Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT2EDHU)

• DTT Name: Insulin-degrading enzyme (IDE)
• Synonyms: Insulysin; Insulinase; Insulin protease; Abeta-degrading protease
• Gene Name: IDE
• DTT Type: Successful target; [1]
• BioChemical Class: Peptidase
• UniProt ID: IDE_HUMAN
• TTD ID: T81900
• EC Number: EC 3.4.24.56
• Sequence:
  MRYRLAWLLHPALPSTFRSVLGARLPPPERLCGFQKKTYSKMNNPAIKRIGNHITKSPED
  KREYRGLELANGIKVLLISDPTTDKSSAALDVHIGSLSDPPNIAGLSHFCEHMLFLGTKK
  YPKENEYSQFLSEHAGSSNAFTSGEHTNYYFDVSHEHLEGALDRFAQFFLCPLFDESCKD
  REVNAVDSEHEKNVMNDAWRLFQLEKATGNPKHPFSKFGTGNKYTLETRPNQEGIDVRQE
  LLKFHSAYYSSNLMAVCVLGRESLDDLTNLVVKLFSEVENKNVPLPEFPEHPFQEEHLKQ
  LYKIVPIKDIRNLYVTFPIPDLQKYYKSNPGHYLGHLIGHEGPGSLLSELKSKGWVNTLV
  GGQKEGARGFMFFIINVDLTEEGLLHVEDIILHMFQYIQKLRAEGPQEWVFQECKDLNAV
  AFRFKDKERPRGYTSKIAGILHYYPLEEVLTAEYLLEEFRPDLIEMVLDKLRPENVRVAI
  VSKSFEGKTDRTEEWYGTQYKQEAIPDEVIKKWQNADLNGKFKLPTKNEFIPTNFEILPL
  EKEATPYPALIKDTAMSKLWFKQDDKFFLPKACLNFEFFSPFAYVDPLHCNMAYLYLELL
  KDSLNEYAYAAELAGLSYDLQNTIYGMYLSVKGYNDKQPILLKKIIEKMATFEIDEKRFE
  IIKEAYMRSLNNFRAEQPHQHAMYYLRLLMTEVAWTKDELKEALDDVTLPRLKAFIPQLL
  SRLHIEALLHGNITKQAALGIMQMVEDTLIEHAHTKPLLPSQLVRYREVQLPDRGWFVYQ
  QRNEVHNNCGIEIYYQTDMQSTSENMFLELFCQIISEPCFNTLRTKEQLGYIVFSGPRRA
  NGIQGLRFIIQSEKPPHYLESRVEAFLITMEKSIEDMTEEAFQKHIQALAIRRLDKPKKL
  SAECAKYWGEIISQQYNFDRDNTEVAYLKTLTKEDIIKFYKEMLAVDAPRRHKVSVHVLA
  REMDSCPVVGEFPCQNDINLSQAPALPQPEVIQNMTEFKRGLPLFPLVKPHINFMAAKL
• Function: 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. 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. Plays a role in the cellular breakdown of insulin, APP peptides, IAPP peptides, glucagon, bradykinin, kallidin and other peptides, and thereby plays a role in intercellular peptide signaling.
• KEGG Pathway: Alzheimer's disease (hsa05010)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Ub-specific processing proteases (R-HSA-5689880)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bacitracin	DM5OHYE	Blepharoconjunctivitis		Approved	[1]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PRO-001	DM5ZTE4	Retinitis pigmentosa	9B70	Phase 2	[2]

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GNF-PF-4478	DMCDU8K	Discovery agent	N.A.	Investigative	[3]
NTE-1	DMFIE0U	Discovery agent	N.A.	Investigative	[4]
NTE-2	DM4DB0W	Discovery agent	N.A.	Investigative	[4]
quinoline 2	DM1QIPZ	Discovery agent	N.A.	Investigative	[4]

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Insulin-degrading enzyme (IDE) DME Info
• Gene Name: IDE

1 Approved Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Insulin	DMB7CE0	Diabetic complication	5A2Y	Approved	[5]

References

• [1] Brain insulin impairs amyloid-beta(1-40) clearance from the brain. J Neurosci. 2004 Oct 27;24(43):9632-7.
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2371).
• [3] In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6.
• [4] Dual Exosite-binding Inhibitors of Insulin-degrading Enzyme Challenge Its Role as the Primary Mediator of Insulin Clearance in Vivo. J Biol Chem. 2015 Aug 14;290(33):20044-59.
• [5] Alternative splicing of human insulin-degrading enzyme yields a novel isoform with a decreased ability to degrade insulin and amyloid beta-protein. Biochemistry. 2005 May 3;44(17):6513-25.