Insulin degrading enzyme

Insulin-degrading enzyme, also known as IDE, is a human gene.cite web | title = Entrez Gene: IDE insulin-degrading enzyme| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3416| accessdate = ]

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. Known alternatively as insulysin or insulin protease, IDE was first identified by its ability to degrade the B chain of the hormone insulin. This activity was observed over fifty years ago,cite journal | author = Mirsky IA, Broh-Kahn RH | title = The inactivation of insulin by tissue extracts. I. The distribution and properties of insulin inactivating extracts (insulinase) | journal = Arch Biochem. | volume = 20 | issue = | pages = 1–9 | year = 1949 | pmid = | doi = | issn = ] though the enzyme specifically responsible for B chain cleavage was identified more recently.cite journal | author = 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 | year = 1988 | pmid = 3059494 | doi = 10.1126/science.3059494 | issn = ] This discovery revealed considerable amino acid sequence homology 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 | author = Wang DS, Dickson DW, Malter JS | title = beta-Amyloid Degradation and Alzheimer's Disease | journal = J. Biomed. Biotechnol. | volume = 2006 | issue = 3 | pages = 58406 | year = 2006 | pmid = 17047308 | doi = 10.1155/JBB/2006/58406 | issn = ]

IDE and Alzheimer's Disease

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 | author = Kurochkin IV, Goto S | title = Alzheimer's beta-amyloid peptide specifically interacts with and is degraded by insulin degrading enzyme | journal = FEBS Lett. | volume = 345 | issue = 1 | pages = 33–7 | year = 1994 | pmid = 8194595 | doi = 10.1016/0014-5793(94)00387-4 | issn = ] 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 | author = 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 = J. Neurosci. Res. | volume = 80 | issue = 2 | pages = 151–9 | year = 2005 | pmid = 15672415 | doi = 10.1002/jnr.20408 | issn = ]

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 | author = Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S | title = Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 7 | pages = 4162–7 | year = 2003 | pmid = 12634421 | doi = 10.1073/pnas.0230450100 | issn = ] Studies of genetically inherited forms of Alzheimer’s show reduction in both IDE expressioncite journal | author = Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA, Schellenberg GD, Jin LW, Kovacina KS, Craft S | title = Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele | journal = Am. J. Pathol. | volume = 162 | issue = 1 | pages = 313–9 | year = 2003 | pmid = 12507914 | doi = | issn = | url = http://ajp.amjpathol.org/cgi/content/abstract/162/1/313 ] and catalytic activitycite journal | author = Kim M, Hersh LB, Leissring MA, Ingelsson M, Matsui T, Farris W, Lu A, Hyman BT, Selkoe DJ, Bertram L, Tanzi RE | title = Decreased catalytic activity of the insulin-degrading enzyme in chromosome 10-linked Alzheimer disease families | journal = J. Biol. Chem. | volume = 282 | issue = 11 | pages = 7825–32 | year = 2007 | pmid = 17244626 | doi = 10.1074/jbc.M609168200 | issn = ] 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 | author = Duckworth WC, Bennett RG, Hamel FG | title = Insulin degradation: progress and potential | journal = Endocr. Rev. | volume = 19 | issue = 5 | pages = 608–24 | year = 1998 | pmid = 9793760 | doi = 10.1210/er.19.5.608 | issn = ] and the surface of cerebrovascular endothelial cells.cite journal | author = Lynch JA, George AM, Eisenhauer PB, Conn K, Gao W, Carreras I, Wells JM, McKee A, Ullman MD, Fine RE | title = Insulin degrading enzyme is localized predominantly at the cell surface of polarized and unpolarized human cerebrovascular endothelial cell cultures | journal = J. Neurosci. Res. | volume = 83 | issue = 7 | pages = 1262–70 | year = 2006 | pmid = 16511862 | doi = 10.1002/jnr.20809 | issn = ]

IDE Structure and Function

Structural studies of IDE by Shen et al.cite journal | author = 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 | year = 2006 | pmid = 17051221 | doi = 10.1038/nature05143 | issn = ] 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.

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