWLLGAEAQEPGAPAAGMRRRRRLQQEDGISFEYHRYPELR
  EALVSVWLQCTAISRIYTVGRSFEGRELLVIELSDNPGVHEPGEPEFKYIGNMHGNEAVG
  RELLIFLAQYLCNEYQKGNETIVNLIHSTRIHIMPSLNPDGFEKAASQPGELKDWFVGRS
  NAQGIDLNRNFPDLDRIVYVNEKEGGPNNHLLKNMKKIVDQNTKLAPETKAVIHWIMDIP
  FVLSANLHGGDLVANYPYDETRSGSAHEYSSSPDDAIFQSLARAYSSFNPAMSDPNRPPC
  RKNDDDSSFVDGTTNGGAWYSVPGGMQDFNYLSSNCFEITVELSCEKFPPEETLKTYWED
  NKNSLISYLEQIHRGVKGFVRDLQGNPIANATISVEGIDHDVTSAKDGDYWRLLIPGNYK
  LTASAPGYLAITKKVAVPYSPAAGVDFELESFSERKEEEKEELMEWWKMMSETLNF
• Function: Sorting receptor that directs prohormones to the regulated secretory pathway. Acts also as a prohormone processing enzyme in neuro/endocrine cells, removing dibasic residues from the C-terminal end of peptide hormone precursors after initial endoprotease cleavage.
• KEGG Pathway: Type I diabetes mellitus (hsa04940)
• Reactome Pathway: Insulin processing (R-HSA-264876)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
BDV syndrome	DISILUOD	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Reserpine	DM6VM38	Approved	Carboxypeptidase E (CPE) increases the Metabolic disorder ADR of Reserpine.	[25]

23 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 E (CPE).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Carboxypeptidase E (CPE).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Carboxypeptidase E (CPE).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Carboxypeptidase E (CPE).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Carboxypeptidase E (CPE).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Carboxypeptidase E (CPE).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Carboxypeptidase E (CPE).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Carboxypeptidase E (CPE).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Carboxypeptidase E (CPE).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Carboxypeptidase E (CPE).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Carboxypeptidase E (CPE).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Carboxypeptidase E (CPE).	[11]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Carboxypeptidase E (CPE).	[14]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Carboxypeptidase E (CPE).	[15]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Carboxypeptidase E (CPE).	[16]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Carboxypeptidase E (CPE).	[17]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Carboxypeptidase E (CPE).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Carboxypeptidase E (CPE).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Carboxypeptidase E (CPE).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Carboxypeptidase E (CPE).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Carboxypeptidase E (CPE).	[22]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Carboxypeptidase E (CPE).	[23]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Carboxypeptidase E (CPE).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Carboxypeptidase E (CPE).	[13]

References

• [1] Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity. Hum Mutat. 2001 Aug;18(2):120-31. doi: 10.1002/humu.1161.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [9] 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.
• [10] Global effects of inorganic arsenic on gene expression profile in human macrophages. Mol Immunol. 2009 Feb;46(4):649-56.
• [11] 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.
• [12] Dissecting progressive stages of 5-fluorouracil resistance in vitro using RNA expression profiling. Int J Cancer. 2004 Nov 1;112(2):200-12. doi: 10.1002/ijc.20401.
• [13] 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.
• [14] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [15] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [16] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [17] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [18] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [19] 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.
• [20] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [21] 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.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [23] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [24] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [25] 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.