insulysin

Summary

Summary: An enzyme the catalyzes the degradation of insulin, glucagon and other polypeptides. It is inhibited by bacitracin, chelating agents EDTA and 1,10-phenanthroline, and by thiol-blocking reagents such as N-ethylmaleimide, but not phosphoramidon. (Eur J Biochem 1994;223:1-5) EC 3.4.24.56.

Top Publications

  1. Kim M, Hersh L, Leissring M, Ingelsson M, Matsui T, Farris W, et al. Decreased catalytic activity of the insulin-degrading enzyme in chromosome 10-linked Alzheimer disease families. J Biol Chem. 2007;282:7825-32 pubmed
  2. Neant Fery M, Garcia Ordonez R, Logan T, Selkoe D, Li L, Reinstatler L, et al. Molecular basis for the thiol sensitivity of insulin-degrading enzyme. Proc Natl Acad Sci U S A. 2008;105:9582-7 pubmed publisher
    ..Moreover, this work uncovers key details about the mechanistic basis of the unusual substrate selectivity of IDE that may aid the development of pharmacological agents or IDE mutants with therapeutic value. ..
  3. Messier C, Teutenberg K. The role of insulin, insulin growth factor, and insulin-degrading enzyme in brain aging and Alzheimer's disease. Neural Plast. 2005;12:311-28 pubmed
    ..Such a decrease involves the insulin receptor cascade and can also increase amyloid toxicity. Insulin and IGF-I may modulate brain levels of insulin degrading enzyme, which would also lead to an accumulation of Abeta amyloid. ..
  4. Shii K, Roth R. Inhibition of insulin degradation by hepatoma cells after microinjection of monoclonal antibodies to a specific cytosolic protease. Proc Natl Acad Sci U S A. 1986;83:4147-51 pubmed
    ..Thus, these results support a role for this enzyme in insulin degradation in the intact cell. ..
  5. Wang S, Wang R, Chen L, Bennett D, Dickson D, Wang D. Expression and functional profiling of neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme in prospectively studied elderly and Alzheimer's brain. J Neurochem. 2010;115:47-57 pubmed publisher
    ..In contrast, neither IDE nor ECE-1 correlated with A? or clinical diagnosis. These findings provide additional support for NEP as the major protease involved in A? degradation and suggest its possible therapeutic targeting in AD. ..
  6. Bulloj A, Leal M, Xu H, Castano E, Morelli L. Insulin-degrading enzyme sorting in exosomes: a secretory pathway for a key brain amyloid-beta degrading protease. J Alzheimers Dis. 2010;19:79-95 pubmed publisher
    ..Our results reinforce the relevance of functional IDE in the catabolism of extracellular Abeta. ..
  7. Manolopoulou M, Guo Q, Malito E, Schilling A, Tang W. Molecular basis of catalytic chamber-assisted unfolding and cleavage of human insulin by human insulin-degrading enzyme. J Biol Chem. 2009;284:14177-88 pubmed publisher
  8. Ali M, Li Q, Fischer E, Cohen J. The insulin degrading enzyme binding domain of varicella-zoster virus (VZV) glycoprotein E is important for cell-to-cell spread and VZV infectivity, while a glycoprotein I binding domain is essential for infection. Virology. 2009;386:270-9 pubmed publisher
    ..We conclude that the IDE binding domain is important for efficient cell-to-cell spread and infectivity of cell-free virus. ..
  9. Zuo X, Jia J. Promoter polymorphisms which modulate insulin degrading enzyme expression may increase susceptibility to Alzheimer's disease. Brain Res. 2009;1249:1-8 pubmed publisher
    ..The present study provides evidence that IDE promoter polymorphisms that significantly decrease IDE expression levels are associated with development of SAD. ..

More Information

Publications62

  1. Llovera R, de Tullio M, Alonso L, Leissring M, Kaufman S, Roher A, et al. The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid beta peptide: implications for Alzheimer disease pathogenesis. J Biol Chem. 2008;283:17039-48 pubmed publisher
    ..Taken together, these results are suggestive of an unprecedented mechanism of conformation-dependent substrate binding that may perturb Abeta clearance, insulin turnover, and promote AD pathogenesis. ..
  2. Farris W, Leissring M, Hemming M, Chang A, Selkoe D. Alternative splicing of human insulin-degrading enzyme yields a novel isoform with a decreased ability to degrade insulin and amyloid beta-protein. Biochemistry. 2005;44:6513-25 pubmed
    ..Our results identify a novel, catalytically inefficient form of IDE expressed in brain and non-neural tissues and recommend novel regions of the IDE gene in which to search for mutations predisposing patients to AD and DM2. ..
  3. Udrisar D, Wanderley M, Porto R, Cardoso C, Barbosa M, Camberos M, et al. Androgen- and estrogen-dependent regulation of insulin-degrading enzyme in subcellular fractions of rat prostate and uterus. Exp Biol Med (Maywood). 2005;230:479-86 pubmed
  4. Mueller J, Riemenschneider M, Schoepfer Wendels A, Gohlke H, Konta L, Friedrich P, et al. Weak independent association signals between IDE polymorphisms, Alzheimer's disease and cognitive measures. Neurobiol Aging. 2007;28:727-34 pubmed
    ..A subgroup analysis indicated more prominent associations with AD in younger, and with MMSE in older patients. There may be two independent effects mediated by IDE variants, risk for AD and modification of disease progression. ..
  5. Gu H, Efendic S, Nordman S, Ostenson C, Brismar K, Brookes A, et al. Quantitative trait loci near the insulin-degrading enzyme (IDE) gene contribute to variation in plasma insulin levels. Diabetes. 2004;53:2137-42 pubmed
  6. Im H, Manolopoulou M, Malito E, Shen Y, Zhao J, Neant Fery M, et al. Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE. J Biol Chem. 2007;282:25453-63 pubmed
    ..Together, our results highlight the importance of the closed conformation for regulating the activity of IDE and provide new molecular details that will facilitate the development of activators and inhibitors of IDE. ..
  7. Leissring M, Farris W, Chang A, Walsh D, Wu X, Sun X, et al. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003;40:1087-93 pubmed
    ..Our findings demonstrate that chronic upregulation of Abeta-degrading proteases represents an efficacious therapeutic approach to combating Alzheimer-type pathology in vivo. ..
  8. Yfanti C, Mengele K, Gkazepis A, Weirich G, Giersig C, Kuo W, et al. Expression of metalloprotease insulin-degrading enzyme insulysin in normal and malignant human tissues. Int J Mol Med. 2008;22:421-31 pubmed
    Insulin-degrading enzyme (IDE, insulysin, insulinase; EC 3.4.22.11), a thiol metalloendopeptidase, is involved in intracellular degradation of insulin, thereby inhibiting its translocation and accumulation to the nucleus...
  9. Edland S, Wavrant De Vriesé F, Compton D, Smith G, Ivnik R, Boeve B, et al. Insulin degrading enzyme (IDE) genetic variants and risk of Alzheimer's disease: evidence of effect modification by apolipoprotein E (APOE). Neurosci Lett. 2003;345:21-4 pubmed
    ..Confirmation of this finding with a larger sample of cases and controls is warranted. ..
  10. Mukherjee A, Song E, Kihiko Ehmann M, Goodman J, Pyrek J, Estus S, et al. Insulysin hydrolyzes amyloid beta peptides to products that are neither neurotoxic nor deposit on amyloid plaques. J Neurosci. 2000;20:8745-9 pubmed
    b>Insulysin (EC. 3.4.22.11) has been implicated in the clearance of beta amyloid peptides through hydrolytic cleavage. To further study the action of insulysin on Abeta peptides recombinant rat insulysin was used...
  11. Affholter J, Hsieh C, Francke U, Roth R. Insulin-degrading enzyme: stable expression of the human complementary DNA, characterization of its protein product, and chromosomal mapping of the human and mouse genes. Mol Endocrinol. 1990;4:1125-35 pubmed
    ..In addition, expression of various site-directed mutants of IDE will aid in identifying the residues of IDE and protease III that are essential to the activity of this unique family of proteinases. ..
  12. Vepsäläinen S, Hiltunen M, Helisalmi S, Wang J, van Groen T, Tanila H, et al. Increased expression of Abeta degrading enzyme IDE in the cortex of transgenic mice with Alzheimer's disease-like neuropathology. Neurosci Lett. 2008;438:216-20 pubmed publisher
    ..mRNA and protein levels of NEP were also nominally up-regulated in Tg mice compared to controls. These data may reflect up-regulation of the IDE and possibly of NEP expression in response to the Abeta accumulation. ..
  13. Shen Y, Joachimiak A, Rosner M, Tang W. Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism. Nature. 2006;443:870-4 pubmed
    ..The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid-beta and blood sugar concentrations. ..
  14. Björk B, Katzov H, Kehoe P, Fratiglioni L, Winblad B, Prince J, et al. Positive association between risk for late-onset Alzheimer disease and genetic variation in IDE. Neurobiol Aging. 2007;28:1374-80 pubmed
    ..These findings indicate a role for IDE in AD, and provide models that may improve chances of further independent replication. ..
  15. Cabrol C, Huzarska M, Dinolfo C, Rodriguez M, Reinstatler L, Ni J, et al. Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening. PLoS ONE. 2009;4:e5274 pubmed publisher
    ..Several larger lessons abstracted from this screen will help inform the design of future screening campaigns and facilitate the eventual development of IDE activators with therapeutic utility. ..
  16. Cordes C, Bennett R, Siford G, Hamel F. Redox regulation of insulin degradation by insulin-degrading enzyme. PLoS ONE. 2011;6:e18138 pubmed publisher
  17. Kim S, Lapham A, Freedman C, Reed T, Schmidt W. Yeast as a tractable genetic system for functional studies of the insulin-degrading enzyme. J Biol Chem. 2005;280:27481-90 pubmed
  18. Espinosa R, Lemons R, Perlman R, Kuo W, Rosner M, Le Beau M. Localization of the gene encoding insulin-degrading enzyme to human chromosome 10, bands q23----q25. Cytogenet Cell Genet. 1991;57:184-6 pubmed
    ..The murine Ide gene was previously mapped to Chromosome 19; together, these results suggest that the IDE gene is a member of a conserved syntenic group on human chromosome 10, bands q23----q25 and mouse Chromosome 19. ..
  19. Ding L, Becker A, Suzuki A, Roth R. Comparison of the enzymatic and biochemical properties of human insulin-degrading enzyme and Escherichia coli protease III. J Biol Chem. 1992;267:2414-20 pubmed
    ..Finally, sucrose gradient centrifugation and cross-linking studies both in vitro and in vivo indicated that active human enzyme partially existed as a homo- or heterodimer, whereas the bacterial enzyme was active as a monomer. ..
  20. Seta K, Roth R. Overexpression of insulin degrading enzyme: cellular localization and effects on insulin signaling. Biochem Biophys Res Commun. 1997;231:167-71 pubmed
    To investigate the role of insulin degrading enzyme (insulysin, EC 3.4.24...
  21. Zhao L, Teter B, Morihara T, Lim G, Ambegaokar S, Ubeda O, et al. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer's disease intervention. J Neurosci. 2004;24:11120-6 pubmed
    ..These in vitro and in vivo analyses validate the use of enhanced CNS insulin signaling as a potential strategy for AD intervention to correct the IDE defects occurring in AD. ..
  22. Qiu W, Walsh D, Ye Z, Vekrellis K, Zhang J, Podlisny M, et al. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem. 1998;273:32730-8 pubmed
    ..We conclude that a principal protease capable of down-regulating the levels of secreted Abeta extracellularly is IDE. ..
  23. Morelli L, Llovera R, Mathov I, Lue L, Frangione B, Ghiso J, et al. Insulin-degrading enzyme in brain microvessels: proteolysis of amyloid {beta} vasculotropic variants and reduced activity in cerebral amyloid angiopathy. J Biol Chem. 2004;279:56004-13 pubmed
    ..Moreover they raise the possibility that IDE inhibition or inactivation is a pathogenic mechanism that may open novel strategies for the treatment of cerebrovascular Abeta amyloidoses. ..
  24. Song E, Mukherjee A, Juliano M, Pyrek J, Goodman J, Juliano L, et al. Analysis of the subsite specificity of rat insulysin using fluorogenic peptide substrates. J Biol Chem. 2001;276:1152-5 pubmed
    Recombinant rat insulysin was shown to cleave the internally quenched fluorogenic peptide 2-aminobenzyl-GGFLRKVGQ-ethylenediamine-2,4-dinitrophenol at the R-K bond, exhibiting a K(m) of 13 microm and a V(max) of 2...
  25. Leissring M, Farris W, Wu X, Christodoulou D, Haigis M, Guarente L, et al. Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria. Biochem J. 2004;383:439-46 pubmed
    ..Our results identify new mechanisms regulating the subcellular localization of IDE and suggest previously unrecognized roles for IDE within mitochondria. ..
  26. Nowotny P, Hinrichs A, Smemo S, Kauwe J, Maxwell T, Holmans P, et al. Association studies between risk for late-onset Alzheimer's disease and variants in insulin degrading enzyme. Am J Med Genet B Neuropsychiatr Genet. 2005;136B:62-8 pubmed
    ..Although our results are not universally negative, we were unable to replicate the results of previous studies and conclude that common variants or haplotypes of these variants in IDE are not major risk factors for LOAD. ..
  27. Noinaj N, Bhasin S, Song E, Scoggin K, Juliano M, Juliano L, et al. Identification of the allosteric regulatory site of insulysin. PLoS ONE. 2011;6:e20864 pubmed publisher
    ..Our findings indicate that a region remote from the active site mediates allosteric activation of insulysin by peptides...
  28. Li Q, Ali M, Wang K, Sayre D, Hamel F, Fischer E, et al. Insulin degrading enzyme induces a conformational change in varicella-zoster virus gE, and enhances virus infectivity and stability. PLoS ONE. 2010;5:e11327 pubmed publisher
    ..The ability of rIDE to enhance infectivity of cell-free VZV over a wide range of incubation times and temperatures suggests that rIDE may be useful for increasing the stability of varicella or zoster vaccines. ..
  29. Leissring M, Malito E, Hedouin S, Reinstatler L, Sahara T, Abdul Hay S, et al. Designed inhibitors of insulin-degrading enzyme regulate the catabolism and activity of insulin. PLoS ONE. 2010;5:e10504 pubmed publisher
  30. Fernandez Gamba A, Leal M, Morelli L, Castano E. Insulin-degrading enzyme: structure-function relationship and its possible roles in health and disease. Curr Pharm Des. 2009;15:3644-55 pubmed
    Insulin-degrading enzyme (IDE) or insulysin is a highly conserved Zn(2+) -dependent endopeptidase with an "inverted" HxxEH motif...
  31. Vepsalainen S, Helisalmi S, Mannermaa A, Pirttila T, Soininen H, Hiltunen M. Combined risk effects of IDE and NEP gene variants on Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009;80:1268-70 pubmed publisher
    ..Although no significant interaction was observed between NEP and IDE genes, these data suggest that NEP and IDE exhibit an additive risk effect in AD. ..
  32. Sakai A, Ujike H, Nakata K, Takehisa Y, Imamura T, Uchida N, et al. No association between the insulin degrading enzyme gene and Alzheimer's disease in a Japanese population. Am J Med Genet B Neuropsychiatr Genet. 2004;125B:87-91 pubmed
    ..The present study indicates that the IDE gene polymorphisms do not confer susceptibility to early- or late-onset AD at least in a Japanese population. ..
  33. Ertekin Taner N, Allen M, Fadale D, Scanlin L, Younkin L, Petersen R, et al. Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease. Hum Mutat. 2004;23:334-42 pubmed
    ..007) in our family series. These results provide strong evidence for pathogenic variant(s) in the 276-kb region harboring IDE that influence intermediate AD phenotypes and risk for AD. ..
  34. Song E, Hersh L. Insulysin: an allosteric enzyme as a target for Alzheimer's disease. J Mol Neurosci. 2005;25:201-6 pubmed
    That the zinc metalloendopeptidase insulysin (insulin-degrading enzyme IDE) is a major b-amyloid (A(beta)) peptide-degrading enzyme in vivo is shown by the higher A(beta) peptide levels in the brain of an insulysin-deficient mouse...
  35. Morelli L, Llovera R, Alonso L, Frangione B, de Prat Gay G, Ghiso J, et al. Insulin-degrading enzyme degrades amyloid peptides associated with British and Danish familial dementia. Biochem Biophys Res Commun. 2005;332:808-16 pubmed
    ..Specific sites of cleavage within the C-terminal pathogenic extensions raise the possibility that proteolysis of monomeric soluble precursors by IDE may delay ABri and ADan aggregation in vivo. ..
  36. Ozturk A, DeKosky S, Kamboh M. Lack of association of 5 SNPs in the vicinity of the insulin-degrading enzyme (IDE) gene with late-onset Alzheimer's disease. Neurosci Lett. 2006;406:265-9 pubmed
    ..None of the SNPs examined in this fairly large case-control sample revealed significant association with AD risk. These SNPs also showed no significant association with AD quantitative traits. ..
  37. Caccamo A, Oddo S, Sugarman M, Akbari Y, LaFerla F. Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders. Neurobiol Aging. 2005;26:645-54 pubmed
    ..These findings suggest that age- and region-specific changes in the proteolytic clearance of Abeta represent a critical pathogenic mechanism that may account for the susceptibility of particular brain or muscle regions in AD and IBM. ..
  38. Vepsäläinen S, Parkinson M, Helisalmi S, Mannermaa A, Soininen H, Tanzi R, et al. Insulin-degrading enzyme is genetically associated with Alzheimer's disease in the Finnish population. J Med Genet. 2007;44:606-8 pubmed
    ..Single locus findings were corroborated by the results obtained from haplotype analyses. This suggests that genetic alterations in or near the IDE gene may increase the risk for developing AD. ..
  39. Song E, Cady C, Fried M, Hersh L. Proteolytic fragments of insulysin (IDE) retain substrate binding but lose allosteric regulation. Biochemistry. 2006;45:15085-91 pubmed
    Treatment of an N-terminal-containing His6-tagged insulysin (His6-IDE) with proteinase K led to the initial cleavage of the His tag and linker region...
  40. Prince J, Feuk L, Gu H, Johansson B, Gatz M, Blennow K, et al. Genetic variation in a haplotype block spanning IDE influences Alzheimer disease. Hum Mutat. 2003;22:363-71 pubmed
    ..These results provide substantial evidence that genetic variation within or extremely close to IDE impacts both disease risk and traits related to the severity of AD. ..
  41. Bennett R, Hamel F, Duckworth W. An insulin-degrading enzyme inhibitor decreases amylin degradation, increases amylin-induced cytotoxicity, and increases amyloid formation in insulinoma cell cultures. Diabetes. 2003;52:2315-20 pubmed
    ..IDE inhibition by bacitracin impaired amylin degradation, increased amyloid formation, and increased amylin-induced cytotoxicity, suggesting a role for IDE in amylin clearance and the prevention of amylin aggregation. ..
  42. Dorfman V, Pasquini L, Riudavets M, López Costa J, Villegas A, Troncoso J, et al. Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer's disease. Neurobiol Aging. 2010;31:1743-57 pubmed publisher
  43. Blomqvist M, Chalmers K, Andreasen N, Bogdanovic N, Wilcock G, Cairns N, et al. Sequence variants of IDE are associated with the extent of beta-amyloid deposition in the Alzheimer's disease brain. Neurobiol Aging. 2005;26:795-802 pubmed
    ..Results indicate that alleles of IDE contribute to variability in A beta deposition in the AD brain and suggest that this relationship may have relevance for the degree of cognitive dysfunction in AD patients. ..
  44. Zhao Z, Xiang Z, Haroutunian V, Buxbaum J, Stetka B, Pasinetti G. Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease. Neurobiol Aging. 2007;28:824-30 pubmed
  45. Song E, Juliano M, Juliano L, Fried M, Wagner S, Hersh L. ATP effects on insulin-degrading enzyme are mediated primarily through its triphosphate moiety. J Biol Chem. 2004;279:54216-20 pubmed
    It has been reported previously that ATP inhibits the insulysin reaction (Camberos, M. C., Perez, A. A., Udrisar, D. P., Wanderley, M. I., and Cresto, J. C. (2001) Exp. Biol. Med. 226, 334-341)...
  46. Noinaj N, Song E, Bhasin S, Alper B, Schmidt W, Hersh L, et al. Anion activation site of insulin-degrading enzyme. J Biol Chem. 2012;287:48-57 pubmed publisher
    Insulin-degrading enzyme (IDE) (insulysin) is a zinc metallopeptidase that metabolizes several bioactive peptides, including insulin and the amyloid ? peptide...
  47. Edland S. Insulin-degrading enzyme, apolipoprotein E, and Alzheimer's disease. J Mol Neurosci. 2004;23:213-7 pubmed
    ..Further investigation of the relationship between APOE genotype, IDE genetic variants, and the expression and activity of hippocampal IDE is warranted. ..
  48. Ralat L, Guo Q, Ren M, Funke T, Dickey D, Potter L, et al. Insulin-degrading enzyme modulates the natriuretic peptide-mediated signaling response. J Biol Chem. 2011;286:4670-9 pubmed publisher
    ..Thus, the evolutionarily conserved IDE may play a key role in modulating and reshaping the strength and duration of NP-mediated signaling. ..
  49. Hersh L. The insulysin (insulin degrading enzyme) enigma. Cell Mol Life Sci. 2006;63:2432-4 pubmed
  50. Tanzi R, Moir R, Wagner S. Clearance of Alzheimer's Abeta peptide: the many roads to perdition. Neuron. 2004;43:605-8 pubmed
    ..This minireview will summarize pathways involved in the removal of cerebral Abeta, including enzymatic degradation and receptor-mediated efflux out of the brain. ..
  51. Camberos M, Perez A, Udrisar D, Wanderley M, Cresto J. ATP inhibits insulin-degrading enzyme activity. Exp Biol Med (Maywood). 2001;226:334-41 pubmed
    ..51 and 2.44). The binding constant for allosteric inhibition was KiT = 1.5 x 10(-7) M showing a decrease of enzyme affinity induced by ATP. We conclude that ATP has an inhibitory effect on the insulin degradation activity of the enzyme. ..
  52. Boussaha M, Hannequin D, Verpillat P, Brice A, Frebourg T, Campion D. Polymorphisms of insulin degrading enzyme gene are not associated with Alzheimer's disease. Neurosci Lett. 2002;329:121-3 pubmed
    ..Two intronic single nucleotide polymorphisms (SNPs) were genotyped in a case-control study including 388 French individuals. No association between these SNPs and AD was detected. ..
  53. Groves C, Wiltshire S, Smedley D, Owen K, Frayling T, Walker M, et al. Association and haplotype analysis of the insulin-degrading enzyme (IDE) gene, a strong positional and biological candidate for type 2 diabetes susceptibility. Diabetes. 2003;52:1300-5 pubmed