Information on EC 3.4.24.56 - insulysin

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The expected taxonomic range for this enzyme is: Coelomata

EC NUMBER
COMMENTARY
3.4.24.56
-
RECOMMENDED NAME
GeneOntology No.
insulysin
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
Degradation of insulin, glucagon and other polypeptides. No action on proteins
show the reaction diagram
-
-
-
-
Degradation of insulin, glucagon and other polypeptides. No action on proteins
show the reaction diagram
Glu111 serves as a base to activate a catalytic water molecule within the active site of the enzyme, mediating peptide hydrolysis, mutation of this residue to glutamine renders IDE inactive, the catalytic water that is coordinated by a zinc ion also interacts with a glutamate residue, which serves as the general acid/base catalyst, catalytic mechanism
-
Degradation of insulin, glucagon and other polypeptides. No action on proteins
show the reaction diagram
reaction mechanism, active-site model, detailed overview
-
Degradation of insulin, glucagon and other polypeptides. No action on proteins
show the reaction diagram
molecular basis of catalytic chamber-assisted unfolding and cleavage of human insulin by human insulin-degrading enzyme, IDE utilizes the interaction of its exosite with the N-terminus of the insulin A chain, overview. The unique size, shape, charge distribution, and exosite of the IDE catalytic chamber contribute to its high affinity for insulin
-
Degradation of insulin, glucagon and other polypeptides. No action on proteins
show the reaction diagram
ability of substrates to properly anchor their N-terminus to the exosite of IDE and undergo a conformational switch upon binding to the catalytic chamber of IDE can also contribute to the selective degradation of structurally related growth factors. The high dipole moment of substrates complements the charge distribution of the IDE catalytic chamber for the substrate selectivity
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
EC 3.4.22.11
-
-
formerly
-
EC 3.4.22.11
-
formerly
EC 3.4.99.10
-
-
formerly
-
EC 3.4.99.45
-
-
formerly
-
gamma-endorphin-generating enzyme
-
-
IDE
-
-
-
-
IDE
P14735
-
IDE
Q8CGB9
-
insulin degrading enzyme
-
-
insulin degrading enzyme
-
-
insulin degrading enzyme
-
-
Insulin protease
-
-
-
-
Insulin protease
-
-
Insulin proteinase
-
-
-
-
Insulin-degrading enzyme
-
-
-
-
Insulin-degrading enzyme
P14735
-
Insulin-degrading enzyme
-
-
Insulin-degrading enzyme
Rattus norvegicus Wistar
-
-
-
Insulin-degrading enzyme
-
-
Insulin-degrading neutral proteinase
-
-
-
-
Insulin-glucagon protease
-
-
-
-
Insulin-specific protease
-
-
-
-
Insulinase
-
-
-
-
Insulinase
-
-
Insulysin
-
-
-
-
Insulysin
-
-
Metalloinsulinase
-
-
-
-
additional information
-
IDE belongs to the family of cryptidases
additional information
-
IDE belongs to the protease M16A subfamily
additional information
-
the enzyme belongs to the inverzincin family
additional information
-
IDE belongs to the family of cryptidases
additional information
-
IDE belongs to the M16A enzyme family
CAS REGISTRY NUMBER
COMMENTARY
9013-83-6
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
Frog
-
-
-
Manually annotated by BRENDA team
Chinese Han populations
-
-
Manually annotated by BRENDA team
Chinese population
-
-
Manually annotated by BRENDA team
chromosome 10-linked Alzheimer disease families
-
-
Manually annotated by BRENDA team
Finnish population
-
-
Manually annotated by BRENDA team
healthy individuals and patients with Alzheimers disease with cerebral amyloid angiopathy
-
-
Manually annotated by BRENDA team
isoform IDE-15a using the canonical exon 15a; identification of six distinct enzyme transcripts, in isoform IDE-15b exon 15b replaces the canonical exon 15a
UniProt
Manually annotated by BRENDA team
patients with diabetes
-
-
Manually annotated by BRENDA team
patients with sporadic and familial Alzheimer's disease
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
enzyme-deficient strain
-
-
Manually annotated by BRENDA team
mouse, Omnibank B6.129
SwissProt
Manually annotated by BRENDA team
transgenic mice with Alzheimer's disease-like neuropathology
-
-
Manually annotated by BRENDA team
exprsssion in Sacchaoromyces cerevisiae
-
-
Manually annotated by BRENDA team
healthy and type 2 diabetic GK rats
-
-
Manually annotated by BRENDA team
male Wistar rats
-
-
Manually annotated by BRENDA team
rat, Sprague-Dawley
-
-
Manually annotated by BRENDA team
rat, Wistar; Wistar strain
-
-
Manually annotated by BRENDA team
recombinant enzyme
-
-
Manually annotated by BRENDA team
Sprague-Dawley rat
-
-
Manually annotated by BRENDA team
Sprague-Dawley rats
-
-
Manually annotated by BRENDA team
Rattus norvegicus Wistar
Wistar strain
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
deficiency in IDE function is associated with Alzheimer's disease and type 2 diabetes mellitus pathology. IDE levels are decreased in type 2 diabetes mellitus. Regulation of IDE by PPARgamma and their roles in Alzheimer's disease and type 2 diabetes mellitus pathology
malfunction
-
IDE catalyzes the degradation of the monomeric forms of Alzheimer amyloid beta peptides, which is critical for preventing the progression of Alzheimer's disease, overview
malfunction
-
reduced neuronal expression of insulin-degrading enzyme in the left and right dorsolateral prefrontal cortex, but not in other brain areas investigated, of haloperidol-treated patients or patients with chronic schizophrenia. Reduced cortical IDE expression might be part of the disturbed insulin signaling cascades found in schizophrenia. Furthermore, it might contribute to the altered metabolism of certain neuropeptides, IGF-I and IGF-II, betab-endorphin, in schizophrenia
malfunction
-
reduced neuronal expression of insulin-degrading enzyme in the left and right dorsolateral prefrontal cortex, but not in other brain areas investigated, of haloperidol-treated rats
malfunction
-
genetic variants in the insulin-degrading enzyme gene are associated with metabolic syndrome in Chinese elders, relationship between the IDE gene and the development of metabolis syndrome, overview
malfunction
-
hypocatabolism of the amyloid beta-protein by insulin-degrading enzyme is implicated in the pathogenesis of Alzheimer's disease
malfunction
-
susceptibility of Goto-Kakizaki rats to diabetes due to IDE polymorphisms
malfunction
-
reduction of IDE expression diminishes the ability of natriuretic peptides ANP and BNP to stimulate natriuretic peptide receptor NPR-B
metabolism
-
IDE levels are significantly inversely correlated with plasma insulin, fasting blood glucose, triglyceride, total cholesterol, low-density lipoprotein, but not high-density lipoprotein, indicating IDE is possibly involved in insulin turnover and its effects on carbohydrate and lipid metabolism, overview
metabolism
-
IDE plays a primary role in insulin degradation and cellular insulin processing and therefore affects glucose and lipid metabolism
physiological function
-
IDE is a ubiquitously expressed metalloproteinase responsible for the intracellular degradation of insulin, but possibly also for the cellular proteolysis of relaxin, InsL3 and relaxin-3
physiological function
-
IDE plays a key role in degrading both amyloid beta and insulin
physiological function
-
IDE is involved in amyloid beta degradation. Cerebral accumulation of amyloid beta protein is believed to play a central role in the pathogenesis of Alzheimer's disease. Therefore the gene encoding for insulin degrading enzyme is one of the candidate genes risky for Alzheimer's disease
physiological function
-
IDE is involved in the clearance of many bioactive peptide substrates, including insulin and amyloid-beta, peptides vital to the development of diabetes and Alzheimer's disease, respectively. IDE can also rapidly degrade hormones that are held together by intramolecular disulfide bond(s) without their reduction. Furthermore, IDE exhibits a remarkable ability to preferentially degrade structurally similar peptides such as the selective degradation of insulin-like growth factor-II and transforming growth factor-alpha, TGF-alpha, over IGF-I and epidermal growth factor, respectively
physiological function
-
IDE plays a primary role in insulin degradation and cellular insulin processing
physiological function
-
IDE is an important protease responsible for the degradation of amyloid-beta in neural cells
physiological function
-
responsible for in vivo degradation of insulin, amyloid beta, and other peptide hormones, e.g. of insulin-like peptide 3, INSL3, an insulin superfamily peptide hormone, primarily expressed in the testes and playing a key role in the fetus testes descent and suppression of male germ cell apoptosis
physiological function
-
IDE is important in maintaining insulin levels. IDE is involved in Alzheimer's disease, diabetes, and cardiovascular disease via oxidation and nitrosylation of IDE in oxidative stress. Reduced IDE activity, e.g. due to genetic dysfunction, leads to hyperinsulinemia and type 2 diabetes mellitus
physiological function
-
IDE is important in maintaining insulin levels
physiological function
-
IDE is important in maintaining insulin levels and in insulin catabolism
physiological function
-
reducing expression levels of IDE profoundly alters the response of natriuretic peptide receptors (NPR-A and NPR-B) to the stimulation of ANP, BNP, and CNP in cultured cells. IDE rapidly cleaves ANP and CNP, thus inactivating their ability to raise intracellular cGMP. Reduced IDE expression enhances the stimulation of NPR-A and NPR-B by ANP and CNP, respectively. IDE cleavage can lead to hyperactivation of BNP toward NPR-A. Conversely, decreasing IDE expression reduces BNP-mediated signaling
metabolism
-
palmitic acid and docosahexaenoic acid opposingly regulate the expression of insulin-degrading enzyme in neurons
additional information
-
interplay between retinoblastoma tumor suppressor protein and IDE within the proteasome that may have important growth-regulatory consequences
additional information
-
IDE can be intricately regulated by reactive oxygen or nitrogen species, identification of oxidation and nitrosylation sites, structure of IDE, and molecular basis for the long distance interactions, and mechanism of oxidative and nitrosylative modification of IDE, overview
additional information
-
IDE activity protects against Alzheimer's disease, IDE suppression of IDE induces the pathology
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(7-methoxycoumarin-4-yl)acetyl-NPPGFSAFK-2,4-dinitrophenyl + H2O
?
show the reaction diagram
-
bradykinin mimetic substrate V
-
-
?
(7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK-2,4-dinitrophenyl + H2O
?
show the reaction diagram
-
-
-
-
?
(7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK-2,4-dinitrophenyl + H2O
?
show the reaction diagram
P14735
-
-
-
?
2-amino-benzoyl-GGFLRKAGQ-ethylenediamine-2,4-dinitrophenyl + H2O
?
show the reaction diagram
-
-
-
?
2-amino-benzoyl-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl + H2O
?
show the reaction diagram
-
-
-
?
2-amino-benzoyl-GGFLRKMGQ-ethylenediamine-2,4-dinitrophenyl + H2O
?
show the reaction diagram
-
-
-
?
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) + H2O
?
show the reaction diagram
-
-
-
-
?
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) + H2O
?
show the reaction diagram
-
-
-
-
?
2-aminobenzoyl-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl + H2O
2-aminobenzoyl-GGFLR + KHGQ-ethylenediamine-2,4-dinitrophenyl
show the reaction diagram
-
-
-
-
?
7-methoxycoumarin-4-yl-acetyl-RPPGFSAFK-2,4-dinitrophenyl + H2O
?
show the reaction diagram
-
fluorogenic bradykinin-mimetic IDE substrate V
-
-
?
7-methoxycoumarin-4-ylacetyl-NPPGFSAFK-2,4-dinitrophenyl + H2O
?
show the reaction diagram
-
-
-
-
?
Abz-GFLRKGVQ-EDDnp + H2O
?
show the reaction diagram
-
-
-
-
?
Abz-GGFLRKHGQ-EDDnp + H2O
Abz-GGFLR + KHGQ-EDDnp
show the reaction diagram
-
-
-
-
?
Abz-GGFLRKHGQ-EDDnp + H2O
Abz-GGFLR + KHGQ-EDDnp
show the reaction diagram
-
substrate or small peptide activation occurs through a cis effect
-
-
?
Abz-GGFLRKHGQEDDnp + H2O
Abz-GGFLRKHGQ + EDDnp
show the reaction diagram
-
synthetic fluorogenic substrate
-
-
?
Abz-SEKKDNYIIKGV-nitroY-OH + H2O
?
show the reaction diagram
-
a substrate based on the polypeptide sequence of the yeast P2 a-factor mating propheromone
-
-
?
amylin + H2O
?
show the reaction diagram
-
-
-
?
amylin + H2O
?
show the reaction diagram
-
-
-
-
?
amylin + H2O
?
show the reaction diagram
-
-
-
?
amylin + H2O
?
show the reaction diagram
-
degradation
-
-
?
amylin + H2O
?
show the reaction diagram
-
degradation
-
-
?
amylin + H2O
?
show the reaction diagram
-
degradation
-
-
?
amylin + H2O
amylin peptide fragments
show the reaction diagram
-
-
-
-
?
amylin + H2O
amylin peptide fragments
show the reaction diagram
-
identification of cleavage sites by mass spectrometry and NMR. The presence of a disulfide bond in amylin allows IDE to cut at an additional site in the middle of the peptide, amino acids 18-19, binding structure, overview
-
-
?
amyloid beta + H2O
amyloid beta peptide fragments
show the reaction diagram
-
-
-
-
?
amyloid beta + H2O
amyloid beta peptide fragments
show the reaction diagram
-
-
-
-
?
amyloid beta peptide + H2O
?
show the reaction diagram
-
-
-
-
?
amyloid beta peptide + H2O
?
show the reaction diagram
-
-
-
?
amyloid beta peptide + H2O
?
show the reaction diagram
-
-
-
-
?
amyloid beta peptide + H2O
?
show the reaction diagram
-
the catalytic mechanisms for the hydrolysis of the three different peptide bonds (Lys28-Gly29, Phe19-Phe20, and His14-Gln15) of amyloid beta peptide is determined: For all these peptides, the nature of the substrate is found to influence the structure of the active enzyme-substrate complex. (1) activation of the metal-bound water molecule, (2) formation of the gem-diol intermediate, and (3) cleavage of the peptide bond. The process of water activation is found to be the rate-determining step for all three substrates
-
-
?
amyloid beta peptide 1-40 + H2O
?
show the reaction diagram
-
physiolgical substrate
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
degradation
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
degradation
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
degradation
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
degradation, amyloid beta-peptide is the key component of Alzheimer disease-associated senile plaques, genetic linkage and association of Alzheimer disease on chromosome 10q23-24 in the region harboring the IDE gene, chromosome 10-linked Alzheimer disease families show decreased enzyme activity, overview
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
P14735
degradation, IDE has no effect on the secreted ectodomain of the amyloid precursor protein derivative generated by alpha-secretase
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
degradation, role for insulysin in regulating amyloid beta peptide levels in the brain
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
IDE is involved in clearance of amyloid-beta pepetide in the brain, enzyme deficiency may participate in the progression of Alzheimer's disease
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
activation in trans is observed with extended substrates that occupy both the active and distal sites
-
-
?
amyloid beta-peptide 1-40 + H2O
?
show the reaction diagram
-
-, 76 kDa and 56 kDa fragments of IDE, derived from cleavage with proteinase K, exhibit a low level of catalytic activity but retain the ability to bind the substrate with a similar affinity as the full-length enzyme, and they retain the regulatory cationic binding site that binds ATP
-
-
?
amyloid beta-peptide1-40 + H2O
?
show the reaction diagram
P14735
degradation
-
-
?
amyloid beta-protein + H2O
?
show the reaction diagram
-
-
-
?
amyloid beta-protein + H2O
?
show the reaction diagram
-
-
-
-
?
amyloid beta-protein + H2O
?
show the reaction diagram
-
-
-
-
?
amyloid beta-protein + H2O
?
show the reaction diagram
P14735
-
-
-
?
amyloid beta-protein A21G + H2O
?
show the reaction diagram
-
Flemish genetic variant
-
-
?
amyloid beta-protein E22K + H2O
?
show the reaction diagram
-
Italian genetic variant
-
-
?
amyloid beta-protein E22Q + H2O
?
show the reaction diagram
-
Dutch genetic variant
-
-
?
amyloid beta1-40 + H2O
?
show the reaction diagram
-
-
-
-
?
amyloid beta40 + H2O
amyloid beta40 peptide fragments
show the reaction diagram
-
-
-
-
?
amyloid beta40 + H2O
amyloid beta40 peptide fragments
show the reaction diagram
-
Abeta40, an Alzheimer amyloid beta peptide, an Alzheimer amyloid beta peptide
-
-
?
amyloid beta42 + H2O
amyloid beta42 peptide fragments
show the reaction diagram
-
Abeta42, an Alzheimer amyloid beta peptide, an Alzheimer amyloid beta peptide
-
-
?
amyloid peptide + H2O
?
show the reaction diagram
-
23 amino acid peptide resulting from internal proteolysis of wild-type type 2 transmembrane protein BRI2
-
-
?
amyloid peptide ABri + H2O
?
show the reaction diagram
-
34 amino acid peptide resulting from internal proteolysis of genetically defect type 2 transmembrane protein BRI2 in patients with familial British dementia. Enzymic degradation of peptide is more efficient with monomeric peptide than with aggregated peptide
-
-
?
amyloid peptide ADan + H2O
?
show the reaction diagram
-
34 amino acid peptide resulting from internal proteolysis of genetically defect type 2 transmembrane protein BRI2 in patients with familial Danish dementia
-
-
?
amyloid-beta peptide + H2O
?
show the reaction diagram
-
-
-
?
amyloid-beta peptide + H2O
?
show the reaction diagram
Q8CGB9
-
-
?
ATP + H2O
ADP + phosphate
show the reaction diagram
-
insulin-binding and degradation are dependent on ATP concentration, however, insulin does not modify the ATPase activity of IDE, the enzyme contains one ATP binding site per enzyme molecule
-
-
?
Atrial natriuretic factor + H2O
?
show the reaction diagram
-
-
-
-
-
atrial natriuretic peptide + H2O
?
show the reaction diagram
-
-
-
?
beta-amyloid peptide + H2O
?
show the reaction diagram
-
-
-
?
beta-amyloid precursor protein intracellular domain + H2O
?
show the reaction diagram
-
-
-
?
beta-amyloid protein + H2O
?
show the reaction diagram
-
-
-
?
beta-endorphin + H2O
gamma-endorphin + ?
show the reaction diagram
-
-
-
-
?
beta-endorphin + H2O
gamma-endorphin + ?
show the reaction diagram
-
-
-
?
beta-endorphin + H2O
gamma-endorphin + ?
show the reaction diagram
-
-
-
-
?
beta-endorphin + H2O
gamma-endorphin + ?
show the reaction diagram
Q8CGB9
-
-
?
beta-endorphin + H2O
?
show the reaction diagram
-
-
-
?
beta-endorphin + H2O
?
show the reaction diagram
-
-
-
?
beta-endorphin + H2O
?
show the reaction diagram
-
-
-
-
?
beta-endorphin + H2O
?
show the reaction diagram
-
76 kDa and 56 kDa fragments of IDE, derived from cleavage with proteinase K, exhibit a low level of catalytic activity but retain the ability to bind the substrate with a similar affinity as the full-length enzyme, and they retain the regulatory cationic binding site that binds ATP
-
-
?
Bradykinin + H2O
?
show the reaction diagram
-
-
-
?
Bradykinin + H2O
?
show the reaction diagram
-
cleavage at Pro/Phe site
-
-
?
calcitonin + H2O
?
show the reaction diagram
-
-
-
?
CH3NH-Ala-Ala-Ala-CONHCH3 + H2O
?
show the reaction diagram
-
energetic profile of proteolysis mechanism of IDE
-
-
?
CH3NH-Leu-Tyr-Leu-CONHCH3 + H2O
?
show the reaction diagram
-
energetic profile of proteolysis mechanism of IDE
-
-
?
Dabcyl-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Glu(EDANS)-NH2 + H2O
?
show the reaction diagram
-
fluorogenic derivative of amyloid beta containing residues 10-25
-
-
?
dynorphin A-17 + H2O
?
show the reaction diagram
-
-
-
?
dynorphin B-13 + H2O
?
show the reaction diagram
-
-
-
?
dynorphin B-9 + H2O
?
show the reaction diagram
-
-
-
?
epidermal growth factor + H2O
epidermal growth factor peptide fragments
show the reaction diagram
-
identification of cleavage sites by mass spectrometry and NMR
-
-
?
Fragment of cytochrome c + H2O
Hydrolyzed fragment of cytochrome c
show the reaction diagram
-
Ile81-Glu108
cleavage at Tyr97-Leu98 bond
-
Glucagon + H2O
Hydrolyzed glucagon
show the reaction diagram
-
-
-
-
-
Glucagon + H2O
Hydrolyzed glucagon
show the reaction diagram
-
-
-
-
-
Glucagon + H2O
Hydrolyzed glucagon
show the reaction diagram
-
-
-
-
-
Glucagon + H2O
Hydrolyzed glucagon
show the reaction diagram
-
-
appearance of: tyrosine, leucine, lysine, alanine and phenylalanine
-
Glucagon + H2O
?
show the reaction diagram
-
-
-
?
Glucagon + H2O
?
show the reaction diagram
-
-
-
-
?
Glucagon + H2O
?
show the reaction diagram
-
-
-
-
?
Glucagon + H2O
?
show the reaction diagram
-
degradation
-
-
?
glucagon + H2O
glucagon peptide fragments
show the reaction diagram
-
-
-
-
?
haemoglobin + H2O
?
show the reaction diagram
-
damaged haemoglobin oxidatively degraded
-
?
InsL3 + H2O
InsL3 fragments
show the reaction diagram
-
-, human substrate, degradation
-
-
?
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
-
-
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
-
-
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
-
-
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
-
-
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
-
-
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
-
-
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
-
-
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
bovine
-
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
porcine
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
much better degradation than insulin growth factor II
-
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
not: individual A and B-chains of insulin
-
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
not: individual A and B-chains of insulin
-
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
Drosophila and rat enzyme cleave the A-chain of intact insulin between residues A13-A14 and A14-A15
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
degradation of 4 monoiodoinsulin isomers
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
the Drosophila enzyme cleaves the B-chain of intact insulin at B10-B11, B14-B15, B16-B17 and B25-B26
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
equine
-
-
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
specific for insulin
degradation products are smaller than the A-chain of insulin
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
specific for insulin
stepwise degradation occurs in vivo, an early step in the process is the cleavage of the B-chain at Tyr16-Leu17
-
Insulin + H2O
Hydrolyzed insulin
show the reaction diagram
-
the insulin protease appears to first degrade insulin to multiple products with molecular sizes slightly smaller than insulin and subsequently to small peptides (e.g. containing tyrosine A-19) and amino acids (e.g. tyrosine A-14, B-16 and B-26)
-
-
insulin + H2O
?
show the reaction diagram
-
-
-
-
?
insulin + H2O
?
show the reaction diagram
-
-
-
?
insulin + H2O
?
show the reaction diagram
-
-
-
?
insulin + H2O
?
show the reaction diagram
-
-
-
?
insulin + H2O
?
show the reaction diagram
-
-
-
?
insulin + H2O
?
show the reaction diagram
-
-
-
-
?
insulin + H2O
?
show the reaction diagram
Q8CGB9
-
-
?
insulin + H2O
?
show the reaction diagram
P14735
-
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation
-
-
?
insulin + H2O
?
show the reaction diagram
-
physiolgical substrate
-
?
insulin + H2O
?
show the reaction diagram
-
insulin degrading enzyme is unlikely to be the relevant enzyme for endosomal proteolysis of internalized insulin in liver parenchyma
-
-
-
insulin + H2O
?
show the reaction diagram
-
stepwise degradation occurs in vivo, an early step in the process is the cleavage of the B-chain between Tyr16 and Leu17, that renders the molecule susceptible to further degradation by nonspecific proteases
-
-
-
insulin + H2O
?
show the reaction diagram
-
seems to be implicated in insulin metabolism to terminate the response of cells to hormone, as well as in other biological functions, including muscle differentiation, regulation of growth factor levels and antigen processing
-
-
-
insulin + H2O
?
show the reaction diagram
-
implicated in the process of membrane fusion and cell development
-
-
-
insulin + H2O
?
show the reaction diagram
-
major route of insulin catabolism in body
-
-
-
insulin + H2O
?
show the reaction diagram
-
insulin degradation
-
-
-
insulin + H2O
?
show the reaction diagram
-
the enzyme may play a general role in hormone metabolism and cellular regulation
-
-
-
insulin + H2O
?
show the reaction diagram
-
important role in the metabolism of insulin
-
-
-
insulin + H2O
?
show the reaction diagram
-
degradation, insulin internalized into Hep-G2 cells is able cross-link with intracellular insulysin
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation, insulin occurs only in grade 3 tumors, whereas grade 2 carcinomas and the normal mammary gland are each insulin-negative, overview
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation, insulin-binding and degradation are dependent on ATP concentration, however, insulin does not modify the ATPase activity of IDE
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation, reduced insulin degradation leads to type 2 diabetes, regulation, overview
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation, tissue-specific regulation, overview
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation, type 2 diabetic GK rats exhibit defects in both insulin action and insulin degradation mainly due to mutation H18R and A890V in the insulysin protein
-
-
?
insulin + H2O
?
show the reaction diagram
-
IDE is involved in the cellular insulin metabolism, insulin inhibits protein degradation via an interaction with IDE, regulation of protein degradation by insulin-degrading enzyme, overview
-
-
?
insulin + H2O
?
show the reaction diagram
-
76 kDa and 56 kDa fragments of IDE, derived from cleavage with proteinase K, exhibit a low level of catalytic activity but retain the ability to bind the substrate with a similar affinity as the full-length enzyme, and they retain the regulatory cationic binding site that binds ATP
-
-
?
insulin + H2O
?
show the reaction diagram
-
bovine substrate, degradation, identification of clevage sites in the alpha- and beta-chains, and of the produced proteolytic fragments by AP/MALDI-mass spectrometry, method evaluation, overview
-
-
?
insulin + H2O
?
show the reaction diagram
-
porcine substrate, degradation
-
-
?
insulin + H2O
?
show the reaction diagram
-
investigation of activity of IDE regarding cleavage site's preferentiality upon modification of environmental factors by atmospheric pressure/laser desorption ionization-mass spectrometry. The first insulin fragments produced by IDE are mainly [A (1-13) + B (1-9)], [A (1-14) + B (1-9)] and [A (1-14) + B (1-10)]. A second set of insulin fragments involving the C-terminal residues of the insulin A chain [A (14-21) and A (15-21)] and the fragments B (17-24) and B (17-25) are then produced, confirming a delayed action of IDE on these cleavage sites. A third set of insulin fragments at lower and higher m/z values start to appear soon after and their intensity increases as the intensity of the middle fragments intensity decreases
-
-
?
insulin + H2O
insulin fragments
show the reaction diagram
-
-, degradation
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
-
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
-
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
-
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
-
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
high specificity
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
cleavage of the B-chain
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
rapid degradation into inactive peptide fragments
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
IDE forms an enclosed catalytic chamber that completely engulfs and intimately interacts with a partially unfolded insulin molecule. The unique size, shape, charge distribution, and exosite of the IDE catalytic chamber contribute to its high affinity for insulin, IDE-insulin binding structure and interaction analysis, overview
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
IDE uses the size and charge distribution of the catalytic chamber and structural flexibility of the substrates to selectively recognize and degrade insulin
-
-
?
Insulin B-chain + H2O
?
show the reaction diagram
-
-
-
-
?
Insulin B-chain + H2O
?
show the reaction diagram
-
-
-
?
Insulin growth factor II + H2O
?
show the reaction diagram
-
-
-
-
-
Insulin growth factor II + H2O
?
show the reaction diagram
-
-
-
-
-
insulin-like growth factor I + H2O
insulin-like growth factor I peptide fragments
show the reaction diagram
-
-
-
-
?
insulin-like growth factor II + H2O
insulin-like growth factor II peptide fragments
show the reaction diagram
-
-
-
-
?
insulin-like growth factor-II + H2O
insulin-like growth factor-II peptide fragments
show the reaction diagram
-
identification of cleavage sites by mass spectrometry and NMR
-
-
?
insulin-like peptide 3 + H2O
processed insulin-like peptide 3 + WSTEA
show the reaction diagram
-
IDE cleaves the peptide bond between R26 and W27 of the B-chain, and releases a pentapeptide, WSTEA, from the C-terminal of the B-chain, IDE cleaves the peptide bond between R26 and W27 of the B-chain, and releases a pentapeptide, WSTEA, from the C-terminal of the B-chain, cleavage product identification by mass spectrometry, INSL-3 structure, overview
-
-
?
kallidin + H2O
?
show the reaction diagram
-
cleavage at Pro/Phe site
-
-
?
o-aminobenzoic acid-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl + H2O
?
show the reaction diagram
P14735
-
-
-
?
Oxidatively damaged hemoglobin + H2O
?
show the reaction diagram
-
-
-
-
-
peptide containing the mitochondrial targeting sequence of E1alpha subunit of human pyruvate dehydrogenase + H2O
?
show the reaction diagram
-
hydrolysis occurs at several sites
-
-
?
peptide V + H2O
?
show the reaction diagram
-
a bradykinin-mimetic fluorogenic peptide substrate V
-
-
?
peptide V + H2O
?
show the reaction diagram
-
a bradykinin-mimetic fluorogenic peptide substrate V
-
-
?
Porcine proinsulin intermediates + H2O
?
show the reaction diagram
-
cleaved proinsulin, desdipeptide-proinsulin, desnonapeptide-proinsulin, destridecapeptide-proinsulin, desalanine-insulin, monoarginine-insulin and diarginine-proinsulin are degraded at 19.8%, 25.6%, 63.5%, 73.7%, 101.5%, 98% and 98% of the activity of insulin, respectively
-
-
-
Proinsulin + H2O
Hydrolyzed proinsulin
show the reaction diagram
-
15fold greater rate of insulin destruction over that for proinsulin
-
-
-
protein ANP + H2O
?
show the reaction diagram
-
-
-
-
?
protein BNP + H2O
?
show the reaction diagram
-
-
-
-
?
protein CNP + H2O
?
show the reaction diagram
-
-
-
-
?
protein DNP + H2O
?
show the reaction diagram
-
-
-
-
?
reduced amylin + H2O
reduced amylin peptide fragments
show the reaction diagram
-
identification of cleavage sites by mass spectrometry
-
-
?
relaxin + H2O
relaxin fragments
show the reaction diagram
-
-, procine substrate, degradation
-
-
?
relaxin-3 + H2O
relaxin-3 fragments
show the reaction diagram
-
-, human substrate, degradation
-
-
?
somatostatin + H2O
?
show the reaction diagram
-
cleavage at Phe6-Phe7 bond
-
-
?
Transforming growth factor + H2O
?
show the reaction diagram
-
-
-
-
-
transforming growth factor alpha + H2O
?
show the reaction diagram
-
-
-
?
transforming growth factor-alpha + H2O
transforming growth factor-alpha peptide fragments
show the reaction diagram
-
identification of cleavage sites by mass spectrometry
-
-
?
Tryptic fragment of bovine serum albumin + H2O
Hydrolyzed tryptic fragment of bovine serum albumin
show the reaction diagram
-
Leu503-Lys518
cleaved at Phe506-His507
-
ubiquitin + H2O
?
show the reaction diagram
-
IDE cleaves ubiquitin in a biphasic manner, first, by rapidly removing the two C-terminal glycines (kcat = 2/sec) followed by a slow cleavage between residues 72-73 (kcat = 0.07/sec), thereby producing the inactive Ub1-74 and Ub1-72
-
-
?
urodilatin + H2O
?
show the reaction diagram
-
-
-
-
?
Lysozyme + H2O
?
show the reaction diagram
-
degradation of oxidatively damaged lysozyme
-
?
additional information
?
-
-
-
-
-
-
additional information
?
-
-
requirement for optimal substrate activity is the deblocking of the amino end of the A-chain
-
-
-
additional information
?
-
-
fructose 1,6-bisphosphatase, hexosephosphate isomerase, aldolase
-
-
-
additional information
?
-
-
the conserved glutamate in the zinc-binding site of human enzyme is a major catalytic residue, while a conserved cysteine in this region is not essential for catalysis
-
-
-
additional information
?
-
-
preference for small substrates 2000-6000 MW
-
-
-
additional information
?
-
-
insulin-like growth factor I
-
-
-
additional information
?
-
-
human growth hormone is not appreciably degraded
-
-
-
additional information
?
-
-
no inactivation of: lactate dehydrogenase, thyroid-stimulating hormone, prolactin, hexokinase, not: growth hormone
-
-
-
additional information
?
-
-
does not act on glucagon-like peptide 1, nerve growth factor, somatostatin, bradykinin, vasopressin, platelet-derived growth factor, and vasoactive intestinal peptide, proinsulin, epidermal growth factor and IGF-I bind to the enzyme but are not efficiently degraded
-
?
additional information
?
-
-
EGF and insulin C-peptide are no substrates
-
?
additional information
?
-
-
gamma-endorphin, Leu-Arg, and Leu-enkephalin are not significantly cleaved
-
?
additional information
?
-
-
enzyme can degrade cleaved mitochondrial targeting sequences, role of enzyme within mitochondria
-
-
-
additional information
?
-
-
enzyme may participate in prostatic and uterine growth
-
-
-
additional information
?
-
-
hyperinsulinemia is probably elevated through insulin's competition with amyloid beta-peptide for the enzyme, IDE deficiency might be involved in development of Alzheimer's disease, regulation, overview
-
-
-
additional information
?
-
-
hyperinsulinemia is probably elevated through insulin's competitition with amyloid beta-peptide for the enzyme, IDE deficiency might be involved in development of Alzheimer's disease, regulation, overview
-
-
-
additional information
?
-
-
membrane-bound, but not cytosolic, enzyme selectively decreases during hippocampal development from mild cognitive impairment to mild to severe Alzheimer's disease, overview
-
-
-
additional information
?
-
-
no association of IDE haplotypes with the risk of dementia, IDE may be indirectly related to dementia via its regulation of insulin levels, but it is not a major gene for Alzheimers disease
-
-
-
additional information
?
-
-
regulation of enzyme expression in the liver, overview
-
-
-
additional information
?
-
-
the human enzyme interacts with Varicella-zoster virus glycoprotein E, gE, facilitating viral infection and cell-to-cell spread of the virus, and thus serving as a cellular receptor for the virus, the binding region of the viral protein is located at amino acids 32 to 71 of gE, deletion of this sequence leads to loss of binding ability, overview, the secondary structure of the IDE binding domain is likely important for its interaction with IDE
-
-
-
additional information
?
-
-
the insulin-degrading enzyme is genetically associated with Alzheimer's disease in the Finnish population, overview
-
-
-
additional information
?
-
-
IDE has a preference for basic or hydrophobic amino acids at the carboxyl side of cleavage sites, overview, the catalytic domain of IDE is located in the amino subunit
-
-
-
additional information
?
-
-
the enzyme is a neutral thiol metalloprotease with the active site sequence HEXXH
-
-
-
additional information
?
-
-
IDE interacts with vimentin and nestin, vimentin binds IDE with a higher affinity than nestin in vitro. A nestin tail fragment interacts with insulin-degrading enzyme in Xenopus egg extracts, overview. The interaction between vimentin and IDE is enhanced by vimentin phosphorylation at Ser55, the interaction between nestin and IDE is phosphorylation-independent. Nestin-mediated disassembly of vimentin IFs generates a structure capable of sequestering and modulating the activity of IDE, overview
-
-
-
additional information
?
-
-
IDE interacts with vimentin and with nestin during mitosis, vimentin binds IDE with a higher affinity than nestin in vitro. The interaction between vimentin and IDE is enhanced by vimentin phosphorylation at Ser55, the interaction between nestin and IDE is phosphorylation-independent. Nestin-mediated disassembly of vimentin IFs generates a structure capable of sequestering and modulating the activity of IDE, overview
-
-
-
additional information
?
-
-
IDE is a neutral thiol metalloprotease
-
-
-
additional information
?
-
-
IDE is involved in the clearance of many bioactive peptide substrates, including insulin and amyloid beta, peptides vital to the development of diabetes and Alzheimer's disease, respectively. IDE can also rapidly degrade hormones that are held together by intramolecular disulfide bond(s) without their reduction. Furthermore, IDE exhibits a remarkable ability to preferentially degrade structurally similar peptides such as the selective degradation of insulin-like growth factor-II and transforming growth factor-alpha, TGF-alpha, over IGF-I and epidermal growth factor, respectively. IDE cleaves its substrates at multiple sites in a biased stochastic manner
-
-
-
additional information
?
-
-
active site structure of IDE, overview. Interactions of the two full-length Alzheimer amyloid beta peptides, Abeta40 and Abeta42, with the fully active form of IDE through unrestrained, all-atom molecular dynamics simulations, using free and small fragment-bound, Asp1-Glu3 and Lys16-Asp23 of Abeta40 and Asp1-Glu3 and Lys16-Glu22 of Abeta42, mutated forms of IDE and NMR structures of the full-length Abeta40 and Abeta42, overview. 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. Both the substrates adopt more beta-sheet character in the IDE environment. Hydrogen bonding interactions between IDE and substrates amyloidbeta40 and amyloidbeta42, overview
-
-
-
additional information
?
-
-
IDE shows catalytic activity toward two peptides of different length, simulating a portion of B chain of insulin, analysis by density functional theory method and the hybrid exchange-correlation functional B3LYP in gas phase and in the protein environment, modelling, reaction mechanism, overview. The proteolysis reaction is exothermic and proceeds quickly as the barrier in the rate-limiting step falls widely within the range of values expected for an enzymatic catalysis
-
-
-
additional information
?
-
-
the putative ATP-binding domain is a key modulator of IDE proteolytic activity
-
-
-
additional information
?
-
-
the substrates often possess disulfide bonds that are involved in enzyme-substrate interactions, e.g. insulin possesses three disulfide bonds. The exosite interaction serves as a molecular tether allowing the proper positioning of the C-terminal end of the substrate to the catalytic site, exosite binding ligands can activate the enzyme, the exosite has regulatory function. IDE is an allosteric enzyme
-
-
-
additional information
?
-
-
the substrates often possess disulfide bonds that are involved in enzyme-substrate interactions, e.g. insulin possesses three disulfide bonds. The exosite interaction serves as a molecular tether allowing the proper positioning of the C-terminal end of the substrate to the catalytic site, exosite binding ligands can activate the enzyme, the exosite has regulatory function. Regulatory mechanism, overview. IDE is an allosteric enzyme
-
-
-
additional information
?
-
-
the substrates often possess disulfide bonds that are involved in enzyme-substrate interactions, e.g. insulin possesses three disulfide bonds. The exosite interaction serves as a molecular tether allowing the proper positioning of the C-terminal end of the substrate to the catalytic site, exosite binding ligands can activate the enzyme, the exosite has regulatory function. Tyr831 is also involved in substrate positioning, enzyme-substrate interactions required for the regulation of the enzyme with open and closed stages, mechanism, overview. The closed stage in absence of substrate is unstable. IDE is an allosteric enzyme
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
amylin + H2O
?
show the reaction diagram
-
degradation
-
-
?
amylin + H2O
?
show the reaction diagram
-
degradation
-
-
?
amylin + H2O
?
show the reaction diagram
-
degradation
-
-
?
amylin + H2O
amylin peptide fragments
show the reaction diagram
-
-
-
-
?
amylin + H2O
amylin peptide fragments
show the reaction diagram
-
identification of cleavage sites by mass spectrometry and NMR. The presence of a disulfide bond in amylin allows IDE to cut at an additional site in the middle of the peptide, amino acids 18-19, binding structure, overview
-
-
?
amyloid beta + H2O
amyloid beta peptide fragments
show the reaction diagram
-
-
-
-
?
amyloid beta + H2O
amyloid beta peptide fragments
show the reaction diagram
-
-
-
-
?
amyloid beta peptide 1-40 + H2O
?
show the reaction diagram
-
physiolgical substrate
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
degradation
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
degradation
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
degradation
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
degradation, amyloid beta-peptide is the key component of Alzheimer disease-associated senile plaques, genetic linkage and association of Alzheimer disease on chromosome 10q23-24 in the region harboring the IDE gene, chromosome 10-linked Alzheimer disease families show decreased enzyme activity, overview
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
P14735
degradation, IDE has no effect on the secreted ectodomain of the amyloid precursor protein derivative generated by alpha-secretase
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
degradation, role for insulysin in regulating amyloid beta peptide levels in the brain
-
-
?
amyloid beta-peptide + H2O
?
show the reaction diagram
-
IDE is involved in clearance of amyloid-beta pepetide in the brain, enzyme deficiency may participate in the progression of Alzheimer's disease
-
-
?
amyloid beta-peptide 1-40 + H2O
?
show the reaction diagram
-
-
-
-
?
amyloid beta40 + H2O
amyloid beta40 peptide fragments
show the reaction diagram
-
-
-
-
?
amyloid beta40 + H2O
amyloid beta40 peptide fragments
show the reaction diagram
-
Abeta40, an Alzheimer amyloid beta peptide
-
-
?
amyloid beta42 + H2O
amyloid beta42 peptide fragments
show the reaction diagram
-
Abeta42, an Alzheimer amyloid beta peptide
-
-
?
ATP + H2O
ADP + phosphate
show the reaction diagram
-
insulin-binding and degradation are dependent on ATP concentration, however, insulin does not modify the ATPase activity of IDE
-
-
?
beta-endorphin + H2O
gamma-endorphin + ?
show the reaction diagram
-
-
-
-
?
beta-endorphin + H2O
?
show the reaction diagram
-
-
-
-
?
epidermal growth factor + H2O
epidermal growth factor peptide fragments
show the reaction diagram
-
identification of cleavage sites by mass spectrometry and NMR
-
-
?
Glucagon + H2O
?
show the reaction diagram
-
-
-
-
?
Glucagon + H2O
?
show the reaction diagram
-
degradation
-
-
?
glucagon + H2O
glucagon peptide fragments
show the reaction diagram
-
-
-
-
?
InsL3 + H2O
InsL3 fragments
show the reaction diagram
-
-
-
-
?
insulin + H2O
?
show the reaction diagram
-
-
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation
-
-
?
insulin + H2O
?
show the reaction diagram
-
physiolgical substrate
-
?
insulin + H2O
?
show the reaction diagram
-
insulin degrading enzyme is unlikely to be the relevant enzyme for endosomal proteolysis of internalized insulin in liver parenchyma
-
-
-
insulin + H2O
?
show the reaction diagram
-
stepwise degradation occurs in vivo, an early step in the process is the cleavage of the B-chain between Tyr16 and Leu17, that renders the molecule susceptible to further degradation by nonspecific proteases
-
-
-
insulin + H2O
?
show the reaction diagram
-
seems to be implicated in insulin metabolism to terminate the response of cells to hormone, as well as in other biological functions, including muscle differentiation, regulation of growth factor levels and antigen processing
-
-
-
insulin + H2O
?
show the reaction diagram
-
implicated in the process of membrane fusion and cell development
-
-
-
insulin + H2O
?
show the reaction diagram
-
major route of insulin catabolism in body
-
-
-
insulin + H2O
?
show the reaction diagram
-
insulin degradation
-
-
-
insulin + H2O
?
show the reaction diagram
-
the enzyme may play a general role in hormone metabolism and cellular regulation
-
-
-
insulin + H2O
?
show the reaction diagram
-
important role in the metabolism of insulin
-
-
-
insulin + H2O
?
show the reaction diagram
-
degradation, insulin internalized into Hep-G2 cells is able cross-link with intracellular insulysin
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation, insulin occurs only in grade 3 tumors, whereas grade 2 carcinomas and the normal mammary gland are each insulin-negative, overview
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation, insulin-binding and degradation are dependent on ATP concentration, however, insulin does not modify the ATPase activity of IDE
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation, reduced insulin degradation leads to type 2 diabetes, regulation, overview
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation, tissue-specific regulation, overview
-
-
?
insulin + H2O
?
show the reaction diagram
-
degradation, type 2 diabetic GK rats exhibit defects in both insulin action and insulin degradation mainly due to mutation H18R and A890V in the insulysin protein
-
-
?
insulin + H2O
?
show the reaction diagram
-
IDE is involved in the cellular insulin metabolism, insulin inhibits protein degradation via an interaction with IDE, regulation of protein degradation by insulin-degrading enzyme, overview
-
-
?
insulin + H2O
insulin fragments
show the reaction diagram
-
-
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
-
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
-
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
-
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
-
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
high specificity
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
cleavage of the B-chain
-
-
?
insulin + H2O
insulin peptide fragments
show the reaction diagram
-
rapid degradation into inactive peptide fragments
-
-
?
insulin-like growth factor I + H2O
insulin-like growth factor I peptide fragments
show the reaction diagram
-
-
-
-
?
insulin-like growth factor II + H2O
insulin-like growth factor II peptide fragments
show the reaction diagram
-
-
-
-
?
insulin-like growth factor-II + H2O
insulin-like growth factor-II peptide fragments
show the reaction diagram
-
identification of cleavage sites by mass spectrometry and NMR
-
-
?
reduced amylin + H2O
reduced amylin peptide fragments
show the reaction diagram
-
identification of cleavage sites by mass spectrometry
-
-
?
relaxin + H2O
relaxin fragments
show the reaction diagram
-
-
-
-
?
relaxin-3 + H2O
relaxin-3 fragments
show the reaction diagram
-
-
-
-
?
transforming growth factor-alpha + H2O
transforming growth factor-alpha peptide fragments
show the reaction diagram
-
identification of cleavage sites by mass spectrometry
-
-
?
insulin-like peptide 3 + H2O
processed insulin-like peptide 3 + WSTEA
show the reaction diagram
-
IDE cleaves the peptide bond between R26 and W27 of the B-chain, and releases a pentapeptide, WSTEA, from the C-terminal of the B-chain
-
-
?
additional information
?
-
-
enzyme can degrade cleaved mitochondrial targeting sequences, role of enzyme within mitochondria
-
-
-
additional information
?
-
-
enzyme may participate in prostatic and uterine growth
-
-
-
additional information
?
-
-
hyperinsulinemia is probably elevated through insulin's competition with amyloid beta-peptide for the enzyme, IDE deficiency might be involved in development of Alzheimer's disease, regulation, overview
-
-
-
additional information
?
-
-
hyperinsulinemia is probably elevated through insulin's competitition with amyloid beta-peptide for the enzyme, IDE deficiency might be involved in development of Alzheimer's disease, regulation, overview
-
-
-
additional information
?
-
-
membrane-bound, but not cytosolic, enzyme selectively decreases during hippocampal development from mild cognitive impairment to mild to severe Alzheimer's disease, overview
-
-
-
additional information
?
-
-
no association of IDE haplotypes with the risk of dementia, IDE may be indirectly related to dementia via its regulation of insulin levels, but it is not a major gene for Alzheimers disease
-
-
-
additional information
?
-
-
regulation of enzyme expression in the liver, overview
-
-
-
additional information
?
-
-
the human enzyme interacts with Varicella-zoster virus glycoprotein E, gE, facilitating viral infection and cell-to-cell spread of the virus, and thus serving as a cellular receptor for the virus, the binding region of the viral protein is located at amino acids 32 to 71 of gE, deletion of this sequence leads to loss of binding ability, overview, the secondary structure of the IDE binding domain is likely important for its interaction with IDE
-
-
-
additional information
?
-
-
the insulin-degrading enzyme is genetically associated with Alzheimer's disease in the Finnish population, overview
-
-
-
additional information
?
-
-
IDE interacts with vimentin and nestin, vimentin binds IDE with a higher affinity than nestin in vitro. A nestin tail fragment interacts with insulin-degrading enzyme in Xenopus egg extracts, overview. The interaction between vimentin and IDE is enhanced by vimentin phosphorylation at Ser55, the interaction between nestin and IDE is phosphorylation-independent. Nestin-mediated disassembly of vimentin IFs generates a structure capable of sequestering and modulating the activity of IDE, overview
-
-
-
additional information
?
-
-
IDE interacts with vimentin and with nestin during mitosis, vimentin binds IDE with a higher affinity than nestin in vitro. The interaction between vimentin and IDE is enhanced by vimentin phosphorylation at Ser55, the interaction between nestin and IDE is phosphorylation-independent. Nestin-mediated disassembly of vimentin IFs generates a structure capable of sequestering and modulating the activity of IDE, overview
-
-
-
additional information
?
-
-
IDE is a neutral thiol metalloprotease
-
-
-
additional information
?
-
-
IDE is involved in the clearance of many bioactive peptide substrates, including insulin and amyloid beta, peptides vital to the development of diabetes and Alzheimer's disease, respectively. IDE can also rapidly degrade hormones that are held together by intramolecular disulfide bond(s) without their reduction. Furthermore, IDE exhibits a remarkable ability to preferentially degrade structurally similar peptides such as the selective degradation of insulin-like growth factor-II and transforming growth factor-alpha, TGF-alpha, over IGF-I and epidermal growth factor, respectively. IDE cleaves its substrates at multiple sites in a biased stochastic manner
-
-
-
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Ca2+
-
chelator-treated enzyme can be reactivated by Ca2+
Ca2+
-
required
Ca2+
-
stimulates cytosolic activity, inhibits particulate activity
Ca2+
-
activates
Ca2+
-
activates (at 1 mM)
Mg2+
-
stimulates cytosolic activity, inhibits particulate activity
Mg2+
-
activates
Mg2+
-
activates
Mg2+
-
addition increases insulin degradation
Mg2+
-
activates at concentration up to 0.05 mM, less active than Mn2+, inhibitory at above 0.05 mM
Mn2+
-
chelator-treated enzyme can be reactivated by Mn2+
Mn2+
-
zinc and manganese are associated with the enzyme, with approximately 10times more zinc than manganese being present, one or both of these two metals are endogenously associated with this enzyme
Mn2+
-
reactivates after EDTA inhibition
NaCl
-
activates IDE at high concentration
thiol
-
the enzyme is a neutral thiol metalloprotease requiring both free thiol and divalent cations for activity
Zinc
-
zinc and manganese are associated with the enzyme, with approximately 10times more zinc than manganese being present, one or both of these two metals are endogenously associated with this enzyme
Zn2+
-
zinc metallopeptidase
Zn2+
Q8CGB9
zinc metalloprotease
Zn2+
-
zinc metalloprotease
Zn2+
-
zinc metallomeptidase
Zn2+
-
contains zinc, essential for its proteolytic activity
Zn2+
-
zinc metallomeptidase
Zn2+
-
one Zn2+ bound at the active site, with the zinc-binding motif HXXEH
Zn2+
-
a zinc metalloprotease, the catalytic water that is coordinated by a zinc ion also interacts with a glutamate residue, which serves as the general acid/base catalyst
Zn2+
-
a zinc metalloprotease
Zn2+
-
zinc metalloprotease
Zn2+
-
the enzyme is a neutral thiol metalloprotease requiring both free thiol and divalent cations for activity
Zn2+
-
dependent on, zinc metallopeptidase, simulated structures of the Zn2+ metal center, overview
Zn2+
-
a zinc-binding protease. The metal center in human IDE is chelated by His108, His112, and Glu189. The more external residues Tyr831, Glu111, Thr220, Gly221, Glu182, and Arg824 are also determined. Among these last residues, mainly Glu182, although not directly involved as metal ligand, plays a fundamental role in influencing metal recognition and binding by zinc proteins
Zn2+
-
dependent on, metallopeptidase
Zn2+
-
metallopeptidase
Zn2+
-
dependent on, IDE is a zinc-metalloprotease
Zn2+
-
dependent on
Zn2+
-
dependent on
Zn2+
-
dependent on
Mn2+
-
activates, best at 1 mM, preferred divalent cation for both insulin degradation and ATP hydrolysis
additional information
-
potential metal ligands
additional information
-
metalloenzyme, removal of the protein-bound metal(s) results in nearly total and irreversible loss of activity
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
1,10-phenanthroline
-
-
1,10-phenanthroline
-
Zn2+, Co2+, Mn2+ and to a smaller extent Cd2+ and Fe2+ are capable of preventing the inhibition
1,10-phenanthroline
-
a Zn-chelator
1,10-phenanthroline
-
a Zn2+ chelator
1,10-phenanthroline
-
-
1,10-phenanthroline
-
-
2,6-dichlorophenol-indophenol
-
uncompetitive
2-mercaptoethanol
-
-
4,7-phenanthroline
-
-
adenosine 5'-diphosphate
-
74% inhibition
adenosine 5'-O-(3thiotriphosphate)
-
36% inhibition
adrenocorticotropic hormone
-
competitive inhibition of amylin degradation
-
amylin
-
excess amylin inhibits amylin degradation, competitive inhibition
-
Aprotinin
-
22.4% inhibition
ATP
-
ATP hydrolysis is a mechanism for reversion of this inhibition, however, insulin does not modify the ATPase activity of IDE
ATP
-
interacts via the phosphate moiety, inhibits IDE and shifts the oligomeric equilibrium promoting the transition from tetramer to dimer and from closed to open state
atrialnatriuretic peptide
-
competitive inhibition of amylin degradation
-
Bacitracin
-
-
Bacitracin
-
-
Bacitracin
-
the inhibitory effect in enhanced by ATP
beta-gamma-methyleneadenosine 5'-triphosphate
-
65% inhibition
bradykinin
-
mixed competitive-noncompetitive
Ca2+
-
stimulates cytosolic activity, inhibits particulate activity
Chelating agents
-
-
cholesterol
-
membranes isolated from mouse brain with endogenous reduced levels of cholesterol due to targeted deletion of one seladin-I allele show a reduced amount of IDE
diphosphate
-
46% inhibition
dynorphin B-9
-
inhibitory with insulin as substrate
-
EDTA
-
21% inhibition; 35.7% inhibition
EDTA
-
0.1 mM, wild-type, 91% residual activity, mutants H112D, H112Q, less than 2.5% residual activity
EDTA
-
the activation of IDE disappears upon inactivation by EDTA, which chelates the catalytic Zn2+ ion
Fragment of cytochrome c
-
-
-
Glucagon
-
competitive inhibition of amylin degradation
glutathione
-
oxidized glutathione inhibits IDE through glutathionylation, which is reversible by dithiothreitol but not by ascorbic acid
guanosine 5'-triphosphate
-
38% inhibition
hydrogen peroxide
-
-
hydrogen peroxide
-
the oxidative burst of BV-2 microglial cells leads to oxidation of secreted IDE at Cys residues, e.g. Cys819, Cys110, Cys257, and Cys178, leading to the reduced activity after 4 h versus amyloid beta degradation, increases IDE oligomerization, and decreases IDE thermostability. Within the first 4 h of incubation at 37C, the control and H2O2-treated enzyme does not lose any relative activity. The inhibitory response of IDE is substrate-dependent, biphasic for amyloid beta degradation but monophasic for a shorter bradykinin-mimetic substrate, mutational analysis, overview. Only Cys819 modification plays a prominent role in the change of enzyme properties
Indole derivatives
-
-
-
Inhibitor from rat liver homogenate
-
purification of endogenous inhibitor from rat liver
-
Inhibitor from rat liver homogenate
-
low-molecular-weight protein, order of greatest to least activity: pancreas, liver, kidney, testes, adrenal, lung, spleen, diaphragm, heart, muscle, brain, epididymal fad pad, skin
-
Inhibitors purified from human serum
-
-
-
InsL3
-
competitively inhibits the degradation of insulin, and crosslinking of insulin to IDE
-
Insulin
-
inhibits amylin degradation, excess insulin inhibits insulin degradation
-
Insulin
-
substrate inhibition
-
insulin-like peptide 3
-
IDE degrades insulin quickly, and addition of INSL3 significantly decreases insulin degradation, competitive inhibition
-
Li+
-
inhibits at 1 mM
Mg2+
-
stimulates cytosolic activity, inhibits particulate activity
Mg2+
-
activates, less active than Mn2+, inhibitory at above 0.05 mM
N-ethylmaleimide
-
-
N-ethylmaleimide
-
-
Natural inhibitor of MW 67000 or 80000-120000 MW
-
reduces activity reversibly, nonprogressively, and noncompetitively with respect to insulin
-
NEM
-
modifies Cys819 and inhibits IDE
nestin
-
insulin degradation activity of IDE is suppressed by about 50% by either nestin or phosphorylated vimentin, while the cleavage of bradykinin-mimetic peptide by IDE is increased 2 to 3fold
-
nestin
-
potently inhibits the cleavage of ubiquitin by IDE
-
nitric oxide
-
amyloid beta peptide degradation by IDE is inhibited by NO donor Sin-1
nitric oxide
-
incubation with NO donor Sin-1 results in a strong reduction of IDE activity. In vivo the activity of insulin-degrading enzyme is lowered in APP/PS1 mice, but not in APP/PS1/NOS2(-/-) mice
o-phenanthroline
-
0.1 mM, wild-type, 73% residual activity, mutants H112D, H112Q, less than 2.5% residual activity
orthovanadate
-
inhibits ATP hydrolysis and insulin degradation
p-hydroxymercuribenzoate
-
-
phosphorylated vimentin
-
insulin degradation activity of IDE is suppressed by about 50% by either nestin or phosphorylated vimentin, while the cleavage of bradykinin-mimetic peptide by IDE is increased 2 to 3fold
-
PMSF
-
14.4% inhibition
Proinsulin
-
-
-
Proinsulin
-
competitive
-
protein ANP
-
-
-
protein BNP
-
-
-
protein CNP
-
-
-
protein DNP
-
-
-
Quinoline-2-thiol
-
mixed competitive-noncompetitive
relaxin
-
competitively inhibits the degradation of insulin, and crosslinking of insulin to IDE
-
relaxin-3
-
competitively inhibits the degradation of insulin, and crosslinking of insulin to IDE
-
S-nitroso-N-acetylpenicillamine
-
nitric oxide donors decrease both insulin and amyloid beta degrading activities of insulysin. Insulin-degrading activity is more sensitive to nitric oxide inhibition than amyloid beta degrading activity. Insulysin-mediated regulation of proteasome activity is affected similarly to insulin-degrading activity. S-nitrosylation of enzyme does not affect the insulin degradation products produced by the enzyme, nor does nitric oxide affect insulin binding to insulysin. Inhibition is noncompetitive
S-nitrosoglutathione
-
potent inhibition at physiologically relevant concentrations
S-nitrosoglutathione
-
the oxidative burst of BV-2 microglial cells leads nitrosylation of secreted IDE at Cys residues, e.g. Cys819, Cys110, Cys257, and Cys178, leading to the reduced activity versus amyloid beta degradation, increases IDE oligomerization, and decreases IDE thermostability. This inhibitory response of IDE is substrate-dependent, biphasic for amyloid beta degradation but monophasic for a shorter bradykinin-mimetic substrate, mutational analysis, overview. Only Cys819 modification plays a prominant role in the change of enzyme properties
S-nitrosoglutathione
-
inhibits IDE-mediated degradation of two IDE substrates, insulin and amyloid beta
SH-group blocking reagents
-
-
-
sodium nitroprusside
-
nitric oxide donors decrease both insulin and amyloid beta degrading activities of insulysin. Insulin-degrading activity is more sensitive to nitric oxide inhibition than amyloid beta degrading activity. Insulysin-mediated regulation of proteasome activity is affected similarly to insulin-degrading activity. S-nitrosylation of enzyme does not affect the insulin degradation products produced by the enzyme, nor does nitric oxide affect insulin binding to insulysin. Inhibition is noncompetitive
Sulfhydryl-alkylating agents
-
-
-
Sulfhydryl-modifying reagents
-
Drosophila, human and rat enzyme inhibited, bacterial enzyme not
-
Tolbutamide
-
-
Tryptic fragment of bovine serum albumin
-
-
-
Ub1-72
-
cleaved ubiquitin
-
Ub1-74
-
cleaved ubiquitin
-
ubiquitin
-
-
urodilatin
-
-
-
[(Z)-1-[N-3-aminopropyl]-N-(n-propyl)amino]diazen-1-ium-1,2-dolate
-
nitric oxide donors decrease both insulin and amyloid beta degrading activities of insulysin. Insulin-degrading activity is more sensitive to nitric oxide inhibition than amyloid beta degrading activity. Insulysin-mediated regulation of proteasome activity is affected similarly to insulin-degrading activity. S-nitrosylation of enzyme does not affect the insulin degradation products produced by the enzyme, nor does nitric oxide affect insulin binding to insulysin. Inhibition is noncompetitive
additional information
-
not: phenylmethanesulfonyl fluoride; not: phosphoramidon
-
additional information
-
not: leupeptin; not: pepstatin
-
additional information
-
not: leupeptin
-
additional information
-
not: bestatine
-
additional information
-
not: benzamidine; not: bestatine; not: phenylmethanesulfonyl fluoride
-
additional information
-
not: the enzyme is inhibited by cysteine protease inhibitors as well as metalloprotease inhibitors
-
additional information
-
not: aprotinin; not: pancreatic trypsin inhibitor
-
additional information
-
not: antipain; not: bestatine; not: chymostatin; not: elastatinal; not: leupeptin; not: pepstatin; not: phosphoramidon
-
additional information
-
not: overview: various amino acid derivatives, small polypeptides, indole and quinoline derivatives, dyes and dye derivatives
-
additional information
-
pepstatin-A, leupeptin, and calpains are ineffective as inhibitors, no competitive inhibition with EGF or insulin C-peptide
-
additional information
-
in patients with V97L mutation of presenilin 1, insulysin activity on the plasma membranes is reduction concomitantly with increased levels of extracellular and intracellular amyloid beta42. In the presenilin 1 V97L mutant-transfected SH-SY5Y cell line, increase of intracellular amyloid beta42 is associated with decreased expression and activity of insulysin in the cytosol and endoplasmic reticulum
-
additional information
-
amyloid beta-induced oxidation of IDE by 4-hydroxy-nonenal does not affect IDE activity in human neuroblastoma SH-SY5Y cells, but rapidly induces IDE expression
-
additional information
-
IDE is inhibited by metal chelators, thiol modifiers, inhibitors of cysteine protease activity and insulin, no inhibition by GTP and DMSO, poor inhibition by ATP
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
2',3'-O-(2,4,6-trinitrophenyl)adenosine triphosphate
-
about 15fold activation, 50% activation at o.0016 mM, activation is inhibited by Mg2+
2'-O-(2,4,6-trinitrophenyl) adenosine triphosphate
-
ATP-derivative TNP-ATP
3'-O-(2,4,6-trinitrophenyl) adenosine triphosphate
-
ATP-derivative TNP-ATP
5-(4-chlorophenyl)-2-[(E)-{[(5-chloro-1,2,3-thiadiazol-4-yl)methoxy]imino}methyl]cyclohexane-1,3-dione
-
direct stimulation of IDE, acts highly synergistically with ATP, Ia1 activates the degradation of amyloid beta by about 700% in presence other shorter substrates
A23187
-
calcium ionophore, increases extracellular IDE activity, but only under conditions that also elicit cytotoxicity
ADP
-
inhibition of binding of 2,3-O-(2,4,6-trinitrophenyl)adenosine triphosphate with Ki-value 2.2 mM
ADP
-
in Tris buffer, activation for substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine). Activation in decreasing order: ATP, triphosphate, ADP, AMP
ADP
-
activates, the activating effect of ATP is greater than hat of ADP, which in turn is much greater than that of AMP
AMP
-
in Tris buffer, activation for substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine). Activation in decreasing order: ATP, triphosphate, ADP, AMP
AMP
-
activates, the activating effect of ATP is greater than hat of ADP, which in turn is much greater than that of AMP
amyloid beta-peptide 1-40
-
-
-
ATP
-
50% activation at 1.4 mM, activation is inhibited by Mg2+. Inhibition of binding of 2,3-O-(2,4,6-trinitrophenyl)adenosine triphosphate with Ki-value 1.3 mM
ATP
-
in Tris buffer, up to 20fold activation for substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine), noncompetitive activator. Activation in decreasing order: ATP, triphosphate, ADP, AMP. Up to 10fold activation with substrates bradykinin, dynorphin B-9. No activation with substrates insulin or amyloid beta-protein
ATP
-
regulatory cationic binding site, 76 kDa and 56 kDa fragments of IDE, derived from cleavage with proteinase K, retain the ability to bind ATP, 4fold activation at 4 mM of 56 kDa fragment, poor activation of the 76 kDa enzyme fragment, overview
ATP
-
activates the wild-type enzyme by about 300%, mutant D426C/K899C by about 50%, ATP enhances IDE activity by inducing a direct conformational change within individual IDE molecules, overview. The activating effect of ATP is greater than that of ADP, which in turn is much greater than that of AMP. The activation of IDE by ATP might be attributable to non-specific solvent effects rather than to specific interactions with a bona fide nucleotide binding domain
ATP
-
direct stimulation of IDE, acts highly synergistically with Ia1 and Ia2. The putative ATP-binding domain is a key modulator of IDE proteolytic activity
ATP
-
40fold activation for wild-type
beta-endorphin
-
-
-
bradykinin
-
activation of reaction with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) and amyloid beta-protein
bradykinin
-
-
bradykinin
-
4fold activation for wild-type
DTT
-
stimulates
dynorphin A-17
-
-
dynorphin A-17
-
activation of reaction with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) and amyloid beta-protein
dynorphin B-13
-
-
-
dynorphin B-13
-
activation of reaction with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) and amyloid beta-protein
-
dynorphin B-9
-
2.5fold increase in amyloid beta peptide hydrolysis
-
dynorphin B-9
-
activation of reaction with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) and amyloid beta-protein
-
dynorphin B-9
-
-
-
dynorphin B9
-
-
-
glutathione
-
stimulates
Insulin B chain
-
-
Insulin B-chain
-
activation of reaction with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) and amyloid beta-protein
N-(3-chlorophenyl)-4-[5-(furan-2-yl)-1H-pyrazol-3-yl]piperidine-1-carboxamide
-
direct stimulation of IDE, acts highly synergistically with ATP, Ia2 activates the degradation of amyloid beta by about 400% in presence of other shorter substrates
nestin
-
insulin degradation activity of IDE is suppressed by about 50% by either nestin or phosphorylated vimentin, while the cleavage of bradykinin-mimetic peptide by IDE is increased 2 to 3fold
-
phosphorylated vimentin
-
insulin degradation activity of IDE is suppressed by about 50% by either nestin or phosphorylated vimentin, while the cleavage of bradykinin-mimetic peptide by IDE is increased 2 to 3fold
-
Somatostatin
-
somatostatin binding to IDE brings about a concentration-dependent structural change of the secondary and tertiary structure of the enzyme, revealing two possible binding sites. The higher affinity binding site disappears upon inactivation of IDE by ethylenediaminetetraacetic acid, which chelates the catalytic Zn2+ ion
Sulfhydryl-dependent enzyme
-
-
-
Triphosphate
-
inhibition of binding of 2,3-O-(2,4,6-trinitrophenyl)adenosine triphosphate with Ki-value 0.9 mM
Triphosphate
-
in Tris buffer, up to 20fold activation for substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine), noncompetitive activator. Activation in decreasing order: ATP, triphosphate, ADP, AMP. Up to 10fold activation with substrates bradykinin, dynorphin B-9. No activation with substrates insulin or amyloid beta-protein
Triphosphate
-
-
mercaptoethanol
-
stimulates
additional information
-
purine nucleotide triphosphates are better activators than pyrimidine nucleotide triphosphates
-
additional information
-
fibrillar amyloid beta-peptide induces the enzyme in astrocytes through activation of a MAPK cascade via ERK1/2
-
additional information
-
amyloid beta-induced oxidation of IDE by 4-hydroxy-nonenal does not affect IDE activity in human neuroblastoma SH-SY5Y cells, but rapidly induces IDE expression
-
additional information
-
synthesis and analysis of synthetic small-molecule activators, structure-activity relationships, overview
-
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.014
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111L, pH 7.3
0.0156
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111V, pH 7.3
0.0274
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111F, pH 7.3
0.0287
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
wild-type, K0.5-value, pH 7.3
0.083
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant H112D, pH 7.3
0.158
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant H112Q, pH 7.3
0.204
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111A, pH 7.3
0.0066
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, mutant DELTAC lacking the C-terminal region
0.0068
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, mutant T609F, Vmax: 2.6 nmol/min/mg
0.0085
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, mutant I374S, Vmax: 3.45 nmol/min/mg
0.00861
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, mutant V360S, Vmax: 2 nmol/min/mg
0.0091
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, IDE:IDE mutant E111F/Y609F
0.0109
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, mutant Y609F IDE:IDE mutant E111F
0.0113
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, mutant Y609F IDE:IDE mutant H112Q
0.0135
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, IDE:IDE mutant H112Q/Y609F
0.0148
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, mutant Y609F IDE:IDE mutant E111F/Y609F
0.01587
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, wild-type, Vmax: 35.5 nmol/min/mg
0.0192
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, mutant Y609F IDE:IDE mutant H112Q/Y609F
0.0215
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, wild-type
0.0217
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, IDE:IDE mutant E111F
0.0232
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, IDE:IDE mutant H112Q
0.0268
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, mutant Y609F IDE:IDE mutant Y609F
0.0315
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, IDE:IDE, wild-type
9.6
-
Abz-GGFLRKHGQ-EDDnp
-
wild-type, pH 7.4, temperature not specified in the publication
17.3
-
Abz-GGFLRKHGQ-EDDnp
-
mutant K898A/K899A/S901A, pH 7.4, temperature not specified in the publication
21.3
-
Abz-GGFLRKHGQ-EDDnp
-
mutant R429S, pH 7.4, temperature not specified in the publication
0.0059
-
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37C, 56 kDa detagged fragment of recombinant His6-tagged enzyme
0.0075
-
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37C, 76 kDa detagged fragment of recombinant His6-tagged enzyme
0.0254
-
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37C, recombinant His6-tagged full-length enzyme
0.219
-
Abz-SEKKDNYIIKGV-nitroY-OH
-
pH 9.2, 37C, recombinant enzyme
0.08
-
amyloid beta
-
pH 8.0, 37C, wild-type enzyme
-
0.025
-
amyloid beta-peptide1-40
-
recombinant wild-type enzyme, pH 7.4, 37C
-
0.027
-
amyloid beta-peptide1-40
-
recombinant mutant D426C/K899C, pH 7.4, 37C
-
0.00123
-
amyloid beta-protein
P14735
isoform 15a-IDE, pH 7.4, 37C
-
0.00252
-
amyloid beta-protein
P14735
isoform 15b-IDE, pH 7.4, 37C
-
2.5
-
amyloid beta1-40
-
pH 7.3, 37C
-
0.063
-
ATP
-
pH 7.4, 37C
4.2
-
bradykinin
-
pH 7.3, 37C
1.2
-
Dabcyl-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Glu(EDANS)-NH2
-
pH 7.3, 37C, presence of 0.04 mM somatostatin
-
2.3
-
Dabcyl-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Glu(EDANS)-NH2
-
pH 7.3, 37C
-
1.58e-05
-
desalanine-insulin
-
-
-
0.000176
-
desdipeptide-proinsulin
-
-
-
5.5e-05
-
desnonapeptide-proinsulin
-
-
-
4.4e-05
-
destridecapeptide-proinsulin
-
-
-
3e-06
-
Insulin
-
procine substrate
-
2e-05
-
Insulin
-
-
-
2.2e-05
-
Insulin
-
-
-
2.4e-05
-
Insulin
-
-
-
5.2e-05
-
Insulin
-
pH 7.7, 37C
-
5.8e-05
-
Insulin
-
pH 7.4, 37C
-
6.57e-05
-
Insulin
P14735
isoform 15a-IDE, pH 7.4, 37C
-
7e-05
-
Insulin
-
-
-
0.0001
-
Insulin
-
-
-
0.0001
-
Insulin
-
pH not specified in the publication, temperature not specified in the publication
-
0.000222
-
Insulin
P14735
isoform 15b-IDE, pH 7.4, 37C
-
0.00025
0.00065
Insulin
-
Km is species-dependent
-
0.005
0.007
Insulin
-
-
-
5.5e-05
-
insulin-like peptide 3
-
pH 7.7, 37C
-
7.3
-
kallidin
-
pH 7.3, 37C
0.0002342
-
Proinsulin
-
cleaved
-
0.0008572
-
Proinsulin
-
-
-
7.5
-
Somatostatin
-
pH 7.3, 37C
2.44e-05
-
monoarginine-insulin
-
diarginine-insulin
-
additional information
-
additional information
-
no relation between Km and the chemical dissimilarity between bovine insulin and endogenous insulin of the species
-
additional information
-
additional information
-
with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine), enzyme exhibits allosteric kinetics
-
additional information
-
additional information
-
kinetics of wild-type IDE, IDE mutants, and IDE modified at Cys residues by H2O2 or S-nitrosoglutathione, with substrate amyloidbeta, overview. IDE exhibits substantially different enzyme kinetic parameters with the longer peptide amyloidbeta as compared with a shorter peptide substrate, the bradykinin-mimetic substrate V
-
additional information
-
additional information
-
amyloid beta degradation kinetics in presence or absence of activators
-
additional information
-
additional information
-
kinetics, overview
-
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.028
-
(7-methoxycoumarin-4-yl)acetyl-NPPGFSAFK-2,4-dinitrophenyl
-
pH not specified in the publication, 37C
2
3.7
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant H112D, pH 7.3
2.4
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111V, pH 7.3
6.5
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111L, pH 7.3
11.4
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111F, pH 7.3
17.5
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111A, pH 7.3
1953
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant H112Q, pH 7.3
162600
-
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
wild-type, pH 7.3
0.003
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, mutant Y609F IDE:IDE mutant E111F/Y609F
0.01
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, IDE:IDE mutant E111F/Y609F; pH 7.4, 37C, mutant Y609F IDE:IDE mutant E111F
0.01
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, mutant DELTAC lacking the C-terminal region
0.03
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, IDE:IDE mutant H112Q/Y609F; pH 7.4, 37C, mutant Y609F IDE:IDE mutant Y609F
0.043
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, wild-type
0.05
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, mutant Y609F IDE:IDE mutant H112Q
0.06
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, mutant Y609F IDE:IDE mutant H112Q/Y609F
0.078
-
Abz-GGFLRKHGQ-EDDnp
-
mutant R429S, pH 7.4, temperature not specified in the publication
0.086
-
Abz-GGFLRKHGQ-EDDnp
-
wild-type, pH 7.4, temperature not specified in the publication
0.12
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, IDE:IDE mutant H112Q
0.14
-
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37C, IDE:IDE, wild-type
0.258
-
Abz-GGFLRKHGQ-EDDnp
-
mutant K898A/K899A/S901A, pH and temperature not specified in the publication
0.72
-
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37C, 56 kDa detagged fragment of recombinant His6-tagged enzyme
0.77
-
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37C, 76 kDa detagged fragment of recombinant His6-tagged enzyme
93.17
-
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37C, recombinant His6-tagged full-length enzyme
104
-
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37C, recombinant His6-tagged full-length enzyme
70
-
amyloid beta
-
pH 8.0, 37C, wild-type enzyme
-
8
-
amyloid beta-peptide1-40
-
recombinant wild-type enzyme, pH 7.4, 37C
-
20
-
amyloid beta-peptide1-40
-
recombinant mutant D426C/K899C, pH 7.4, 37C
-
0.17
-
amyloid beta-protein
P14735
isoform 15b-IDE, pH 7.4, 37C
-
0.88
-
amyloid beta-protein
P14735
isoform 15a-IDE, pH 7.4, 37C
-
8
-
amyloid beta1-40
-
pH 7.3, 37C
-
61
-
Dabcyl-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Glu(EDANS)-NH2
-
pH 7.3, 37C, presence of 0.04 mM somatostatin
-
62.7
-
Dabcyl-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Glu(EDANS)-NH2
-
pH 7.3, 37C
-
0.017
-
Insulin
P14735
isoform 15b-IDE, pH 7.4, 37C
-
0.025
-
Insulin
P14735
isoform 15a-IDE, pH 7.4, 37C
-
0.05
-
Insulin
-
pH 7.7, 37C
-
0.0025
-
insulin-like peptide 3
-
pH 7.7, 37C
-
10
-
protein ANP
-
pH not specified in the publication, 37C
-
0.2
-
protein BNP
-
pH not specified in the publication, 37C
-
20
-
protein CNP
-
pH not specified in the publication, 37C
-
0.1
-
protein DNP
-
pH not specified in the publication, 37C
-
0.38
-
Somatostatin
-
pH 7.3, 37C
2
-
urodilatin
-
pH not specified in the publication, 37C
-
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
4.5e-05
-
ATP
-
pH 7.4, 37C, 3.0 mM ATP
5.6e-05
-
ATP
-
pH 7.4, 37C, 0.3 mM ATP
0.00015
-
ATP
-
pH 7.4, 37C, allosteric inhibition
additional information
-
additional information
-
inhibition kinetics, overview
-
IC50 VALUE [mM]
IC50 VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.11
-
Bacitracin
-
recombinant wild-type enzyme, in in presence of ATP
0.18
-
Bacitracin
-
recombinant mutant D426C/K899C, in in presence of ATP
0.2
-
Bacitracin
-
recombinant mutant D426C/K899C, in absence of ATP
0.4
-
Bacitracin
-
recombinant wild-type enzyme, in absence of ATP
0.9
-
hydrogen peroxide
-
pH 8.0, 37C
4.44e-05
-
InsL3
-
pH not specified in the publication, temperature not specified in the publication
-
0.04
-
protein ANP
-
pH not specified in the publication, 37C
-
0.12
-
protein BNP
-
pH not specified in the publication, 37C
-
0.07
-
protein CNP
-
pH not specified in the publication, 37C
-
1.3
-
protein DNP
-
pH not specified in the publication, 37C
-
0.000182
-
relaxin
-
pH not specified in the publication, temperature not specified in the publication
-
5.37e-05
-
relaxin-3
-
pH not specified in the publication, temperature not specified in the publication
-
1.2
-
S-nitrosoglutathione
-
pH 8.0, 37C
0.001
-
Ub1-72
-
pH not specified in the publication, 37C
-
0.1
-
Ub1-72
-
pH not specified in the publication, 37C
-
0.09
-
ubiquitin
-
pH not specified in the publication, 37C
0.8
-
urodilatin
-
pH not specified in the publication, 37C
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.22
-
-
pH 9.2, 37C, purified recombinant His-tagged enzyme, substrate Abz-SEKKDNYIIKGV-nitroY-OH
additional information
-
-
assay methods
additional information
-
-
-
additional information
-
-
-
additional information
-
-
-
additional information
-
-
-
additional information
-
-
activities of recombinant His-tagged full-length enzyme and detagged recombinant enzyme fragments with different substrates, overview
additional information
-
-
determination of insulin in extracts of 23 primary breast cancer specimens and of non-neoplastic breast tissues by a chemiluminescent immunoassay, insulin occurs only in grade 3 tumors, whereas grade 2 carcinomas and the normal mammary gland are each insulin-negative, overview
additional information
-
-
-
additional information
-
-
quantitative enzyme expression analysis by comeptitive RT-PCR, age-related insulin degradation in trangenic mice, radiolabeled substrate, overview
additional information
-
-
cytosolic IDE and membrane-bound IDE activity, and clinical dementia scores, overview
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7
-
-
assay at
7.2
-
-
assay at
7.3
-
-
assay at, substrate (7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK-2,4-dinitrophenyl
7.4
-
-
assay at
7.4
-
-
assay at
7.4
-
-
assay at, substrates amyloid beta-peptide and o-aminobenzoic acid-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl
7.4
-
-
assay at
7.4
-
-
assay at
7.4
-
-
assay at
7.5
-
-
assay at
7.5
-
-
assay at
7.7
-
-
assay at
8
-
-
assay at
additional information
-
-
pI: 5.8
pH RANGE
pH RANGE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
5.8
9.2
-
pH profile, recombinant enzyme, overview
6.5
8.5
-
pH 6.5: about 30% of activity maximum, pH 8.5: about 60% of activity maximum
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
22
-
-
assay at, substrate o-aminobenzoic acid-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl
30
-
-
assay at
30
-
-
assay at
37
-
-
assay at
37
-
-
assay at
37
-
-
assya at
37
-
-
assay at
37
-
-
assay at, substrates amyloid beta-peptide and (7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK-2,4-dinitrophenyl
37
-
-
assay at
37
-
-
assay at
37
-
-
assay at
37
-
-
assay at
37
-
-
assay at
TEMPERATURE RANGE
TEMPERATURE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
25
49
-
temperature profile, recombinant enzyme, overview
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
endothelium of the cerebrovascular blood vessel, expression of enzyme
Manually annotated by BRENDA team
-
isolated brain microvessels, in patients with Alzheimers disease with cerebral amyloid angiopathy enzyme protein level is up to 44% increased, but enzyme activity is significantly reduced
Manually annotated by BRENDA team
-
in enzyme-deficient strain, accumulation of amyloid beta-protein
Manually annotated by BRENDA team
-
post-mortal brains, regional and cellular distribution pattern, immunohistochemic analysis, overview
Manually annotated by BRENDA team
-
mutant brains expressing the Swedish mutant precursor of amyloid beta-peptide, enzyme level, activity and distribution, immunohistochemic analysis, overview
Manually annotated by BRENDA team
-
high expression level, increased expression level during development
Manually annotated by BRENDA team
-
post-mortal samples
Manually annotated by BRENDA team
-
native enzyme, insulysin is able to form a stable complex with amyloid beta
Manually annotated by BRENDA team
-
membranes isolated from mouse brain with endogenous reduced levels of cholesterol due to targeted deletion of one seladin-I allele show a reduced amount of IDE
Manually annotated by BRENDA team
-
left and right dorsolateral prefrontal cortex, expression of IDE protein in postmortem brains of healthy subjects and patients with schizophrenia, immunohistochemic analysis, overview
Manually annotated by BRENDA team
-
left and right dorsolateral prefrontal cortex, immunohistochemic IDE expression analysis, overview
Manually annotated by BRENDA team
-
female breast
Manually annotated by BRENDA team
-
isolated brain microvessels, in patients with Alzheimers disease with cerebral amyloid angiopathy enzyme protein level is up to 44% increased, but enzyme activity is significantly reduced
Manually annotated by BRENDA team
-
after the development of first amyloid beta plaques in brain of transgenic mice with alzheimer's disease-like neuropathology, cortical mRNAand protein levels of IDE are significantly up-regulated in the transgenic mice compared to their non-transgenic littermates. Up-regulation of IDE mRNA-levels occurrs in parallel with increased amyloid beta40 and amyloid beta42 production. A significant positive correlation is observed between protein levels of IDE and full-length amyloid precursor protein in the cerebral cortex
Manually annotated by BRENDA team
-
cells express enzyme and respond to exposure to low levels of amyloid beta-protein by upregulation of enzyme expression
Manually annotated by BRENDA team
-
cultured cell, expression of enzyme
Manually annotated by BRENDA team
-
cerebrovascular, the this cell surface form is the major form of insulysin responsible for degrading amyloid beta-peptides
Manually annotated by BRENDA team
-
endothelium of the cerebrovascular blood vessel, expression of enzyme
Manually annotated by BRENDA team
-
from type 2 diabetes mellitus patients and control subjects
Manually annotated by BRENDA team
-
hepatoma cells
Manually annotated by BRENDA team
-
insulysin is reduced in the hippocampus of Alzheimer's disease patients with an apolipoprotein E-4 allele
Manually annotated by BRENDA team
-
high IDE content
Manually annotated by BRENDA team
-
expression in tubular cells
Manually annotated by BRENDA team
-
regulation of enzyme expression, overview
Manually annotated by BRENDA team
-
high expression level
Manually annotated by BRENDA team
-
high expression level
Manually annotated by BRENDA team
-
expression in respiratory epithelia, alveolar macrophages, pneumocytes
Manually annotated by BRENDA team
-
breast cancer cells
Manually annotated by BRENDA team
-
high expression level
Manually annotated by BRENDA team
-
high expression level
Manually annotated by BRENDA team
-
N2a cells stably expressing the vector pEGFP
Manually annotated by BRENDA team
-
N2a cells stably expressing human amyloid prepcursor protein Swedish mutation
Manually annotated by BRENDA team
-
neuroblastoma cell
Manually annotated by BRENDA team
-
primary cell culture
Manually annotated by BRENDA team
-
hippocampal neuron
Manually annotated by BRENDA team
-
primary culture, immunohistochemic expression analysis, overview
Manually annotated by BRENDA team
-
central nervous system
Manually annotated by BRENDA team
-
expression in islet cells, acinar cells
Manually annotated by BRENDA team
-
post-mortal samples, regional and cellular distribution pattern, immunohistochemic analysis, overview
Manually annotated by BRENDA team
-
activity and amount of enzyme decrease in the cytosolic fraction with castration and increase with testpsterone treatment
Manually annotated by BRENDA team
-
neuroblastoma cells
Manually annotated by BRENDA team
-
a neuroblastoma cell line
Manually annotated by BRENDA team
-
high expression level, increased expression level during development
Manually annotated by BRENDA team
-
high expression level, increased expression level during development
Manually annotated by BRENDA team
-
activity and amount of enzyme decrease during metestrus and increase with estradiol treatment and proestrus
Manually annotated by BRENDA team
additional information
-
insulysin activity declines with aging in the hippocampus of a mouse model of Alzheimers disease
Manually annotated by BRENDA team
additional information
-
tissue expression pattern in wild-type mice, tissue-specific regulation, overview
Manually annotated by BRENDA team
additional information
-
insulin occurs only in grade 3 tumors, whereas grade 2 carcinomas and the normal mammary gland are each insulin-negative, overview
Manually annotated by BRENDA team
additional information
-
ubiquitous tissue expression
Manually annotated by BRENDA team
additional information
-
insulysin is expressed in all tissues assessed, including non-malignant tissues and all tumor cells except for Raji and Hl-60 cell. Normal lymphocytes are insulysin-negative
Manually annotated by BRENDA team
additional information
-
IDE is a ubiquitously expressed metalloproteinase
Manually annotated by BRENDA team
additional information
-
IDE activity levels in decreasing order in liver, pancreas, kidney, testis, adrenal gland, spleen, ovary, lung, heart, muscle, brain, and adipose tissue
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
IDE colocalizes with retinoblastoma tumor suppressor protein in cancer cells, overview. The amount of retinoblastoma tumor suppressor protein-IDE complex seems to be lower in Hep-G2 cells versus MCF-7 cells with increased nuclear localization, overview
Manually annotated by BRENDA team
P14735
isoform IDE-15b, both in cytosol and mitochondrion
Manually annotated by BRENDA team
-
cytosolic enzyme shows a longer half-life compared with the detergent-resistant membrane-associated form
Manually annotated by BRENDA team
Rattus norvegicus Wistar
-
-
-
Manually annotated by BRENDA team
-
membrane-associated activity is highly latent
Manually annotated by BRENDA team
-
associated to plasma membrane, mainly at basolateral cell surface
-
Manually annotated by BRENDA team
-
IDE secretion is unaffected by the classical secretion inhibitors brefeldin A, monensin, or nocodazole. IDE secretion is similarly unaffected by multiple stimulators of protein secretion, including glyburide and 3'-O-(4-benzoyl)benzoyl-ATP
-
Manually annotated by BRENDA team
-
IDE is secreted by BV-2 microglial cells
-
Manually annotated by BRENDA team
-
cytosolic enzyme shows a longer half-life compared with the detergent-resistant membrane-associated form. The detergent-resistant membrane-associated enzyme co-localizes with amyloid beta. Distribution and activity is sensitive to manipulation of lipid composition in vitro and in vivo. Membranes isolated from mouse brain with endogenous reduced levels of cholesterol due to targeted deletion of one seladin-I allele show a reduced amount of IDE
Manually annotated by BRENDA team
-
cytosolic enzyme shows a longer half-life compared with the detergent-resistant membrane-associated form. The detergent-resistant membrane-associated enzyme co-localizes with amyloid beta. Distribution and activity is sensitive to manipulation of lipid composition in vitro and in vivo
Manually annotated by BRENDA team
-
isoform generated by translation of enzyme at an in-frame initiation codon 123 nucleotides upstream of the canonical translation start site, resulting in addition of a 41 amino acid N-terminal mitochondrial targeting sequence
Manually annotated by BRENDA team
P14735
isoform IDE-15b, both in cytosol and mitochondrion
Manually annotated by BRENDA team
-
a form of the enzyme derived from an alternative translational start site that can localize to mitochondria
Manually annotated by BRENDA team
-
IDE colocalizes with retinoblastoma tumor suppressor protein in cancer cells, overview. The amount of retinoblastoma tumor suppressor protein-IDE complex seems to be lower in Hep-G2 cells versus MCF-7 cells with increased nuclear localization, overview
Manually annotated by BRENDA team
-
cloned cDNAs of insulin degrading enzyme (human, rat and Drosophila melanogaster) reveal a deduced classical peroxisomal targeting sequence A/SKL at their carboxyl termini, this may account for the peroxisomal location of the enzyme
Manually annotated by BRENDA team
additional information
-
cellular distribution patterns in different tissues and brain regions, immunohistochemic analysis, overview
-
Manually annotated by BRENDA team
additional information
-
interplay between retinoblastoma tumor suppressor protein and IDE within the proteasome that may have important growth-regulatory consequences
-
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
80000
-
-
rat, gel filtration
110000
115000
Q8CGB9
SDS-PAGE
110000
-
-
Drosophila melanogaster, gel filtration
110000
-
-
SDS-PAGE
110000
-
-
SDS-PAGE
110000
-
-
gel filtration
110000
-
-
monomeric enzyme
110500
-
-
human, calculation from sequence of cDNA
113000
-
Q8CGB9
Western blot
135000
-
-
pig, gel filtration
150000
160000
-
human, gel chromatography, gel electrophoresis
150000
-
-
monomer/dimer mixture of solubilized enzyme, gel filtration
170000
-
-
gel filtration
220000
-
P14735
native PAGE
300000
-
-
rat, gel filtration
300000
-
-
gel filtration
300000
-
-
gel filtration
additional information
-
-
amino acid sequence of insulinase and homologues
additional information
-
-
amino acid sequence
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 110000, human, SDS-PAGE
?
-
x * 110000, rat, human, SDS-PAGE
?
-
x * 110000, pig, SDS-PAGE
?
-
x * 60000, pig, SDS-PAGE
?
-
x * 113000, native enzyme, x * 56000, isolated C-terminal domain IDE-C, 1 * 60000, isolated N-terminal domain IDE-N, SDS-PAGE
?
-
x * 105000, SDS-PAGE
dimer
P14735
2 * 113000, homodimer or heterodimer of isoforms 15a-IDE and 15b-IDE, SDS-PAGE
dimer
-
-
monomer
-
1 * 110000, Drosophila melanogaster, SDS-PAGE
monomer
-
1 * 110000, about
monomer
-
1 * 110000, SDS-PAGE
monomer
-
1 * 110000
monomer
-
mutant with a deleted putative dimer interface in the C-terminal region is created, which results in a monomeric variant. Monomeric IDE retains 25% of the wild type activity substrate (Abz-GGFLRKHGQ-EDDnp). With the peptide substrates beta-endorphin and amyloid beta peptide, monomeric IDE retains 1 to 0.25% of wild type activity. No activation through bradykinin or dynorphin B-9. Monomeric IDE is not activated by polyphosphates
oligomer
-
monomeric IDE is composed of two domains, N- and C-terminal domain, of about 55000 Da, can occur as tetramer or dimer
tetramer
-
4 * 37000, human, SDS-PAGE of denatured enzyme
trimer
-
3 * 110000, SDS-PAGE
monomer or dimer
-
in solution the enzyme exists as a monomer/dimer mixture
additional information
-
human enzyme partially exists as homodimer or heterodimer
additional information
-
the protease is a complex of rather easily dissociating units, which severly complicates its purification
additional information
-
enzyme may be subdivided into roughly equal sized domains IDE-C and IDE-N by limited proteolysis. Separation and analysis of domains show that IDE-N is a monomer and IDE-C serves to oligomerize IDE-N. IDE-C alone does not have catalytic activity, IDE-N alone has 2% of wild-type activity. By complexing IDE-C with IDE-N, activity can be restored to 30% of wild-type
additional information
-
enzyme interacts with Varicella zoster virus glycoprotein E through its extracellular domain
additional information
-
sedimentation analysis shows that enzyme in Tris buffers mainly consists of monomers and dimers, in phosphate buffer there are monomers, dimers and tetramers. Tris buffer supplemented with 4 mM triphosphate contains enzyme as monomer and high oligomers, but without dimers
additional information
-
the enzyme is probably part of a multienzyme complex and co-isolates with the multicatalytic proteinase
additional information
-
the catalytic domain of IDE is located in the amino subunit, the secondary structure of the IDE binding domain is likely important for its interaction with IDE
additional information
-
both recombinant and brain enzyme are able to form a stable complex with amyloid beta that resists dissociation after treatment with strong denaturants. Amyloid beta sequence 17-27 is sufficient to form a stable complex with IDE. Monomeric as opposed to aggregated amyloid beta is competent to associate irreversibly with IDE following a very slow kinetics. Partial denaturation of IDE as well as preincubation with a 10fold molar excess of insulin prevent complex formation. Amyloid beta remains bound to a 25 kDa N-terminal fragment of IDE in an SDS-resistant manner
additional information
-
oligomeric forms of IDE treated with H2O2 and GSN, 280-290 kDa, overview
additional information
-
the two domains of the monomer form a crypt to enclose the substrate and prevent entry or escape of the substrates
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
proteolytic modification
-
for the mitochondrial isoform, mitochondrial targeting sequence of 41 amino acids is probably removed upon import into mitochondria
proteolytic modification
-
treatment of the recombinant N-terminally His6-tagged IDE with proteinase K leads to the initial cleavage of the His tag and linker region, followed by C-terminal cleavages resulting in intermediate fragments of 95 and 76 kDa and finally a relatively stable 56 kDa fragment, overview
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
analysis of the crystal structure of IDE active site, overview
-
IDE in closed conformation
-
in complex with bradykinin, to 1.9 A resolution. Bradykinin binds to the exosite. Residue C819 is located inside the catalytic chamber pointing toward an extended hydrophobic pocket. Specific activity similar to wild-type using substrate 7-methoxycoumarin-4-ylacetyl-NPPGFSAFK-2,4-dinitrophenyl
-
mutant E111Q in complex with substrates insulin B-chain, amyloid beta-protein, amylin and glucagon. Enzyme forms an enclosed cage just large enough to encapsulate insulin. enclosed substrate undergoes conformational changes to form beta-sheets with two discrete regions of enzyme for degradation
-
purified recombinant mutant E110Q with bound insulin, hanging drop vapor diffusion method, 0.001 ml of 16-20 mg/ml protein in 20 mM Tris-HCl, pH 8.0, 50 mM NaCl, is mixed with 0.001 ml of reservoir solution containing, 10-13% PEG MME 5000, 100 mM HEPES, pH 7.0, 4-14% tacsimate, and 10% dioxane, equilibration over 0.5 ml of reservoir solution, 18C, 3-5 days, X-ray diffraction structure determination and analysis at 2.6-2.8 A resolution, molecular replacement
-
purified recombinant mutant E11Q in complex with peptide substrate, and substrate-free mutant Y831F, hanging drop vapour diffusion method, 0.001 ml of 15-20 mg/ml protein and 0.001 ml of crystallization solution, containing 10-13% PEGMME 5000, 100 mM HEPES, pH 7.0, 4-14% Tacsimate, and 10% dioxane, are mixed and equilibrated with 0.5 ml of well solution at 18 C, 3-5 days, cryoprotection by 15-30% glycerol, X-ray diffraction structure determination and analysis at 2.8-3.0 A resolution, modeling
-
X-ray diffraction structure determination and analysis of enzyme-substrate complexes IDE-IGF-II and IDE-TGF-alpha at 2.3 A resolution and IDE-amylin at 2.9 A resolution
-
pH STABILITY
pH STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
5.5
9
-
unstable below pH 5.5 and above pH 9.0
7.5
-
-
maximal stability
TEMPERATURE STABILITY
TEMPERATURE STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
40
-
-
irreversible inactivation and denaturation
additional information
-
-
the oxidative burst of BV-2 microglial cells leads to oxidation or nitrosylation of secreted IDE, leading to decreased IDE thermostability
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
repeated freezing and thawing inactivates
-
STORAGE STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
-40C, neutral pH, stable for a long time
-
4C, neutral pH, stable for several days but specific activity decreases
-
4C or frozen, unstable
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
isolation of the IDE/proteasomal complex from MCF-7 cells and HepG2 cells, IDE copurifies with the retinoblastoma tumor suppressor protein, overview
-
recombinant His-tagged IDE from Escherichia coli strain Rosetta (DE3) by nickel affinity chromatography
-
recombinant His-tagged wild-type and mutant IDEs from Escherichia coli strain Rosetta (DE3) by nickel affinity chromatography
-
recombinant wild-type and catalytically inactive mutants
-
using Ni-affinity chromatography
-
using Ni-NTA chromatography
-
wild-type and mutant enzymes
-
; the protease is a complex of rather easily dissociating units, which severly complicates its purification
-
IDE is associated with other cellular proteins in its freshly isolated state and co-purifies to a variable degree with other proteins including multicatalytic proteinase
-
immunoaffinity method
-
native enzyme from liver by a series of chromatographic steps
-
native enzyme from skeletal muscle by anion exchange chromatography and chromatofocusing to homogeneity
-
recombinant GST-tagged wild-type and mutant IDEs
-
recombinant His6-tagged IDE from Escherichia coli strain BL21(DE3) by nickel affinity chromatography and gel filtration
-
using Ni-NTA chromatography
-
native enzyme from oocytes
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
cDNA cloned and expressed
-
Drosophila melanogaster; Eimeria bovis; human
-
a form of the enzyme derived from an alternative translational start site that can localize to mitochondria instead of the cytosol
-
determination of allele frequencies for Caucasians and Japanese, genotyping, single nucleotide polymorphism in the IDE gene, no association of IDE haplotypes with the risk of dementia, overview
-
DNA and amino acid sequence determination and analysis, genotyping, overview
-
Drosophila melanogaster; Eimeria bovis; human
-
expressed in bacteria
-
expressed in BV-2 cells; expression of His-tagged wild-type and mutant IDEs in Escherichia coli strain Rosetta (DE3)
-
expressed in Escherichia coli
-
expression in cells of Spodoptera frugiperda
-
expression of His-tagged IDE in Escherichia coli strain Rosetta (DE3)
-
expression of the enzyme in transgenic mice under control of the H1 CMV promoter
-
expression of wild-type and mutant enzymes in Escherichia coli
-
expression of wild-type and mutant enzymes in HEK-293swe.3 cells, that stably expresses Myc-epitope tagged human APP-695 harboring the FAD-linked, socalled Swedish mutation
-
genetic linkage and association of Alzheimer disease on chromosome 10q23-24 in the region harboring the IDE gene
-
genotyping, IDE shows a large genetic variability
-
IDE expression analysis in neuron tissue, overview
-
IDE gene is localized on chromosome 10q24, genotyping of IDE in the Finnish population, overview
-
IDE gene, genotyping in Chinese population, Shanghai, China
-
IDE genotyping, expression of promoter constructs in Hela cells and SH-SY5Y cells
-
IDE is expressed in Sf9 insect cells by using baculovirus system
-
polyhistidine- and haemagglutinin-tagged recombinant wild-type and catalytically inactive mutants expressed in bacteria
-
recombinantly expressed
-
the gene encoding IDE is located on chromosome 10q23-q25, a gene locus linked to schizophrenia
-
a form of the enzyme derived from an alternative translational start site that can localize to mitochondria instead of the cytosol
-
genotyping, IDE shows a large genetic variability
-
recombinantly expressed
-
a form of the enzyme derived from an alternative translational start site that can localize to mitochondria instead of the cytosol
-
cDNA cloned and overexpressed in human embryonic kidney 293 cells
-
cloning from C6 glioma cells, expression of recombinant GST-tagged wild-type IDE, and of recombinant IDE mutant E111Q
-
expressed as hexahistidine fusion proteins in SF9 insect cell
-
expression in Escherichia coli
-
expression of the N-terminally His6-tagged enzyme in Spodopterafrugiperda Sf9 cells using the baculovirus transfection system
-
genotyping, IDE shows a large genetic variability
-
IDE expression analysis in neuron tissue, overview
-
recombinant enzyme produced in Sf9 cells
-
recombinant expression of His6-tagged IDE in Escherichia coli strain BL21(DE3)
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
IDE levels are decreased in type 2 diabetes mellitus. IDE levels are significantly inversely correlated with plasma insulin, fasting blood glucose, triglyceride, total cholesterol, low-density lipoprotein, but not high-density lipoprotein
-
reduced neuronal expression of insulin-degrading enzyme in the dorsolateral prefrontal cortex of patients with haloperidol-treated, chronic schizophrenia
-
peroxisome proliferator-activated receptor gamma, PPARgamma, increases IDE levels acting as a positive regulator. PPARgamma participates in the insulin-induced IDE expression in neurons, it binds to the IDE gene promoter flanking a functional PPRE in primary neurons
-
amyloid beta-induced oxidation of IDE by 4-hydroxy-nonenal does not affect IDE activity in human neuroblastoma SH-SY5Y cells, but rapidly induces IDE expression
-
reduced neuronal expression of insulin-degrading enzyme in the left and right dorsolateral prefrontal cortex, but not in other brain areas investigated, of haloperidol-treated rats
-
palmitic acid suppresses the expression of IDE and induces Alzheimer's disease
-
peroxisome proliferator-activated receptor gamma, PPARgamma, increases IDE levels acting as a positive regulator. PPARgamma participates in the insulin-induced IDE expression in neurons, it binds to the IDE gene promoter flanking a functional PPRE in primary neurons
-
docosahexaenoic acid induces the expression of IDE in primary hippocampal neurons and prevents Alzheimer's disease
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
C819A
-
thiol-directed modification of C819 likely causes local structure perturbation to reduce substrate binding and catalysis
D426C/K899C
-
30-40fold increase in activty compared to wild-type
D426C/K899C
-
site-directed mutagenesis, hyperactive IDE mutation, the mutant shows increased activity, but reduced activationby ATP compared to the wild-type enzyme
E110Q
-
structure comparison to wild-type enzyme structure
E111F
-
a mixed dimer in which one subunit contains the wild-type sequence and the other contains a E111F mutation that permits substrate binding, but not catalysis (E111F), exhibits a decrease in turnover number. A mixed dimer consisting of IDE:mutant E111F/Y609F IDE shows a high reduction in kcat, Km (Abz-GGFLRKHGQ-EDDnp) is 66% reduced compared to wild-type. Mixed dimer IDE:mutant E111F in which the inactive subunit can bind substrate exhibites a decreased activity than wild-type IDE towards substrate amyloid beta peptide
E111Q
-
catalytically inactive mutant
E111Q
-
crystallization data
E111Q
-
site-directed mutagenesis, inactive mutant
E111Q
-
site-directed mutagenesis, the mtant shows highly reduced catalytic activity compared to the wild-typ enzyme
E111Q
-
catalysitcally inactive. Mutant forms ordered crystals of considerable size at a more rapid rate than the wild type
E341A
-
mutant is active in degrading substrate V, relative activity closed to wild-type
E341K
-
mutant is active in degrading substrate V, relative activity 15% compared to wild-type. Exosite mutant is unable to further degrade the Ub1-74 fragment
E341Q
-
mutant is active in degrading substrate V, relative activity 20% compared to wild-type. Exosite mutant is unable to further degrade the Ub1-74 fragment
G339P
-
mutant is active in degrading substrate V, relative activity 75% compared to wild-type. Exosite mutant is unable to further degrade the Ub1-74 fragment
G361P
-
mutant is active in degrading substrate V, relative activity 80% compared to wild-type. Exosite mutant is unable to further degrade the Ub1-74 fragment
N184C/Q828C
-
30-40fold increase in activty compared to wild-type
S132C/E817C
-
30-40fold increase in activty compared to wild-type
Y609F
-
mutation Y609F in the distal part of the substrate binding site of the active subunit blocks allosteric activation regardless of the activity of the other subunit. A mixed dimer consisting of mutant Y609F IDE: mutant E111F IDE shows a high reduction in kcat and a reduction in Km compared to wild-type. A mixed dimer consisting of mutant Y609F IDE: mutant E111F/Y609F IDE shows a high reduction in kcat, Km (Abz-GGFLRKHGQ-EDDnp) is 50% reduced compared to wild-type. Substrate amyloid beta peptide: When the distal site is mutated on both subunits (Y609F IDE:IDE Y609F) there is an even greater decrease in the reaction rate
E111A
-
change in the substrate response from sigmoidal to hyperbolic. Activating effect of ATP or triphosphate with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) on wild-type is dampened. Mutant recognizes additional cleavage sites in substrate beta-endorphin
E111F
-
change in the substrate response from sigmoidal to hyperbolic. Activating effect of ATP or triphosphate with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) on wild-type is dampened. Mutant recognizes additional cleavage sites in substrate beta-endorphin
E111F
-
crystal structure of a catalytically compromised E111F mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2
E111L
-
change in the substrate response from sigmoidal to hyperbolic. Activating effect of ATP or triphosphate with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) on wild-type is dampened. Mutant recognizes additional cleavage sites in substrate beta-endorphin
E111Q
-
inactive mutant
E111V
-
change in the substrate response from sigmoidal to hyperbolic. Activating effect of ATP or triphosphate with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) on wild-type is dampened. Mutant recognizes additional cleavage sites in substrate beta-endorphin
E768A
-
naturally occuring mutation of IDE
H112D
-
change in the substrate response from sigmoidal to hyperbolic. Activating effect of ATP or triphosphate with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) on wild-type is changed to inhibition. Affinity to Zn2+ is lower than in wild-type
H112Q
-
change in the substrate response from sigmoidal to hyperbolic. Activating effect of ATP or triphosphate with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) on wild-type is changed to inhibition. Affinity to Zn2+ is lower than in wild-type
H18R/A890V
P35559
plus silent mutation at codon 934, naturally occuring missense mutations occuring in a rat model of type 2 diabetes mellitus, resulting in decreased catalytic efficiency and 15-30% deficit in degradation of both insulin and insulin Abeta. Endogenously secreted insulin Abeta40 and Abeta42 are significantly elevated in primnary neuronal cultures from mutant animals
H18R/A890V
-
naturally occuring mutations in the insulysin gene in GK rats causing 30% reduced enzyme activity and type 2 diabetes as well as increased amyloid beta peptide levels , the rats exhibit defects in both insulin action and insulin degradation, the increased amyloid beta-peptide levels do not lead to increased steady-state levels of its activity due to compensatory degradative mechanisms in the brain
I374S
-
mutation in the distal site eliminates allosterism, Vmax decreased approximately 10fold compared to wild-type, Km (Abz-GGFLRKHGQ-EDDnp) roughly similar to wild-type, no heterotropic activation with bradykinin, no significant activation through ATP
R429S
-
mutant shows greatly decreased activation by the polyphosphate anions ATP and PPP. kcat (Abz-GGFLRKHGQ-EDDnp) comparable to wild-type and Km (Abz-GGFLRKHGQ-EDDnp) higher than wild-type
V360S
-
mutation in the distal site eliminates allosterism, Vmax decreased approximately 10fold compared to wild-type, Km (Abz-GGFLRKHGQ-EDDnp) roughly similar to wild-type, no heterotropic activation with bradykinin, ATP activation is reduced to 8fold
Y248C
-
naturally occuring mutation of IDE
Y609F
-
mutation in the distal site eliminates allosterism, Vmax decreased approximately 10fold compared to wild-type, Km (Abz-GGFLRKHGQ-EDDnp) roughly similar to wild-type, no heterotropic activation with bradykinin, no significant activation through ATP
H112Q
-
a mixed dimer composed of one wild-type subunit and the other subunit containing a H112Q mutation that neither permits substrate binding nor catalysis exhibits the same turnover number per active subunit as wild-type IDE. Mixed oligomer IDE:IDE mutant H112Q shows similar kcat and Km (Abz-GGFLRKHGQ-EDDnp) compared to wild-type. Mixed dimer IDE:mutant H112Q IDE in which the inactive subunit does not bind substrate exhibits a slightly higher activity than wild-type IDE towards substrate amyloid beta peptide
additional information
-
siRNA-mediated gene silencing of IDE in Hep-G2 cells leading to 50% reduction of IDE mRNA and protein, short-lived protein degradation is unchanged in the cells with reduced IDE expression, while long-lived and very-long-lived protein degradation is reduced, overview
additional information
-
overexpression of insulysin in human amyloid precursor protein transgenic mice leads to a decrease in amyloid beta peptide levels
additional information
-
construction of transgenic mice, termed H1/siRNAinsulin-CMV/hIDE transgenic mice, TG9385, co-expressing specific insulin siRNA sequences and the human insulin degrading enzyme, hIDE, gene resulting in changes in the proteins in the endoplasmic reticulum stress signal pathway and a diabetes-like phenotype with impaired glucose tolerance and lower serum insulin levels compared to the wild-type mice, expression pattern in muscle, lung, brain, liver, kidney, heart, and intestine, tissue-specific regulation, overview
additional information
-
human enzyme co-expression with specific insulin siRNA in H1/siRNAinsulin-CMV/hIDE transgenic mice, TG9385, using a chromosome integrated dual-recombinant expression system, in lung, brain, liver, kidney, heart, and intestine, with significantly increased enzyme level and activity in the liver, the transgenic mice show impaired glucose tolerance and reduced serum insulin levels compared to wild-type mice, down-regulation of gene transcripts in the liver of H1/siRNAinsulin-CMV/hIDE mice, gene ontology, overview
additional information
-
chromosome 10-linked Alzheimer disease families show decreased enzyme activity
additional information
-
genotyping of single nucleotide polymorphisms in the IDE gene in Finnish patients with Alzheimer's disease, SNPs rs4646953 and rs4646955 to be associated with Alzheimer's disease, the insulin-degrading enzyme is genetically associated with Alzheimer's disease in the Finnish population, overview
additional information
-
enzyme deficiency leads to development of either Alzheimer's disease and type 2 diabetes, overview
additional information
-
no correlation of single nucleotide polymorphisms and IDE haplotypes with the risk of dementia, overview
additional information
-
construction of mutants lacking one or severall cysteine resiudes. A mutant devoid of all 13 cysteine residues is insensitive to the inhibition by S-nitrosoglutathione, hydrogen peroxide, or N-ethylmaleimide
additional information
-
IDE genotyping identification of polymorphisms, three polymorphisms occur in IDE promoter: -1002T/G (rs3758505), -179T/C (rs4646953) and -51C/T (rs4646954). The -1002T and -51C alleles are overrepresented in 357 sporadic Alzheimer disease patients when compared to those in 331 healthy individuals. Furthermore, -1002T/G and -51C/T are in strong linkage disequilibrium and they construct a relatively risky -1002T/-51C and a relatively protective -1002G/-51T
additional information
-
construction of Cys residue mutants of IDE, properties of oxidized and/or nitrosylated mutant enzymes compared to wild-type enzyme, overview
additional information
-
IDE genotyping and identification of genetic variants, the A/T allele of IDE gene variant rs11187033 is associated with the metabolic syndrome, and might contribute to metabolic syndrome susceptibility in Chinese elders, overview
additional information
-
identification of a genetic variant 311 rs6583817, found in two Croatian isolated populations, unequivocally associated with increased IDE expression that is also associated with reduced plasma amyloidbeta40 and decreased late onset Alzheimer's disease susceptibility. rs6583817 increases reporter gene expression in Be(2)-C and Hep-G2 cell lines. Additional eleven IDE haplotypes, that also show significant association, overview
additional information
-
silencing of IDE in Hep-Ge cells by siRNA inhibits insulin degradation by up to 76%
Y831F
-
site-directed mutagenesis, the mutant shows catalytic activity similar to the wild-type enzyme
additional information
-
Tg3576 transgenic mice express the Swedish mutant of amyloid beta-peptide, the expression and activity of IDE in the transgenic mice is increased with age around plaques as a component of astrocyte activation due to amyloid beta-peptide-triggered inflammation in contrast to the behaviour in Alzheimer mice, overview
additional information
-
IDE knockout mice show decreased insulin degradation and associated hyperinsulinemia
K898A/K899A/S901A
-
mutant shows greatly decreased activation by the polyphosphate anions ATP and PPP, mutant is also deficient in activation by small peptides and has reduced intracellular function relative to unmodified IDE. Km and kcat (Abz-GGFLRKHGQ-EDDnp) higher than wild-type
additional information
-
heterologous expression in Saccharomyces cerevisiae, enzyme can promote the in vivo production of yeast a-factor mating pheromone, but cannot substitue for other fuctions of yeast Axl1p. Enzyme requires an intact C-terminus for optimal activity
additional information
-
construction of transgenic mice with increased enzyme levels show that the enzyme prevents and treats Alzheimer's disease formation
additional information
-
mutant with a deleted putative dimer interface in the C-terminal region is created, which results in a monomeric variant. Monomeric IDE retains enzymatic activity. Monomeric IDE retains, 25% of the wild type activity substrate (Abz-GGFLRKHGQ-EDDnp). With the peptide substrates beta-endorphin and amyloid beta peptide 1-40, monomeric IDE retains 1 to 0.25% of wild type activity. No activation through bradykinin or dynorphin B-9. Monomeric IDE is not activated by polyphosphates
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
analysis
-
immunocapture-based assay that uses the fluorogenic peptide substrate (7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK-2,4-dinitrophenyl and allows the specific measurement of insulin-degrading enzyme activity in brain tissue homogenates. The fluorogenic substrate can be cleaved by a number of enzymes including neprilysin endothelin-converting enzyme-1 and angiotensin-converting enzyme, as well as IDE. Discrimination between these individual enzymes is not readily achieved in tissue homogenates, even in the presence of selective inhibitors and pH conditions. Immunocapture with antibody to the inactive domain of IDE prior to the addition of fluorogenic substrate allows sensitive, linear at 156-2500 ng/ml, and specific measurement of IDE activity and negligible cross-reactivity with neprilysin, endothelin-converting enzyme-1 or angiotensin-converting enzyme
medicine
-
substrate amyloid beta-protein is an essential factor in the pathogenesis of Alzheimer's disease
medicine
-
stimulation of enzyme activity can provide a useful therapeutic approach in treatment of diseases caused by amyloidosis, like Alzheimer's disease, type2 non-insulin-dependent diabetes and the spongiform encephalopathies such as Creutzfeldt-Jakob disease
medicine
-
in isolated brain microvessels from patients with Alzheimers disease with cerebral amyloid angiopathy enzyme protein level is up to 44% increased, but enzyme activity is significantly reduced
medicine
-
enzyme is a cellular receptor for both cell-free and cell-associated Varicella-zoster virus. Enzyme interacts with Varicella-zoster virus glycoprotein E through its extracellular domain. Downregulation of enzyme by siRNA, or blocking with antibody inhibited Varicella-zoster infection. Transfection of cell lines impaired for infection with a plasmid expressing human enzyme results in increased entry and increased infection by Varicella-zoster virus
medicine
-
in patients with diabetes, the degradation of insulin by wound fluid correlates with glucose control, patients with worse outcomes have higher wound fluid insulin degradation. Reduction of enzyme activity in the wound fluid as potential therapeutic target
medicine
-
in patients with V97L mutation of presenilin 1, insulysin activity on the plasma membranes is reduction concomitantly with increased levels of extracellular and intracellular amyloid beta42. In the presenilin 1 V97L mutant-transfected SH-SY5Y cell line, increase of intracellular amyloid beta42 is associated with decreased expression and activity of insulysin in the cytosol and endoplasmic reticulum
medicine
-
study on cortical expression of insulysin and neprilysin in sporadic and familial Alzheimer's disease samples carrying the E280A presenilin-1 missense mutation. Insulysin is linked with aggregated amyloid beta40 isoform while neprilysin negatively correlates with amyloid angiopathy. Neprilysin, but not insulysin, is over-expressed in dystrophic neurites, both proteases are immunoreactive in activated astrocytes but not in microglia and insulysin is the only one detected in astrocytes of white matter from familial alzheimer's disease cases
medicine
Q8CGB9
inverse correlation between insulysin activity levels and brain Abeta peptide levels suggest that modulation of insulysin activity may alter the risk for Alzheimer's disease
medicine
-
after the development of first amyloid beta plaques in brain of transgenic mice with alzheimer's disease-like neuropathology, cortical mRNAand protein levels of IDE are significantly up-regulated in the transgenic mice compared to their non-transgenic littermates. Up-regulation of IDE mRNA-levels occurrs in parallel with increased amyloid beta40 and amyloid beta42 production. A significant positive correlation is observed between protein levels of IDE and full-length amyloid precursor protein in the cerebral cortex
medicine
-
the Alzheimer's beta-amyloid peptide is degraded by the enzyme
medicine
-
IDE represents a target for the development of a new class of drugs for the treatment of Alzheimer's disease that lowers amyloid beta-peptide levels by increasing ist rate of catabolism
medicine
-
enzyme is capable of cleavage of the 34 amino acid peptides resulting from internal proteolysis of genetically defect type 2 transmembrane protein BRI2 in patients with familial British dementia or familial Danish dementia. Enzymic degradation of peptide is more efficient with monomeric peptide than with aggregated peptide. Proteolysis of monomeric soluble peptide precursors by enzyme may delay peptide ABri and ADan aggregation in vivo