Insulin-degrading enzyme
Insulin-degrading enzyme, also known as IDE, is an enzyme.[4]
Known alternatively as insulysin or insulin protease, IDE is a large zinc-binding
Structure
Gene
The gene IDE encodes protein Insulin-degrading enzyme. The human gene IDE has 28 exons and is located at chromosome band 10q23-q25.[4]
Protein
Due to alternative splicing, The human protein Insulin-degrading Enzyme has two isoforms. Isoform1 is ~118 kDa in size and composed of 1019 amino acids while the isoform 2 is ~54.2 kDa [7] size and composed of 464 amino acids (missing 1-555 amino acids). The calculated theoretical pI of this protein isoform is 6.26.[8] Structural studies of IDE by Shen et al.[9] 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 favor the open 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.[9]
Function
IDE was first identified by its ability to degrade the B chain of the hormone
Clinical Significance
Alzheimer's disease
Considerable interest in IDE has been stimulated due to the discovery that IDE can degrade
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.[15] Studies of genetically inherited forms of Alzheimer's show reduction in both IDE expression[16] and catalytic activity[17] 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,[18] and the surface of cerebrovascular endothelial cells.[19] Based upon the aforementioned observation in protein structure, 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
Reports of IDE localized to the cytosol and peroxisomes[20] 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,[21][22] 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[23] 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.[24]
Potential role in the oligomerization of Aβ
Recent studies have observed that the oligomerization of synthetic Aβ was completely inhibited by the competitive IDE substrate, insulin.[23] 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.
Mechanism
The mechanism of the IDE enzyme remains poorly understood. The first step of one proposed mechanism[25] 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. After this point, the catalytic event should proceed without particular obstacles.[26][27]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000119912 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b "Entrez Gene: IDE insulin-degrading enzyme".
- PMID 19913481.
- PMID 24931469.
- ^ "IDE - Insulin-degrading enzyme - Homo sapiens (Human) - IDE gene & protein".
- ^ "Uniprot: P14735 - IDE_HUMAN".
- ^ PMID 17051221.
- PMID 18104389.
- PMID 3059494.
- PMID 17047308.
- S2CID 43917847.
- S2CID 31985212.
- PMID 12634421.
- PMID 12507914. Archived from the originalon 2003-08-30. Retrieved 2008-02-10.
- PMID 17244626.
- PMID 9793760.
- S2CID 23670388.
- PMID 7731996.
- PMID 3915257.
- PMID 1283335.
- ^ PMID 9830016.
- PMID 20876579.
- ^ PMID 19785409.
- PMID 19288480.
- S2CID 12536419.
External links
- The MEROPS online database for peptidases and their inhibitors: M16.002
- Insulin-Degrading+Enzyme at the U.S. National Library of Medicine Medical Subject Headings (MeSH)