Insulin-degrading enzyme

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Insulin-degrading enzyme
Protein IDE PDB 2g47.png
PDB rendering based on 2g47.
Available structures
PDB Ortholog search: PDBe, RCSB
External IDs OMIM146680 MGI96412 HomoloGene3645 IUPHAR: 2371 ChEMBL: 1293287 GeneCards: IDE Gene
EC number
RNA expression pattern
PBB GE IDE 203327 at tn.png
PBB GE IDE 203328 x at tn.png
PBB GE IDE 217496 s at tn.png
More reference expression data
Species Human Mouse
Entrez 3416 15925
Ensembl ENSG00000119912 ENSMUSG00000056999
UniProt P14735 Q8CGB9
RefSeq (mRNA) NM_001165946 NM_031156
RefSeq (protein) NP_001159418 NP_112419
Location (UCSC) Chr 10:
94.21 – 94.33 Mb
Chr 19:
37.27 – 37.34 Mb
PubMed search [1] [2]

Insulin-degrading enzyme, also known as IDE is a human enzyme.[1]

Known alternatively as insulysin or insulin protease, Insulin Degrading Enzyme (IDE) is a large zinc-binding protease of the M16A metalloprotease subfamily known to cleave multiple short polypeptides that vary considerably in sequence. IDE was first identified by its ability to degrade the B chain of the hormone insulin. This activity was observed over sixty years ago,[2] though the enzyme specifically responsible for B chain cleavage was identified more recently.[3] This discovery revealed considerable amino acid sequence similarity between IDE and the previously characterized bacterial protease pitrilysin, suggesting a common proteolytic mechanism. IDE, which migrates at 110 kDa during gel electrophoresis under denaturing conditions, has since been shown to have additional substrates, including the signaling peptides glucagon, TGF alpha, and β-endorphin.[4]

Alzheimer's disease[edit]

Considerable interest in IDE has been stimulated due to the discovery that IDE can degrade amyloid beta (Aβ), a peptide implicated in the pathogenesis of Alzheimer's disease.[5] The underlying cause or causes of the disease are unclear, though the primary neuropathology observed is the formation of amyloid plaques and neurofibrillary tangles. One hypothesized mechanism of disease, called the amyloid hypothesis, suggests that the causative agent is the hydrophobic peptide Aβ, which forms quaternary structures that, by an unclear mechanism, cause neuronal death. Aβ is a byproduct generated as the result of proteolytic processing of the amyloid precursor protein (APP) by proteases referred to as the β and γ secretases. The physiological role of this processing is unclear, though it may play a role in nervous system development.[6]

Numerous in vitro and in vivo studies have shown correlations between IDE, Aβ degradation, and Alzheimer’s disease. Mice engineered to lack both alleles of the IDE gene exhibit a 50% decrease in Aβ degradation, resulting in cerebral accumulation of Aβ.[7] Studies of genetically inherited forms of Alzheimer’s show reduction in both IDE expression[8] and catalytic activity[9] among affected individuals. Despite the evident role of IDE in disease, relatively little is known about its physiological functions. These may be diverse, as IDE has been localized to several locations, including the cytosol, peroxisomes, endosomes, proteasome complexes,[10] and the surface of cerebrovascular endothelial cells.[11]

Structure and function[edit]

Structural studies of IDE by Shen et al.[12] have provided insight into the functional mechanisms of the protease. Reminiscent of the previously determined structure of the bacterial protease pitrilysin, the IDE crystal structure reveals defined N and C terminal units that form a proteolytic chamber containing the zinc-binding active site. In addition, it appears that IDE can exist in two conformations: an open conformation, in which substrates can access the active site, and a closed state, in which the active site is contained within the chamber formed by the two concave domains. Targeted mutations that prevent the closed conformation result in a 40-fold increase in catalytic activity. Based upon this observation, it has been proposed that a possible therapeutic approach to Alzheimer’s might involve shifting the conformational preference of IDE to the open state, and thus increasing Aβ degradation, preventing aggregation, and, ideally, preventing the neuronal loss that leads to disease symptoms.

Regulation of extracellular amyloid β-protein[edit]

Reports of IDE localized to the cytosol and peroxisomes [13] have raised concerns regarding how the protease could degrade endogenous Aβ. Several studies have detected insulin-degrading activity in the conditioned media of cultured cells,[14][15] suggesting the permeability of the cell membrane and thus possible release of IDE from leaky cells. Qiu and colleagues revealed the presence of IDE in the extracellular media using antibodies to the enzyme. They also quantified levels of Aβ-degrading activity [16] using elution from column chromatography. Correlating the presence of IDE and Aβ-degrading activity in the conditioning medium confirmed that leaky membranes are responsible for extracellular IDE activity. However, other reports have indicated that it is released via exosomes.[17]

Potential role in the oligomerization of Aβ[edit]

Recent studies have observed that the oligomerization of synthetic Aβ was completely inhibited by the competitive IDE substrate, insulin.[16] These findings suggest that IDE activity is capable of joining of several Aβ fragments together. Qui et al. hypothesized that the Aβ fragments generated by IDE can either enhance oligomerization of the Aβ peptide or can oligomerize themselves. It is also entirely possible that IDE could mediate the degradation and oligomerization of Aβ by independent actions that have yet to be investigated.

Working mechanism[edit]

Despite the enormous attention dedicated to IDE the catalytic mechanism of this enzyme remain poorly understood. Studies present in literature explored many aspects concerning IDE,[18][19][20][21][22][23][24] but none of them deals with the mechanistic details of the proteolysis performed by this enzyme. It is understood that IDE cleaves insulin B chain as well as amyloid β at several sites.[12] Recently, Orazio and colleagues unveil how the cleavage of two peptides occurs by using the density functional theory at the active site of IDE (Scheme 1) to explore the catalytic mechanism of IDE; hence, they provide novel fundamental insights into the behavior of this enzyme.

Scheme 1

The steps involved in the whole process are collected in Scheme 2.[25]

Scheme 2

The first step of the mechanism includes a zinc-bound hydroxide group performing a nucleophilic attack on a carbon substrate that materializes into the intermediate INT1. In this species, we can note that the zinc-bound hydroxide is completely transferred on the carbonyl carbon of substrate as a consequence of the Zn2+−OH bond breaking. In TS2, the Glu111 residue rotates to assume the right disposition to form two hydrogen bonds with the amide nitrogen and the −OH group linked to the carbon atom of substrate, thus behaving as hydrogen donor and acceptor, simultaneously. The formation of the second cited bond favors the re-establishment of the Zn2+−OH bond broken previously at the INT1 level. The nucleophilic addition and the protonation of peptide amide nitrogen is a very fast process that is believed to occur as a single step in the catalytic process. The final species on the path is the product PROD.[25] As a consequence of transfer of the proton of Glu111 onto the amide nitrogen of substrate that occurred in TS3, the peptide N—C bond is broken.

A look at the whole reaction path indicates that the rate-determining step in this process is the nucleophilic addition that implies an expense of 17.2 kcal/mol. After this point, the catalytic event should proceed without particular obstacles.[26][27]

Model organisms[edit]

Model organisms have been used in the study of IDE function. A conditional knockout mouse line, called Idetm1a(EUCOMM)Wtsi[34][35] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[36][37][38]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[32][39] Twenty three tests were carried out on mutant mice and two significant abnormalities were observed. Homozygous mutant animals displayed abnormal drinking behavior, and males also had an increased NK cell number.[32]


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  14. ^ Roth RA, Mesirow ML, Cassell DJ, Yokono K, Baba S (Mar 1985). "Characterization of an insulin degrading enzyme from cultured human lymphocytes". Diabetes Research and Clinical Practice 1 (1): 31–39. doi:10.1016/S0168-8227(85)80026-7. PMID 3915257. 
  15. ^ Semple JW, Lang Y, Speck ER, Delovitch TL (Oct 1992). "Processing and presentation of insulin. III. Insulin degrading enzyme: a neutral metalloendoproteinase that is non-homologous to classical endoproteinases mediates the processing of insulin epitopes for helper T cells". International Immunology 4 (10): 1161–7. doi:10.1093/intimm/4.10.1161. PMID 1283335.  Check date values in: |year= / |date= mismatch (help)
  16. ^ a b Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB et al. (Dec 1998). "Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation". The Journal of Biological Chemistry 273 (49): 32730–8. doi:10.1074/jbc.273.49.32730. PMID 9830016. 
  17. ^ Tamboli IY, Barth E, Christian L, Siepmann M, Kumar S, Singh S et al. (Nov 2010). "Statins promote the degradation of extracellular amyloid {beta}-peptide by microglia via stimulation of exosome-associated insulin-degrading enzyme (IDE) secretion". The Journal of Biological Chemistry 285 (48): 37405–14. doi:10.1074/jbc.M110.149468. PMID 20876579. 
  18. ^ Song ES, Juliano MA, Juliano L, Fried MG, Wagner SL, Hersh LB (Dec 2004). "ATP effects on insulin-degrading enzyme are mediated primarily through its triphosphate moiety". The Journal of Biological Chemistry 279 (52): 54216–20. doi:10.1074/jbc.M411177200. PMID 15494400.  Check date values in: |year= / |date= mismatch (help)
  19. ^ Song ES, Daily A, Fried MG, Juliano MA, Juliano L, Hersh LB (May 2005). "Mutation of active site residues of insulin-degrading enzyme alters allosteric interactions". The Journal of Biological Chemistry 280 (18): 17701–6. doi:10.1074/jbc.M501896200. PMID 15749695. 
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External links[edit]