Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5GQTJ5)

• DOT Name: Insulin-degrading enzyme (IDE)
• Synonyms: EC 3.4.24.56; Abeta-degrading protease; Insulin protease; Insulinase; Insulysin
• Gene Name: IDE
• UniProt ID: IDE_HUMAN
• PDB ID: 2G47 ; 2G48 ; 2G49 ; 2G54 ; 2G56 ; 2JBU ; 2JG4 ; 2WBY ; 2WC0 ; 2WK3 ; 2YPU ; 3CWW ; 3E4A ; 3E4Z ; 3E50 ; 3H44 ; 3HGZ ; 3N56 ; 3N57 ; 3OFI ; 3QZ2 ; 4DTT ; 4DWK ; 4GS8 ; 4GSC ; 4GSF ; 4IFH ; 4IOF ; 4LTE ; 4M1C ; 4NXO ; 4PES ; 4PF7 ; 4PF9 ; 4PFC ; 4QIA ; 4RAL ; 4RE9 ; 5CJO ; 5UOE ; 5WOB ; 6B3Q ; 6B70 ; 6B7Y ; 6B7Z ; 6BF6 ; 6BF7 ; 6BF8 ; 6BF9 ; 6BFC ; 6BYZ ; 6EDS ; 6MQ3 ; 7K1D ; 7K1E ; 7K1F ; 7RZE ; 7RZF ; 7RZG ; 7RZH ; 7RZI
• EC Number: 3.4.24.56
• Pfam ID: PF00675 ; PF05193 ; PF16187
• Sequence:
  MRYRLAWLLHPALPSTFRSVLGARLPPPERLCGFQKKTYSKMNNPAIKRIGNHITKSPED
  KREYRGLELANGIKVLLISDPTTDKSSAALDVHIGSLSDPPNIAGLSHFCEHMLFLGTKK
  YPKENEYSQFLSEHAGSSNAFTSGEHTNYYFDVSHEHLEGALDRFAQFFLCPLFDESCKD
  REVNAVDSEHEKNVMNDAWRLFQLEKATGNPKHPFSKFGTGNKYTLETRPNQEGIDVRQE
  LLKFHSAYYSSNLMAVCVLGRESLDDLTNLVVKLFSEVENKNVPLPEFPEHPFQEEHLKQ
  LYKIVPIKDIRNLYVTFPIPDLQKYYKSNPGHYLGHLIGHEGPGSLLSELKSKGWVNTLV
  GGQKEGARGFMFFIINVDLTEEGLLHVEDIILHMFQYIQKLRAEGPQEWVFQECKDLNAV
  AFRFKDKERPRGYTSKIAGILHYYPLEEVLTAEYLLEEFRPDLIEMVLDKLRPENVRVAI
  VSKSFEGKTDRTEEWYGTQYKQEAIPDEVIKKWQNADLNGKFKLPTKNEFIPTNFEILPL
  EKEATPYPALIKDTAMSKLWFKQDDKFFLPKACLNFEFFSPFAYVDPLHCNMAYLYLELL
  KDSLNEYAYAAELAGLSYDLQNTIYGMYLSVKGYNDKQPILLKKIIEKMATFEIDEKRFE
  IIKEAYMRSLNNFRAEQPHQHAMYYLRLLMTEVAWTKDELKEALDDVTLPRLKAFIPQLL
  SRLHIEALLHGNITKQAALGIMQMVEDTLIEHAHTKPLLPSQLVRYREVQLPDRGWFVYQ
  QRNEVHNNCGIEIYYQTDMQSTSENMFLELFCQIISEPCFNTLRTKEQLGYIVFSGPRRA
  NGIQGLRFIIQSEKPPHYLESRVEAFLITMEKSIEDMTEEAFQKHIQALAIRRLDKPKKL
  SAECAKYWGEIISQQYNFDRDNTEVAYLKTLTKEDIIKFYKEMLAVDAPRRHKVSVHVLA
  REMDSCPVVGEFPCQNDINLSQAPALPQPEVIQNMTEFKRGLPLFPLVKPHINFMAAKL
• Function: Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, natriuretic peptides, glucagon, bradykinin, kallidin, and other peptides, and thereby plays a role in intercellular peptide signaling. Substrate binding induces important conformation changes, making it possible to bind and degrade larger substrates, such as insulin. Contributes to the regulation of peptide hormone signaling cascades and regulation of blood glucose homeostasis via its role in the degradation of insulin, glucagon and IAPP. Plays a role in the degradation and clearance of APP-derived amyloidogenic peptides that are secreted by neurons and microglia (Probable). Degrades the natriuretic peptides ANP, BNP and CNP, inactivating their ability to raise intracellular cGMP. Also degrades an aberrant frameshifted 40-residue form of NPPA (fsNPPA) which is associated with familial atrial fibrillation in heterozygous patients. Involved in antigen processing. Produces both the N terminus and the C terminus of MAGEA3-derived antigenic peptide (EVDPIGHLY) that is presented to cytotoxic T lymphocytes by MHC class I; (Microbial infection) The membrane-associated isoform acts as an entry receptor for varicella-zoster virus (VZV).
• Tissue Specificity: Detected in brain and in cerebrospinal fluid (at protein level).
• KEGG Pathway:
  Virion - Herpesvirus (hsa03266)
  Alzheimer disease (hsa05010)
• Reactome Pathway:
  Insulin receptor recycling (R-HSA-77387)
  Peroxisomal protein import (R-HSA-9033241)
  Ub-specific processing proteases (R-HSA-5689880)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Insulin-degrading enzyme (IDE).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Insulin-degrading enzyme (IDE).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Insulin-degrading enzyme (IDE).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Insulin-degrading enzyme (IDE).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Insulin-degrading enzyme (IDE).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Insulin-degrading enzyme (IDE).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Insulin-degrading enzyme (IDE).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Insulin-degrading enzyme (IDE).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Insulin-degrading enzyme (IDE).	[4]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Insulin-degrading enzyme (IDE).	[7]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Insulin-degrading enzyme (IDE).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Insulin-degrading enzyme (IDE).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Insulin-degrading enzyme (IDE).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Insulin-degrading enzyme (IDE).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Insulin-degrading enzyme (IDE).	[15]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Insulin-degrading enzyme (IDE).	[16]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Insulin-degrading enzyme (IDE).	[11]

References

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• [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] 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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [5] 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.
• [6] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [7] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [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] Rosiglitazone protects neuroblastoma cells against advanced glycation end products-induced injury. Acta Pharmacol Sin. 2011 Aug;32(8):991-8. doi: 10.1038/aps.2011.81. Epub 2011 Jul 18.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [16] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.