insulin-degrading enzyme

The gene IDE encodes protein Insulin-degrading enzyme. The human gene IDE has 28 exons and is located at chromosome band 10q23-q25.

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 {{Cite web | url=https://www.uniprot.org/uniprot/P14735 |title = IDE - Insulin-degrading enzyme - Homo sapiens (Human) - IDE gene & protein}} size and composed of 464 amino acids (missing 1-555 amino acids). The calculated theoretical pI of this protein isoform is 6.26.{{cite web|title=Uniprot: P14735 - IDE_HUMAN|url=https://www.uniprot.org/uniprot/P14735}}

Structural studies of IDE by Shen et al.{{cite journal | vauthors = Shen Y, Joachimiak A, Rosner MR, Tang WJ | title = Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism | journal = Nature | volume = 443 | issue = 7113 | pages = 870–4 | date = October 2006 | pmid = 17051221 | pmc = 3366509 | doi = 10.1038/nature05143 | bibcode = 2006Natur.443..870S }} 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.

IDE was first identified by its ability to degrade the B chain of the hormone insulin. This activity was observed over sixty years ago,{{cite journal | vauthors = Mirsky IA, Broh-Kahn RH | title = The inactivation of insulin by tissue extracts; the distribution and properties of insulin inactivating extracts | journal = Archives of Biochemistry | volume = 20 | issue = 1 | pages = 1–9 | date = January 1949 | pmid = 18104389 }} though the enzyme specifically responsible for B chain cleavage was identified more recently.{{cite journal | vauthors = Affholter JA, Fried VA, Roth RA | title = Human insulin-degrading enzyme shares structural and functional homologies with E. coli protease III | journal = Science | volume = 242 | issue = 4884 | pages = 1415–8 | date = December 1988 | pmid = 3059494 | doi = 10.1126/science.3059494 | bibcode = 1988Sci...242.1415A | doi-access = }} 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.{{cite journal | vauthors = Wang DS, Dickson DW, Malter JS | title = beta-Amyloid degradation and Alzheimer's disease | journal = Journal of Biomedicine & Biotechnology | volume = 2006 | issue = 3 | pages = 58406 | year = 2006 | pmid = 17047308 | pmc = 1559921 | doi = 10.1155/JBB/2006/58406 | doi-access = free }}

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.{{cite journal | vauthors = Kurochkin IV, Goto S | title = Alzheimer's beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme | journal = FEBS Letters | volume = 345 | issue = 1 | pages = 33–7 | date = May 1994 | pmid = 8194595 | doi = 10.1016/0014-5793(94)00387-4 | s2cid = 43917847 | doi-access = free }} 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.{{cite journal | vauthors = Kerr ML, Small DH | title = Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development | journal = Journal of Neuroscience Research | volume = 80 | issue = 2 | pages = 151–9 | date = April 2005 | pmid = 15672415 | doi = 10.1002/jnr.20408 | s2cid = 31985212 }}

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.{{cite journal | vauthors = Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S | display-authors = 6 | title = Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 7 | pages = 4162–7 | date = April 2003 | pmid = 12634421 | pmc = 153065 | doi = 10.1073/pnas.0230450100 | bibcode = 2003PNAS..100.4162F | doi-access = free }} Studies of genetically inherited forms of Alzheimer's show reduction in both IDE expression{{cite journal | vauthors = Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA, Schellenberg GD, Jin LW, Kovacina KS, Craft S | display-authors = 6 | title = Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele | journal = The American Journal of Pathology | volume = 162 | issue = 1 | pages = 313–9 | date = January 2003 | pmid = 12507914 | pmc = 1851126 | doi = 10.1016/s0002-9440(10)63822-9 | url = http://ajp.amjpathol.org/cgi/content/abstract/162/1/313 | access-date = 2008-02-10 | archive-url = https://archive.today/20030830123152/http://ajp.amjpathol.org/cgi/content/abstract/162/1/313 | archive-date = 2003-08-30 | url-status = dead }} and catalytic activity{{cite journal | vauthors = Kim M, Hersh LB, Leissring MA, Ingelsson M, Matsui T, Farris W, Lu A, Hyman BT, Selkoe DJ, Bertram L, Tanzi RE | display-authors = 6 | title = Decreased catalytic activity of the insulin-degrading enzyme in chromosome 10-linked Alzheimer disease families | journal = The Journal of Biological Chemistry | volume = 282 | issue = 11 | pages = 7825–32 | date = March 2007 | pmid = 17244626 | doi = 10.1074/jbc.M609168200 | doi-access = free}} 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,{{cite journal | vauthors = Duckworth WC, Bennett RG, Hamel FG | title = Insulin degradation: progress and potential | journal = Endocrine Reviews | volume = 19 | issue = 5 | pages = 608–24 | date = October 1998 | pmid = 9793760 | doi = 10.1210/edrv.19.5.0349 | doi-access = free }} and the surface of cerebrovascular endothelial cells.{{cite journal | vauthors = Lynch JA, George AM, Eisenhauer PB, Conn K, Gao W, Carreras I, Wells JM, McKee A, Ullman MD, Fine RE | display-authors = 6 | title = Insulin degrading enzyme is localized predominantly at the cell surface of polarized and unpolarized human cerebrovascular endothelial cell cultures | journal = Journal of Neuroscience Research | volume = 83 | issue = 7 | pages = 1262–70 | date = May 2006 | pmid = 16511862 | doi = 10.1002/jnr.20809 | s2cid = 23670388 }}

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.

Reports of IDE localized to the cytosol and peroxisomes{{cite journal | vauthors = Authier F, Bergeron JJ, Ou WJ, Rachubinski RA, Posner BI, Walton PA | title = Degradation of the cleaved leader peptide of thiolase by a peroxisomal proteinase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 9 | pages = 3859–63 | date = April 1995 | pmid = 7731996 | pmc = 42061 | doi = 10.1073/pnas.92.9.3859 | bibcode = 1995PNAS...92.3859A | doi-access = free }} 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,{{cite journal | vauthors = Roth RA, Mesirow ML, Cassell DJ, Yokono K, Baba S | title = Characterization of an insulin degrading enzyme from cultured human lymphocytes | journal = Diabetes Research and Clinical Practice | volume = 1 | issue = 1 | pages = 31–9 | date = March 1985 | pmid = 3915257 | doi = 10.1016/S0168-8227(85)80026-7 }}{{cite journal | vauthors = Semple JW, Lang Y, Speck ER, Delovitch TL | title = 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 | journal = International Immunology | volume = 4 | issue = 10 | pages = 1161–7 | date = October 1992 | pmid = 1283335 | doi = 10.1093/intimm/4.10.1161 }} 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{{cite journal | vauthors = Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB, Rosner MR, Safavi A, Hersh LB, Selkoe DJ | display-authors = 6 | title = Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation | journal = The Journal of Biological Chemistry | volume = 273 | issue = 49 | pages = 32730–8 | date = December 1998 | pmid = 9830016 | doi = 10.1074/jbc.273.49.32730 | doi-access = free }} 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.{{cite journal | vauthors = Tamboli IY, Barth E, Christian L, Siepmann M, Kumar S, Singh S, Tolksdorf K, Heneka MT, Lütjohann D, Wunderlich P, Walter J | display-authors = 6 | title = Statins promote the degradation of extracellular amyloid {beta}-peptide by microglia via stimulation of exosome-associated insulin-degrading enzyme (IDE) secretion | journal = The Journal of Biological Chemistry | volume = 285 | issue = 48 | pages = 37405–14 | date = November 2010 | pmid = 20876579 | pmc = 2988346 | doi = 10.1074/jbc.M110.149468 | doi-access = free }}

Recent studies have observed that the oligomerization of synthetic Aβ was completely inhibited by the competitive IDE substrate, insulin. 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.

The mechanism of the IDE enzyme remains poorly understood. The first step of one proposed mechanism{{cite journal | vauthors = Amata O, Marino T, Russo N, Toscano M | title = Human insulin-degrading enzyme working mechanism | journal = Journal of the American Chemical Society | volume = 131 | issue = 41 | pages = 14804–11 | date = October 2009 | pmid = 19785409 | doi = 10.1021/ja9037142 }} 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. 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.{{cite journal | vauthors = Leopoldini M, Russo N, Toscano M | title = Determination of the catalytic pathway of a manganese arginase enzyme through density functional investigation | journal = Chemistry: A European Journal | volume = 15 | issue = 32 | pages = 8026–36 | date = August 2009 | pmid = 19288480 | doi = 10.1002/chem.200802252 }}{{cite journal | vauthors = Hersh LB | title = The insulysin (insulin degrading enzyme) enigma | journal = Cellular and Molecular Life Sciences | volume = 63 | issue = 21 | pages = 2432–4 | date = November 2006 | pmid = 16952049 | doi = 10.1007/s00018-006-6238-9 | s2cid = 12536419 | pmc = 11136442 }}

{{Reflist|33em}}

• The MEROPS online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=M16.002 M16.002]
• {{MeshName|Insulin-Degrading+Enzyme}}

{{PDB_Gallery|geneid=3416}}

{{Metalloendopeptidases}}

Category:Zinc enzymes

Category:Genes mutated in mice