IDE

General Information

Full gene name:insulin-degrading enzyme Entrez Gene ID:3416 Location:10q23-q25 Synonyms:INSULYSIN Type:protein-coding

User SNPs

SNPs given by the user that are near or inside this gene:

SNP	Distance (bp)	Direction
rs1111875	129030	upstream

NCBI Summary

This gene encodes a zinc metallopeptidase that degrades intracellular insulin, and thereby terminates insulins activity, as well as participating in intercellular peptide signalling by degrading diverse peptides such as glucagon, amylin, bradykinin, and kallidin. The preferential affinity of this enzyme for insulin results in insulin-mediated inhibition of the degradation of other peptides such as beta-amyloid. Deficiencies in this protein’s function are associated with Alzheimer’s disease and type 2 diabetes mellitus but mutations in this gene have not been shown to be causitive for these diseases. This protein localizes primarily to the cytoplasm but in some cell types localizes to the extracellular space, cell membrane, peroxisome, and mitochondrion. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but have not been experimentally verified.[provided by RefSeq, Sep 2009]

OMIM

OMIM ID:`OMIM ID 146680 `_

NCBI Phenotypes

• Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.
• NHGRI GWA Catalog

Gene Ontology

• glycoprotein binding
• protein homodimerization activity
• cytosol
• cytoplasm
• zinc ion binding
• peroxisomal matrix
• mitochondrion
• cell surface
• proteolysis
• ubiquitin homeostasis
• hormone catabolic process
• extracellular space
• protein binding
• metalloendopeptidase activity
• ATP binding
• proteolysis involved in cellular protein catabolic process
• beta-amyloid binding
• ATPase activity
• plasma membrane
• peptide binding
• positive regulation of protein oligomerization
• peroxisome
• bradykinin catabolic process
• protein heterooligomerization
• nucleus
• determination of adult lifespan
• ubiquitin binding
• negative regulation of proteolysis
• receptor binding
• protein homotetramerization
• beta-amyloid metabolic process
• cytosolic proteasome complex
• beta-endorphin binding
• insulin receptor signaling pathway
• protein homooligomerization
• interspecies interaction between organisms
• insulin binding

KEGG Pathways

• Alzheimer’s disease

GeneRIFs

• Allele and genotype frequency distribution for three markers of insulinase differed only in the sample of females between T2D patients and control , while only in case of rs7078413 SNP genotype frequencies varied significantly in the total population [PMID 19239107]
• IDE knockout mice show significantly elevated levels of blood insulin, brain beta-amyloid, and brain amyloid-precursor protein intracellular domain, providing key in vivo evidence that IDE degrades both extracellular and intracellular peptides. [PMID 12634421]
• dimers of insulin-degrading enzyme reveal a cis activation mechanism [PMID 21343292]
• analysis of over 2,400 samples provides no compelling evidence that variation in IDE contributes to diabetes susceptibility in humans [PMID 12716770]
• Affinity Capture-MS [PMID 21903422]
• IDE gene polymorphisms do not confer susceptibility to early- or late-onset AD at least in a Japanese population. [PMID 14755451]
• structural basis of how the high dipole moment of substrates complements the charge distribution of the IDE catalytic chamber for the substrate selectivity [PMID 19896952]
• Observational study of gene-disease association, gene-environment interaction, and pharmacogenomic / toxicogenomic. (HuGE Navigator) [PMID 20628086]
• Polymorphisms in the IDE-KIF11-HHEX gene locus are associated with susceptibility to type 2 diabetes across the boundary of race. [PMID 17971426]
• Polymorphism in this enzyme are associated with NIDDM in men. [PMID 12765971]
• The association of low birth weight and type 2 diabetes risk alleles of the HHEX-IDE locus is confirmed in children of mothers with type 1 diabetes. [PMID 19622614]
• Affinity Capture-MS [PMID 20360068]
• HHEX, IDE and SLC30A8 showed strongest tissue-specific mRNA expression bias and are associated with increased risk of type 2 diabete. [PMID 20703447]
• the catalytic mechanisms for the hydrolysis of the three different peptide bonds of Alzheimer amyloid beta (Abeta) peptide by insulin-degrading enzyme (IDE) [PMID 20033747]
• First demonstration of IDE in normal and neoplastic human mammary tissues, providing an experimental starting point towards exploring a potential role of IDE in the control of tumor progression. [PMID 17143514]
• IDE protein was expressed in all the tissues assessed and all the tumor cell lines except for Raji and HL-60. [PMID 18783335]
• Insulin-degrading enzyme rapidly removes the beta-amyloid precursor protein intracellular domain (AICD). [PMID 11809755]
• the catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid beta peptide [PMID 18411275]
• genomic region in the proximity of IDE that may contribute to Alzheimer and Parkinson disease in a similar manner. [PMID 15088150]
• IDE cleaves ubiquitin in a biphasic manner [PMID 21185309]
• Reconstituted Complex [PMID 21800051]
• there is an association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes in the Chinese population [PMID 19862325]
• To test the hypothesis that insulin might upregulate IDE via a negative feedback control mechanism, we used both in vitro and in vivo strategies to determine the impact of insulin signaling on IDE levels. [PMID 15590928]
• the evolutionarily conserved IDE may play a key role in modulating and reshaping the strength and duration of NP-mediated signaling. [PMID 21098034]
• a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Abeta40 and decreased LOAD susceptibility [PMID 20098734]
• IDE is targeted to mitochondria via alternative initiation of translation. [PMID 15285718]
• 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. [PMID 15718037]
• this study more generally suggests an interplay between RB and IDE within the proteasome that may have important growth-regulatory consequences. [PMID 20362553]
• The upstream polymorphism IDE2 was found to influence AD risk and to trigger the Abeta42 plasma level, whereas the downstream polymorphism IDE7 modified the T2DM risk; no associations were found for the intronic variant IDE9. [PMID 22107728]
• Biochemical characteristics of insulin degradation in wound fluid were consistent with characteristics of insulin-degrading enzyme. Reduction in insulin-degrading activity in wound fluid is potential therapeutic target. [PMID 14764804]
• The C allele of single-nucleotide polymorphism IDE2 associated with Alzheimer disease. There may be a possible synergic interaction between IDE & APOE epsilon4. [PMID 15277615]
• Reconstituted Complex [PMID 1733942]
• Reconstituted Complex [PMID 1733942]
• BRI2 protein regulates beta-amyloid degradation by increasing levels of secreted insulin-degrading enzyme (IDE). [PMID 21873424]
• This study systematically characterizes IDE mRNAs, identifies a novel, catalytically inefficient splice form and compares its subcellular distribution, kinetic properties and ability to degrade amyloid beta protein to the known isoform. [PMID 15850385]
• present study provides evidence that IDE promoter polymorphisms that significantly decrease IDE expression levels are associated with development of sporadic lzheimer disease [PMID 18996360]
• possible mechanism by which the insulin-degrading enzyme (IDE) zinc-binding protease carries out its catalytic function toward two peptides of different length [PMID 19785409]
• kinetics and regulation of human IDE with short peptides [PMID 18986166]
• Study verified associations of two IDE polymorphisms (rs1887922 and rs2149632) with type 2 diabetes risk in two independent German cohorts and evaluated in detail the association of common variants with insulin metabolism and glycemic traits. [PMID 19809796]
• Here we show that a combination of risk genotypes for NEP and IDE genes leads to a higher susceptibility to AD. [PMID 19864659]
• IDE protease binds to the 73-kDa gE precursor and that this event occurs in the cytosol but not as a receptor/ligand interaction. [PMID 19864391]
• Meta-analysis of gene-disease association. (HuGE Navigator) [PMID 17913278]
• Variations in IDE may contribute to diabetes susceptibility in the Korean population. [PMID 17913278]
• Cys-178 has a role in preventing inactivation and oligomerization of human insulin-degrading enzyme by oxidation and nitrosylation [PMID 19808678]
• Insulin degrading enzyme is linked with aggregated Abeta40 isoform while neprilysin negatively correlates with amyloid angiopathy. [PMID 19019493]
• IDE-N is the catalytic domain and IDE-C facilitates substrate recognition as well as plays a key role in the oligomerization of IDE. [PMID 16574064]
• Observational study of gene-disease association. (HuGE Navigator) [PMID 20877624]
• Affinity Capture-MS; Affinity Capture-Western [PMID 17715127]
• Observational study of gene-disease association and gene-environment interaction. (HuGE Navigator) [PMID 20384434]
• In comparison to Abeta40, Abeta42 is more flexible and interacts through a smaller number (17-22) of hydrogen bonds in the catalytic chamber of IDE. [PMID 20380468]
• Data suggest that HEs-1/Hey-1 transcriptional modulation of insulin degrading enzyme may impact amyloid beta metabolism by providing a functional link between Notch signaling and the amyloidogenic pathway. [PMID 22036964]
• Phosphorylation of amyloid-beta peptide at serine 8 attenuates its clearance via insulin-degrading and angiotensin-converting enzymes. [PMID 22267728]
• produce tumor antigenic peptides presented by MHC class I molecules for cytotoxic T lymphocyte recognition [PMID 20364150]
• Meta-analysis and HuGE review of gene-disease association. (HuGE Navigator) [PMID 19602701]
• Meta-analysis and genome-wide association study of gene-disease association. (HuGE Navigator) [PMID 17463249]
• when intracellular long-chain fatty acid concentrations are elevated, they may act directly on insulin-degrading enzyme to decrease insulin metabolism and alter insulin action in intact cells and this mechanism may contribute to insulin resistance [PMID 12746301]
• Beta-amyloid degradation is largely the result of the action of IDE, as it is blocked by insulin in the medium, a competitive substrate of IDE. IDE could be an important therapeutic target to decrease the amount of Abeta in the cerebrovasculature. [PMID 16511862]
• This study provides strong evidence for pathogenic variant(s) in the 276-kb region harboring IDE that influence intermediate Alzheimer’s disease phenotypes and risk for AD. [PMID 15024728]
• Different reconstructed insulin-degrading enzyme haplotypes were associated with Alzheimers disease and lower cognitive ability. [PMID 16675064]
• protein structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta peptide (1-40), amylin and glucagon) [PMID 17051221]
• Significant differences were found in the response to induced ketosis among non-carriers of putative gain-of-function polymorphisms in rs1143627 and rs16944 in the IL-1beta gene and among variants of the polymorphism rs2251101 in the insulysin gene. [PMID 21992747]
• The single nucleotide polymorphism rs2209972 in the human IDE gene is associated with metabolic features of polycystic ovary syndrome women in a Chinese population. [PMID 17953957]
• SNPs rs4646953 & rs4646955 are associated with Alzheimer disease in Finnish patients, conferring an approximately two-fold increased risk. [PMID 17496198]
• Observational study of gene-disease association and gene-gene interaction. (HuGE Navigator) [PMID 20880607]
• IDE gene promoter region variants are associated with AD in subjects without an epsilon4 allele [PMID 15181249]
• Located on chromosome 10 and suscptibility of polymorphisms are related to type 2 diabetes. [PMID 19053027]
• This study demenostrated that insulin-degrading enzyme levels is increased in Alzheimer disease in relation to disease severity. [PMID 19606063]
• IDE forms an enclosed catalytic chamber that completely engulfs and intimately interacts with a partially unfolded insulin molecule. [PMID 19321446]
• This study suggests IDE may be indirectly related to dementia via its regulation of insulin levels, but it is not a major gene for Alzheimer’s. [PMID 17192720]
• The combined genotype data from 1269 late-onset AD cases and 980 controls yielded a significant association to IDE_9 located in the 3’-end of the IDE gene after conservative multiple testing Bonferroni correction (p = 0.005). [PMID 16876916]
• Polymorphism in/near IDE contributes to a large proportion of variance in plasma insulin levels and correlated traits. [PMID 15277398]
• IIA(Glc) of the sugar phosphotransferase system regulates the peptidase activity of a mammalian insulysin homolog in V. vulnificus. [PMID 20971110]
• Importance of the distribution of the enzyme in brain and pituitary is discussed in relation to its main known substrataes. [PMID 18226493]
• Results describe the in vitro degradation of insulin-like peptide 3 by insulin-degrading enzyme. [PMID 20082125]
• a defect in Abeta proteolysis by IDE contributes to the accumulation of this peptide in the cortical microvasculature [PMID 15489232]
• Co-purification [PMID 8051160]
• These results suggest that PPARgamma transcriptionally induces IDE expression. [PMID 19383491]
• This shows that IDE is involved in cellular insulin metabolism and provides further evidence that insulin inhibits protein degradation via an interaction with IDE. [PMID 17964527]
• Insulin-degrading enzyme protein expression was found in normal tissues of the kidney, liver, lung, brain, breast and skeletal muscle, as well as in breast and ovarian cancer tissues. [PMID 18813847]
• This result suggests that the IDE gene might contribute to metabolic syndrome susceptibility in Chinese elders [PMID 19592050]
• the genetic linkage of AD in this set of chromosome 10-linked AD families may be the result of systemic defects in IDE activity in the absence of altered IDE expression [PMID 17244626]
• Observational study and genome-wide association study of gene-disease association. (HuGE Navigator) [PMID 17293876]
• cellular receptor for infection by varicella-zoster virus. Interacts with VZV glycoprotein E. [PMID 17055432]
• Observational study and meta-analysis of gene-disease association. (HuGE Navigator) [PMID 20927120]
• Loss of insulin-induced regulation of IDE activity under hyperglycaemia may contribute to the reduced insulin extraction and peripheral hyperinsulinaemia in type 2 diabetes. [PMID 19396426]
• Affinity Capture-MS [PMID 21906983]
• predict that alkylation of C812 and C819 disrupts substrate binding, whereas alkylation of C178 interferes with the apposition of active-site domains and subtly repositions zinc-binding residues [PMID 18621727]
• IDE is not correlated with amyloig beta or clinical diagnosis Alzheimer disease [PMID 20663017]
• Five IDE variants for altered in vitro reporter gene expression, based on their presence on haplotypes (H2, H6 and H9) and their association with altered IDE mRNA transcript levels , were tested. [PMID 21731745]
• the same genetic HHEX-IDE variant, which is associated with type 2 diabetes from previous studies, also influences pediatric body mass index [PMID 19933996]
• Results suggest a relationship between a gene that is intimately involved in insulin metabolism and the determination of lifespan in humans. [PMID 18448515]
• Common genetic variation at IDE is unlikely to confer clinically significant risk of type 2 diabetes in Caucasians. [PMID 16380485]

PubMed Articles

Recent articles:

• Kumar S et al. “Phosphorylation of amyloid-β peptide at serine 8 attenuates its clearance via insulin-degrading and angiotensin-converting enzymes.” J Biol Chem. 2012 Mar 9;287(11):8641-51. PMID 22267728
• Leal MC et al. “Notch signaling proteins HES-1 and Hey-1 bind to insulin degrading enzyme (IDE) proximal promoter and repress its transcription and activity: implications for cellular Aβ metabolism.” Biochim Biophys Acta. 2012 Feb;1823(2):227-35. PMID 22036964
• Fang Y et al. “The interaction between ubiquitin C-terminal hydrolase 37 and glucose-regulated protein 78 in hepatocellular carcinoma.” Mol Cell Biochem. 2012 Jan;359(1-2):59-66. PMID 21800051
• Bartl J et al. “Disorder-specific effects of polymorphisms at opposing ends of the Insulin Degrading Enzyme gene.” BMC Med Genet. 2011 Nov 22;12:151. PMID 22107728
• Kilger E et al. “BRI2 protein regulates β-amyloid degradation by increasing levels of secreted insulin-degrading enzyme (IDE).” J Biol Chem. 2011 Oct 28;286(43):37446-57. PMID 21873424
• Kim W et al. “Systematic and quantitative assessment of the ubiquitin-modified proteome.” Mol Cell. 2011 Oct 21;44(2):325-40. PMID 21906983
• Henderson ST et al. “Pharmacogenetic analysis of the effects of polymorphisms in APOE, IDE and IL1B on a ketone body based therapeutic on cognition in mild to moderate Alzheimer’s disease; a randomized, double-blind, placebo-controlled study.” BMC Med Genet. 2011 Oct 12;12:137. PMID 21992747
• Wagner SA et al. “A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.” Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. PMID 21890473
• Li S et al. “Mapping a dynamic innate immunity protein interaction network regulating type I interferon production.” Immunity. 2011 Sep 23;35(3):426-40. PMID 21903422
• Belbin O et al. “Multiple insulin degrading enzyme variants alter in vitro reporter gene expression.” PLoS One. 2011;6(6):e21429. PMID 21731745

Top Pubmed articles linked to gene IDE matching any search term:

• Zhang L et al. “Nuclear Respiratory Factor 1 Mediates the Transcription Initiation of Insulin-Degrading Enzyme in a TATA Box-Binding Protein-Independent Manner.” PLoS One. 2012;7(8):e42035. PMID 22870279
• Cabibbo G et al. “Causes of and prevention strategies for hepatocellular carcinoma.” Semin Oncol. 2012 Aug;39(4):374-83. PMID 22846856
• Bartl J et al. “Different effects of soluble and aggregated amyloid β(42) on gene/protein expression and enzyme activity involved in insulin and APP pathways.” J Neural Transm. 2012 Jul 11;. PMID 22782687
• Matsushita K et al. “Glycolysis inhibitors as a potential therapeutic option to treat aggressive neuroblastoma expressing GLUT1.” J Pediatr Surg. 2012 Jul;47(7):1323-30. PMID 22813791
• Kukday SS et al. “Cell-Permeable, Small-Molecule Activators of the Insulin-Degrading Enzyme.” J Biomol Screen. 2012 Jun 26;. PMID 22740246
• Grasso G et al. “Metal ions affect insulin-degrading enzyme activity.” J Inorg Biochem. 2012 Jun 23;. PMID 22819648
• Lin YL et al. “The Components of Flemingia macrophylla Attenuate Amyloid β-Protein Accumulation by Regulating Amyloid β-Protein Metabolic Pathway.” Evid Based Complement Alternat Med. 2012;2012:795843. PMID 22719789
• Kim YG et al. “Peptidomics approach to elucidate the proteolytic regulation of bioactive peptides.” Proc Natl Acad Sci U S A. 2012 May 29;109(22):8523-7. PMID 22586115
• Gallagher JJ et al. “Impaired Performance of Female APP/PS1 Mice in the Morris Water Maze Is Coupled with Increased Aβ Accumulation and Microglial Activation.” Neurodegener Dis. 2012 May 24;. PMID 22627185
• Lhuillier O et al. “[A clinical monitoring tool for diabetic patients for the benefit of freelance nurses].” Soins. 2012 Apr;(764):46-8. PMID 22641947
• Leal MC et al. “Notch signaling proteins HES-1 and Hey-1 bind to insulin degrading enzyme (IDE) proximal promoter and repress its transcription and activity: implications for cellular Aβ metabolism.” Biochim Biophys Acta. 2012 Feb;1823(2):227-35. PMID 22036964
• Bartl J et al. “Disorder-specific effects of polymorphisms at opposing ends of the Insulin Degrading Enzyme gene.” BMC Med Genet. 2011 Nov 22;12:151. PMID 22107728
• Song ES et al. “Mixed dimers of insulin-degrading enzyme reveal a cis activation mechanism.” J Biol Chem. 2011 Apr 22;286(16):13852-8. PMID 21343292
• Zhou DZ et al. “Variations in/nearby genes coding for JAZF1, TSPAN8/LGR5 and HHEX-IDE and risk of type 2 diabetes in Han Chinese.” J Hum Genet. 2010 Dec;55(12):810-5. PMID 20927120
• Winkler C et al. “BMI at age 8 years is influenced by the type 2 diabetes susceptibility genes HHEX-IDE and CDKAL1.” Diabetes. 2010 Aug;59(8):2063-7. PMID 20460429
• Voight BF et al. “Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.” Nat Genet. 2010 Jul;42(7):579-89. PMID 20581827
• Bora RP et al. “Elucidation of interactions of Alzheimer amyloid beta peptides (Abeta40 and Abeta42) with insulin degrading enzyme: a molecular dynamics study.” Biochemistry. 2010 May 11;49(18):3947-56. PMID 20380468
• Radulescu RT et al. “Retinoblastoma protein co-purifies with proteasomal insulin-degrading enzyme: implications for cell proliferation control.” Biochem Biophys Res Commun. 2010 Apr 30;395(2):196-9. PMID 20362553
• Rudovich N et al. “Polymorphisms within insulin-degrading enzyme (IDE) gene determine insulin metabolism and risk of type 2 diabetes.” J Mol Med (Berl). 2009 Nov;87(11):1145-51. PMID 19809796
• Zhao J et al. “Examination of type 2 diabetes loci implicates CDKAL1 as a birth weight gene.” Diabetes. 2009 Oct;58(10):2414-8. PMID 19592620