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Information on EC 3.4.24.56 - insulysin and Organism(s) Homo sapiens and UniProt Accession P14735
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3.4.24.56 insulysinSpecify your search results
Word Map
- 3.4.24.56
- alzheimer
- neprilysin
- abeta
- hippocampus
- dementia
- mellitus
- cerebral
-
morris
- amyloid-beta
- metalloprotease
-
maze
-
neuroprotective
-
amyloidogenic
- tau
- beta-amyloid
- neurodegenerative
-
presenilin
-
endothelin-converting
-
senile
- gamma-secretase
- beta-protein
- 125i-insulin
-
abeta-degrading
- hyperinsulinemia
- metalloendopeptidase
- bacitracin
- beta-secretase
-
late-onset
- amylin
- microglia
- medicine
- adam10
-
non-amyloidogenic
-
glutathione-insulin
- enzyme-1
- b-chains
- analysis
-
ad-like
-
anti-ide
-
exosite
- beta-peptide
- abeta1-40
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Reaction Schemes
Degradation of insulin, glucagon and other polypeptides. No action on proteins
Synonyms
insulin-degrading enzyme, insulin degrading enzyme, insulin protease, insulysin, pitrm1, insulin proteinase, pitrilysin metallopeptidase 1, insulin-specific protease, insulin-glucagon protease, cgd6_5510, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
IDE
-
Insulin-degrading enzyme
-
IDE
Insulin protease
-
-
-
-
Insulin proteinase
-
-
-
-
Insulin-degrading enzyme
Insulin-degrading neutral proteinase
-
-
-
-
Insulin-glucagon protease
-
-
-
-
Insulin-specific protease
-
-
-
-
Insulinase
Insulysin
Metalloinsulinase
-
-
-
-
additional information
IDE
-
-
-
-
IDE
-
-
Insulin-degrading enzyme
-
-
-
-
Insulin-degrading enzyme
-
-
Insulinase
-
-
-
-
Insulysin
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Degradation of insulin, glucagon and other polypeptides. No action on proteins
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
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
-
Degradation of insulin, glucagon and other polypeptides. No action on proteins
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
reaction mechanism, active-site model, detailed overview
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
9013-83-6
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH + H2O
?
-
-
-
?
(7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK(2,4-dinitrophenyl)-OH + H2O
?
-
-
-
?
(7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK-2,4-dinitrophenyl + H2O
?
-
-
-
?
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH + H2O
?
-
-
-
?
7-methoxycoumarin-4-yl-acetyl-RPPGF-SAFK-2,4-dinitrophenyl + H2O
?
-
-
-
?
o-aminobenzoic acid-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl + H2O
?
-
-
-
?
somatostatin + H2O
?
somatostatin in addition to being a substrate, is also able to bind to two additional exosites, which play different roles according to the size of the substrate and its binding mode to the catalytic cleft of the enzyme. One exosite, which displays high affinity for somatostatin, regulates only the interaction of insulin-degrading-enzyme with larger substrates (such as insulin and beta-amyloid1-40) in a differing fashion according to their various modes of binding to the enzyme. A second exosite, which is involved in the regulation of enzymatic processing by the enzyme of all substrates investigated (including a 10-25 amino acid long amyloid-like peptide, bradykinin and somatostatin itself), probably acts through the alteration of an open-closed equilibrium
-
-
?
[(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH + H2O
[(7-methoxycoumarin-4-yl)acetyl]-RPPGF + SAFK(Dnp)-OH
-
-
-
ir
(7-methoxycoumarin-4-yl)acetyl-KLVFFAEDK(Dnp)-OH + H2O
?
fluorogenic substrate derived from the reported Abeta1-40 core peptide cleavage sequence. The R183Q mutant enzyme exhibits significantly decreased rate of fluorogenic peptide hydrolysis, yet retains similar binding affinity by comparison with the wild-type enzyme
-
-
?
(7-methoxycoumarin-4-yl)acetyl-NPPGFSAFK-2,4-dinitrophenyl + H2O
?
-
bradykinin mimetic substrate V
-
-
?
(7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK-2,4-dinitrophenyl + H2O
?
-
-
-
-
?
Abz-GGFLRKHGQ-EDDnp + H2O
Abz-GGFLR + KHGQ-EDDnp
-
substrate or small peptide activation occurs through a cis effect
-
-
?
amyloid beta + H2O
amyloid beta peptide fragments
-
-
-
-
?
amyloid beta-peptide (Abeta1-40) + H2O
?
recombinant R183Q mutant enzyme is less active than the recombinant wild-type enzyme against recombinant amyloid beta-peptide (Abeta1-40)
-
-
?
amyloid beta-peptide 1-40 + H2O
?
-
cleavage occurs at peptide bonds Phe19-Phe20, Phe20-Ala21, and Leu34-Met35, with the latter cleavage site being the initial and principal one
-
?
amyloid beta-peptide 1-42 + H2O
?
-
cleavage occurs at peptide bonds Phe19-Phe20, Phe20-Ala21, and Leu34-Met35, with the latter cleavage site being the initial and principal one
-
?
CH3NH-Ala-Ala-Ala-CONHCH3 + H2O
?
-
energetic profile of proteolysis mechanism of IDE
-
-
?
CH3NH-Leu-Tyr-Leu-CONHCH3 + H2O
?
-
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
?
-
fluorogenic derivative of amyloid beta containing residues 10-25
-
-
?
epidermal growth factor + H2O
epidermal growth factor peptide fragments
-
identification of cleavage sites by mass spectrometry and NMR
-
-
?
insulin-like growth factor I + H2O
insulin-like growth factor I peptide fragments
-
-
-
-
?
insulin-like growth factor II + H2O
insulin-like growth factor II peptide fragments
-
-
-
-
?
insulin-like growth factor-II + H2O
insulin-like growth factor-II peptide fragments
-
identification of cleavage sites by mass spectrometry and NMR
-
-
?
peptide containing the mitochondrial targeting sequence of E1alpha subunit of human pyruvate dehydrogenase + H2O
?
-
hydrolysis occurs at several sites
-
-
?
reduced amylin + H2O
reduced amylin peptide fragments
-
identification of cleavage sites by mass spectrometry
-
-
?
transforming growth factor-alpha + H2O
transforming growth factor-alpha peptide fragments
-
identification of cleavage sites by mass spectrometry
-
-
?
ubiquitin + H2O
?
-
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
-
-
?
amyloid beta + H2O
?
role of insulin-degrading enzyme in the intracytosolic clearance of amyloid beta and other amyloid-like peptides
-
-
?
amyloid beta-peptide + H2O
?
degradation, IDE has no effect on the secreted ectodomain of the amyloid precursor protein derivative generated by alpha-secretase
-
-
?
amyloid beta40 + H2O
amyloid beta40 peptide fragments
Abeta40, an Alzheimer amyloid beta peptide
-
-
?
amyloid beta40 + H2O
amyloid beta40 peptide fragments
an Alzheimer amyloid beta peptide
-
-
?
amyloid beta42 + H2O
amyloid beta42 peptide fragments
Abeta42, an Alzheimer amyloid beta peptide
-
-
?
amyloid beta42 + H2O
amyloid beta42 peptide fragments
an Alzheimer amyloid beta peptide
-
-
?
amyloid-beta + H2O
?
activity is driven by the dynamic equilibrium between Abeta monomers and higher ordered aggregates. Met35-Val36 is a cleavage site in the amyloid-beta sequence. Amyloid-beta fragments resulting from cleavage by insulin-degrading enzyme form non-toxic amorphous aggregates
-
-
?
amyloid-beta + H2O
?
amyloid-beta monomers, either alone in solution or in dynamic equilibrium with higher aggregates, are cleaved at multiple sites by activity of insulin-degrading enzyme. Met35-Val36 is a cleavage site in the amyloid-beta sequence. Amyloid-beta fragments resulting from cleavage by insulin-degrading enzyme form non-toxic amorphous aggregates
-
-
?
Glucagon + H2O
?
the enzyme modulates blood glucose levels by cleaving insulin, a hormone that promotes glucose clearance. It also degrades glucagon, a hormone that elevates glucose levels and opposes the effect of insulin
-
-
?
insulin + H2O
?
in HEK cells the enzyme has little impact on insulin clearance
-
-
?
insulin + H2O
?
the enzyme modulates blood glucose levels by cleaving insulin, a hormone that promotes glucose clearance. It also degrades glucagon, a hormone that elevates glucose levels and opposes the effect of insulin
-
-
?
7-methoxycoumarin-4-yl-acetyl-RPPGFSAFK-2,4-dinitrophenyl + H2O
?
-
-
-
?
7-methoxycoumarin-4-yl-acetyl-RPPGFSAFK-2,4-dinitrophenyl + H2O
?
-
fluorogenic bradykinin-mimetic IDE substrate V
-
-
?
amylin + H2O
amylin peptide fragments
-
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 peptide + H2O
?
-
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 + H2O
?
-
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
?
-
degradation, role for insulysin in regulating amyloid beta peptide levels in the brain
-
-
?
amyloid beta-peptide + H2O
?
-
activation in trans is observed with extended substrates that occupy both the active and distal sites
-
-
?
insulin + H2O
?
-
degradation
-
-
?
insulin + H2O
?
-
insulin degrading enzyme is unlikely to be the relevant enzyme for endosomal proteolysis of internalized insulin in liver parenchyma
-
-
?
insulin + H2O
?
-
implicated in the process of membrane fusion and cell development
-
-
?
insulin + H2O
?
-
the enzyme may play a general role in hormone metabolism and cellular regulation
-
-
?
insulin + H2O
?
-
degradation, insulin internalized into Hep-G2 cells is able cross-link with intracellular insulysin
-
-
?
insulin + H2O
?
-
degradation, insulin occurs only in grade 3 tumors, whereas grade 2 carcinomas and the normal mammary gland are each insulin-negative, overview
-
-
?
insulin + H2O
?
-
degradation, reduced insulin degradation leads to type 2 diabetes, regulation, overview
-
-
?
insulin + H2O
?
-
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
?
-
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
Hydrolyzed insulin
-
-
-
-
?
Insulin + H2O
Hydrolyzed insulin
-
much better degradation than insulin growth factor II
-
-
?
Insulin + H2O
Hydrolyzed insulin
-
specific for insulin
degradation products are smaller than the A-chain of insulin
?
insulin + H2O
insulin peptide fragments
-
-
-
-
?
insulin + H2O
insulin peptide fragments
-
rapid degradation into inactive peptide fragments
-
-
?
insulin + H2O
insulin peptide fragments
-
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
-
IDE uses the size and charge distribution of the catalytic chamber and structural flexibility of the substrates to selectively recognize and degrade insulin
-
-
?
insulin-like peptide 3 + H2O
processed insulin-like peptide 3 + WSTEA
-
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
-
-
?
insulin-like peptide 3 + H2O
processed insulin-like peptide 3 + WSTEA
-
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
-
-
?
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
?
-
the enzyme selectively degrades biologically important substrates associated with type 2 diabetes and Alzheimer's disease
-
-
?
additional information
?
-
a functional requirement for active site residues F115, A140, F141, Y150, W199, F202, F820, and Y831 is established, and specific contributions of residue charge, size, and hydrophobicity to substrate binding, specificity, and proteolysis are demonstrated
-
-
?
additional information
?
-
-
a functional requirement for active site residues F115, A140, F141, Y150, W199, F202, F820, and Y831 is established, and specific contributions of residue charge, size, and hydrophobicity to substrate binding, specificity, and proteolysis are demonstrated
-
-
?
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
?
-
-
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
?
-
-
enzyme can degrade cleaved mitochondrial targeting sequences, role of enzyme within mitochondria
-
-
?
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 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
?
-
-
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. 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 SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
amyloid beta + H2O
?
role of insulin-degrading enzyme in the intracytosolic clearance of amyloid beta and other amyloid-like peptides
-
-
?
amyloid beta40 + H2O
amyloid beta40 peptide fragments
Abeta40, an Alzheimer amyloid beta peptide
-
-
?
amyloid beta42 + H2O
amyloid beta42 peptide fragments
Abeta42, an Alzheimer amyloid beta peptide
-
-
?
amyloid-beta + H2O
?
activity is driven by the dynamic equilibrium between Abeta monomers and higher ordered aggregates. Met35-Val36 is a cleavage site in the amyloid-beta sequence. Amyloid-beta fragments resulting from cleavage by insulin-degrading enzyme form non-toxic amorphous aggregates
-
-
?
Glucagon + H2O
?
the enzyme modulates blood glucose levels by cleaving insulin, a hormone that promotes glucose clearance. It also degrades glucagon, a hormone that elevates glucose levels and opposes the effect of insulin
-
-
?
amyloid beta + H2O
amyloid beta peptide fragments
-
-
-
-
?
epidermal growth factor + H2O
epidermal growth factor peptide fragments
-
identification of cleavage sites by mass spectrometry and NMR
-
-
?
insulin-like growth factor I + H2O
insulin-like growth factor I peptide fragments
-
-
-
-
?
insulin-like growth factor II + H2O
insulin-like growth factor II peptide fragments
-
-
-
-
?
insulin-like growth factor-II + H2O
insulin-like growth factor-II peptide fragments
-
identification of cleavage sites by mass spectrometry and NMR
-
-
?
insulin-like peptide 3 + H2O
processed insulin-like peptide 3 + WSTEA
-
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
-
-
?
reduced amylin + H2O
reduced amylin peptide fragments
-
identification of cleavage sites by mass spectrometry
-
-
?
transforming growth factor-alpha + H2O
transforming growth factor-alpha peptide fragments
-
identification of cleavage sites by mass spectrometry
-
-
?
amyloid beta-peptide + H2O
?
degradation, IDE has no effect on the secreted ectodomain of the amyloid precursor protein derivative generated by alpha-secretase
-
-
?
insulin + H2O
?
in HEK cells the enzyme has little impact on insulin clearance
-
-
?
insulin + H2O
?
the enzyme modulates blood glucose levels by cleaving insulin, a hormone that promotes glucose clearance. It also degrades glucagon, a hormone that elevates glucose levels and opposes the effect of insulin
-
-
?
amylin + H2O
amylin peptide fragments
-
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-peptide + H2O
?
-
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
?
-
degradation, role for insulysin in regulating amyloid beta peptide levels in the brain
-
-
?
insulin + H2O
?
-
insulin degrading enzyme is unlikely to be the relevant enzyme for endosomal proteolysis of internalized insulin in liver parenchyma
-
-
?
insulin + H2O
?
-
implicated in the process of membrane fusion and cell development
-
-
?
insulin + H2O
?
-
the enzyme may play a general role in hormone metabolism and cellular regulation
-
-
?
insulin + H2O
?
-
degradation, insulin internalized into Hep-G2 cells is able cross-link with intracellular insulysin
-
-
?
insulin + H2O
?
-
degradation, insulin occurs only in grade 3 tumors, whereas grade 2 carcinomas and the normal mammary gland are each insulin-negative, overview
-
-
?
insulin + H2O
?
-
degradation, reduced insulin degradation leads to type 2 diabetes, regulation, overview
-
-
?
insulin + H2O
?
-
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 peptide fragments
-
-
-
-
?
insulin + H2O
insulin peptide fragments
-
rapid degradation into inactive peptide fragments
-
-
?
additional information
?
-
the enzyme selectively degrades biologically important substrates associated with type 2 diabetes and Alzheimer's disease
-
-
?
additional information
?
-
-
enzyme can degrade cleaved mitochondrial targeting sequences, role of enzyme within mitochondria
-
-
?
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
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additional information
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the insulin-degrading enzyme is genetically associated with Alzheimer's disease in the Finnish population, overview
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additional information
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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
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Zn2+
Mn2+
thiol
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the enzyme is a neutral thiol metalloprotease requiring both free thiol and divalent cations for activity
Zinc
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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+
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+
dependent on, zinc metallopeptidase, simulated structures of the Zn2+ metal center, overview
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
Zn2+
-
the enzyme is a neutral thiol metalloprotease requiring both free thiol and divalent cations for activity
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
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
((((S)-1-benzylcarbamoyl-2-(1H-imidazol-4-yl)-ethylcarbamoyl)-methyl)-(3-phenyl-propyl)-amino)-acetic acid
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((((S)-2-(1H-imidazol-4-yl)-1-(3-methyl-(1,2,4)oxadiazol-5-yl)-ethylcarbamoyl)-methyl)-(3-phenyl-propyl)-amino)-acetic acid
-
((((S)-2-(1H-imidazol-4-yl)-1-(3-methyl-(1,2,4)oxadiazol-5-yl)-ethylcarbamoyl)-methyl)-(3-phenyl-propyl)-amino)-acetic acid methyl ester
less than 10% inhibition at 0.1 mM
((((S)-2-(1H-imidazol-4-yl)-1-methylcarbamoylethylcarbamoyl)-methyl)-(3-phenyl-propyl)-amino)-acetic acid
BDM43079
((((S)-2-(1H-imidazol-4-yl)-1-methylcarbamoylethylcarbamoyl)-methyl)-(3-phenyl-propyl)-amino)-acetic acid methyl ester
less than 10% inhibition at 0.1 mM
((((S)-2-hydroxy-1-(1H-imidazol-4-ylmethyl)-ethylcarbamoyl)-methyl)-(3-phenyl-propyl)-amino)-acetic acid
-
(11R,12S,13S)-13-(hydroxymethyl)-12-(2'-methylbiphenyl-4-yl)-9-[[2-(trifluoromethyl)phenyl]sulfonyl]-1,9-diazabicyclo[9.2.0]tridecan-2-one
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.00006 mM
(3R,6S,9S,12E,16S)-9-(4-aminobutyl)-3-(4-benzoylbenzyl)-6-(cyclohexylmethyl)-2,5,8,11,14-pentaoxo-1,4,7,10,15-pentaazacycloicos-12-ene-16-carboxamide
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.00005 mM
(7R,8S,9S)-8-(2',3'-dimethylbiphenyl-4-yl)-9-(hydroxymethyl)-5-[[2-(trifluoromethyl)phenyl]sulfonyl]-1,5-diazabicyclo[5.2.0]nonan-2-one
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.00012 mM
(8R,9R,10S)-N-cyclopentyl-10-(hydroxymethyl)-9-(2'-methylbiphenyl-4-yl)-1,6-diazabicyclo[6.2.0]decane-6-carboxamide
the inhibitor fully blocks insulin degradation in a concentration-dependent manner, while only weakly and partially inhibiting glucagon degradation. It inhibits wild-type enzyme, but does not inhibit A479L exo-site variant. It displays decreased affinity
(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-10-(fluoromethyl)-6-[[2-(trifluoromethyl)phenyl]sulfonyl]-1,6-diazabicyclo[6.2.0]decane
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000024 mM
(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-10-(hydroxymethyl)-6-[[2-(trifluoromethyl)phenyl]sulfonyl]-1,6-diazabicyclo[6.2.0]decan-2-one
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.00008 mM
(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-10-(methoxymethyl)-6-[[2-(trifluoromethyl)phenyl]sulfonyl]-1,6-diazabicyclo[6.2.0]decane
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000075 mM
(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[[2-(trifluoromethyl)phenyl]sulfonyl]-1,6-diazabicyclo[6.2.0]decane-10-carboxylic acid
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0005 mM
(9R,10S,11S)-10-(2',3'-dimethylbiphenyl-4-yl)-11-(hydroxymethyl)-7-[[2-(trifluoromethyl)phenyl]sulfonyl]-1,7-diazabicyclo[7.2.0]undecan-2-one
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0001 mM
(benzyl-(((S)-1-benzylcarbamoyl-2-(1H-imidazol-4-yl)-ethylcarbamoyl)-methyl)-amino)-acetic acid
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(benzyl-(((S)-1-carbamoyl-2-(1H-imidazol-4-yl)-ethylcarbamoyl)-methyl)-amino)-acetic acid
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(benzyl-(((S)-1-dimethylcarbamoyl-2-(1H-imidazol-4-yl)-ethylcarbamoyl)-methyl)-amino)-acetic acid
-
(benzyl-(((S)-2-(1H-imidazol-4-yl)-1-methylcarbamoylethylcarbamoyl)-methyl)-amino)-acetic acid
-
(benzyl-(((S)-2-hydroxy-1-(1H-imidazol-4-ylmethyl)-ethylcarbamoyl)-methyl)-amino)-acetic acid
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(benzyl-((2-(1H-imidazol-4-yl)-ethylcarbamoyl)-methyl)-amino)-acetic acid
less than 10% inhibition at 0.1 mM
(S)-2-(2-((4-tert-butyl-benzyl)-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(benzoyl-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-2-(2-(benzyl-(1H-tetrazol-5-ylmethyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-N-methyl-propionamide
less than 10% inhibition at 0.1 mM
(S)-2-(2-(benzyl-(2-carboxy-ethyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-2-(2-(benzyl-(2-hydroxy-3,4-dioxo-cyclobut-1-enyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(benzyl-carbamoylmethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid
less than 10% inhibition at 0.1 mM
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid isopropyl ester
-
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid tert-butyl ester
-
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-(1H-indol-3-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-(3H-imidazol-4-yl)-propionic acid isobutyl ester
-
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-phenyl-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-5-guanidino-pentanoic acid methyl ester
-
(S)-2-(2-(benzyl-hydroxycarbamoylmethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(benzyl-methoxycarbonylmethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-2-(2-(benzyloxycarbonyl-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-2-(2-(carboxymethyl-(1-methyl-3-phenyl-propyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(carboxymethyl-(2-(1H-indol-3-yl)-ethyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(carboxymethyl-(3-phenyl-propionyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-2-(2-(carboxymethyl-(3-phenyl-propyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(carboxymethyl-(3-phenyl-propyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid tert-butyl ester
-
(S)-2-(2-(carboxymethyl-(4-fluoro-benzyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(carboxymethyl-(4-methyl-benzyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(carboxymethyl-(4-phenyl-butyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(carboxymethyl-(4-trifluoromethyl-benzyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(carboxymethyl-(n-hexyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(carboxymethyl-amino)-acetylamino)-3-(1Himidazol-4-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-2-(2-(carboxymethyl-methyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-2-(2-(carboxymethyl-naphthalen-2-ylmethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(carboxymethyl-phenethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-(carboxymethyl-phenyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-2-(2-(carboxymethyl-phenylacetyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-2-(2-(carboxymethyl-pyridin-4-ylmethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
-
(S)-2-(2-benzylamino-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
1-[(8R,9R,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[[2-(trifluoromethyl)phenyl]sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]-N,N-dimethylmethanamine
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0001 mM
1-[(8R,9R,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[[2-(trifluoromethyl)phenyl]sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]-N-methylmethanamine
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000007 mM
3-(((S)-1-methoxy-1-oxo-3-imidazol-2-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-2-ethanoic acid
-
3-benzyl-4-((S)-2-(1H-imidazol-4-yl)-1-methylcarbamoylethylcarbamoyl)-butyric acid
less than 10% inhibition at 0.1 mM
4'-[(8R,9S,10S)-10-(hydroxymethyl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-9-yl]biphenyl-3-ol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0073 mM
methyl 5-[[(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-10-(hydroxymethyl)-1,6-diazabicyclo[6.2.0]dec-6-yl]sulfonyl]-1-methyl-1H-pyrrole-2-carboxylate
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: above 0.005 mM
methyl [(2S)-2-(5-[5-[4-([(2S)-2-[(3S)-3-amino-2-oxopiperidin-1-yl]-2-cyclohexylacetyl]amino)phenyl]pentyl]-2-fluorophenyl)-3-(quinolin-3-yl)propyl]carbamate
-
methyl [(2S)-2-[4-([5-[4-([(2S)-2-[(3S)-3-amino-2-oxopiperidin-1-yl]-2-cyclohexylacetyl]amino)phenyl]pentyl]oxy)phenyl]-3-(quinolin-3-yl)butyl]carbamate
-
N-(4-[[(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-10-(hydroxymethyl)-1,6-diazabicyclo[6.2.0]dec-6-yl]sulfonyl]-3-methylphenyl)acetamide
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0016 mM
N-[[(2R,3S,4S)-1-acetyl-3-(2',3'-dimethylbiphenyl-4-yl)-4-(hydroxymethyl)azetidin-2-yl]methyl]-2-(trifluoromethyl)benzenesulfonamide
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000115 mM
N-[[(2R,3S,4S)-3-(2',3'-dimethylbiphenyl-4-yl)-4-(hydroxymethyl)-1-(prop-2-en-1-yl)azetidin-2-yl]methyl]-2-(trifluoromethyl)benzenesulfonamide
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0001 mM
N-[[(2R,3S,4S)-3-(2',3'-dimethylbiphenyl-4-yl)-4-(hydroxymethyl)azetidin-2-yl]methyl]-2-(trifluoromethyl)benzenesulfonamide
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0006 mM
N2-[(2S)-4-(hydroxyamino)-2-(naphthalen-2-ylmethyl)-4-oxobutanoyl]-L-arginyl-L-tryptophyl-L-glutamine
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0000006 mM
[(3Z,8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-(6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-ylsulfonyl)-1,6-diazabicyclo[6.2.0]dec-3-en-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000042 mM
[(3Z,8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[(1,2-dimethyl-1H-imidazol-5-yl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-3-en-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000001 mM
[(3Z,8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[(1-ethyl-5-methyl-1H-pyrazol-4-yl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-3-en-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000016 mM
[(3Z,8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[(1-propyl-1H-pyrazol-5-yl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-3-en-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000018 mM
[(3Z,8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[(2-methylpyridin-3-yl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-3-en-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000022 mM
[(3Z,8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl]-1,6-diazabicyclo[6.2.0]dec-3-en-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000065 mM
[(8R,9S,10S)-6-(cyclohexylsulfonyl)-9-(2',3'-dimethylbiphenyl-4-yl)-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.00046 mM
[(8R,9S,10S)-6-[(2-methylphenyl)sulfonyl]-9-[2'-methyl-3'-(trifluoromethyl)biphenyl-4-yl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000095 mM
[(8R,9S,10S)-9-(2',3'-dichlorobiphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000009 mM
[(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[(1,3-dimethyl-1H-pyrazol-5-yl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000024 mM
[(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[(1-methyl-1H-imidazol-2-yl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0000005 mM
[(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.00006 mM
[(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0000015 mM
[(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[(4-methylpiperazin-1-yl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000032 mM
[(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[[1-(propan-2-yl)-1H-pyrazol-5-yl]sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000015 mM
[(8R,9S,10S)-9-(2',3'-dimethylbiphenyl-4-yl)-6-[[2-(trifluoromethyl)phenyl]sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000001 mM
[(8R,9S,10S)-9-(2',5'-dimethylbiphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000054 mM
[(8R,9S,10S)-9-(2'-methoxybiphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.00025 mM
[(8R,9S,10S)-9-(2'-methylbiphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000032 mM
[(8R,9S,10S)-9-(3',4'-dimethylbiphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.00014 mM
[(8R,9S,10S)-9-(3',5'-dimethylbiphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000061 mM
[(8R,9S,10S)-9-(3'-chloro-2'-methylbiphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.000035 mM
[(8R,9S,10S)-9-(3'-fluoro-2'-methylbiphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.00007 mM
[(8R,9S,10S)-9-(3'-fluorobiphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.00007 mM
[(8R,9S,10S)-9-(3'-methoxybiphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0005 mM
[(8R,9S,10S)-9-(3'-methylbiphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
the inhibitor fully blocks insulin degradation in a concentration-dependent manner, while only weakly and partially inhibiting glucagon degradation. It inhibits wild-type enzyme, but does not inhibit A479L exo-site variant. It displays decreased affinity
[(8R,9S,10S)-9-(biphenyl-4-yl)-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0004 mM
[(8R,9S,10S)-9-[3'-fluoro-2'-(trifluoromethyl)biphenyl-4-yl]-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.00017 mM
[(8R,9S,10S)-9-[4-(1,3-benzodioxol-5-yl)phenyl]-6-[(2-methylphenyl)sulfonyl]-1,6-diazabicyclo[6.2.0]dec-10-yl]methanol
half-maximum effective concentration in fluorogenic decapeptide ([(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH) cleavage assay: 0.0029 mM
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
insulin-like peptide 3
-
IDE degrades insulin quickly, and addition of INSL3 significantly decreases insulin degradation, competitive inhibition
-
nitric oxide
-
amyloid beta peptide degradation by IDE is inhibited by NO donor Sin-1
sulfhydryl-modifying reagents
-
Drosophila, human and rat enzyme inhibited, bacterial enzyme not
-
EDTA
-
the activation of IDE disappears upon inactivation by EDTA, which chelates the catalytic Zn2+ ion
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 37°C, 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
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
additional information
-
not: the enzyme is inhibited by cysteine protease inhibitors as well as metalloprotease inhibitors
-
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
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ADP
activates, the activating effect of ATP is greater than hat of ADP, which in turn is much greater than that of AMP
alpha-synuclein
a peptide with the C-terminal 44 residues of alpha-synuclein increases insulin-degrading enzyme proteolysis to the same degree as full-length alpha-synuclein. A peptide containing the first 97 residues of alpha-synuclein does not improve insulin-degrading enzyme activity. Because the alpha-synuclein C-terminus is acidic, the interaction appears to involve electrostatic attraction with basic exosite of insulin-degrading enzyme
-
AMP
activates, the activating effect of ATP is greater than hat of ADP, which in turn is much greater than that of AMP
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
resveratrol
incubation with resveratrol results in a substantial increase in Abeta42 fragmentation compared to the control, signifying that the polyphenol sustains insulin-degrading enzyme-dependent degradation of Abeta42 and its fragments
Somatostatin
enhances the proteolytic processing of a synthetic beta-amyloid-peptide. In addition to being a substrate, somatostatin is also able to bind to two additional exosites, which play different roles according to the size of the substrate and its binding mode to the catalytic cleft of the enzyme. One exosite, which displays high affinity for somatostatin, regulates only the interaction of insulin-degrading-enzyme with larger substrates (such as insulin and beta-amyloid1-40) in a differing fashion according to their various modes of binding to the enzyme. A second exosite, which is involved in the regulation of enzymatic processing by the enzyme of all substrates investigated (including a 10-25 amino acid long amyloid-like peptide, bradykinin and somatostatin itself), probably acts through the alteration of an open-closed equilibrium
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
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
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
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
additional information
purine nucleotide triphosphates are better activators than pyrimidine nucleotide triphosphates
-
additional information
-
purine nucleotide triphosphates are better activators than pyrimidine nucleotide triphosphates
-
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]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0099
(7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK(2,4-dinitrophenyl)-OH
37°C, pH not specified in the publication
0.0028
amyloid beta-peptide 1-40
pH not specified in the publication, temperature not specified in the publication
-
0.0023
amyloid beta-peptide 1-42
pH not specified in the publication, temperature not specified in the publication
-
1.2 - 2.3
Dabcyl-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Glu(EDANS)-NH2
0.025
amyloid beta-peptide1-40
recombinant wild-type enzyme, pH 7.4, 37°C
-
0.027
amyloid beta-peptide1-40
recombinant mutant D426C/K899C, pH 7.4, 37°C
-
0.0056
(7-methoxycoumarin-4-yl)acetyl-KLVFFAEDK(Dnp)-OH
pH 7.0, 37°C, mutant enzyme R183Q
0.0076
(7-methoxycoumarin-4-yl)acetyl-KLVFFAEDK(Dnp)-OH
pH 7.0, 37°C, wild-type enzyme
0.0047
7-methoxycoumarin-4-yl-acetyl-RPPGFSAFK-2,4-dinitrophenyl
pH 7.0, 37°C, wild-type enzyme
0.0049
7-methoxycoumarin-4-yl-acetyl-RPPGFSAFK-2,4-dinitrophenyl
pH 7.0, 37°C, mutant enzyme R183Q
0.0148
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37°C, mutant Y609F IDE:IDE mutant E111F/Y609F
0.0192
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37°C, mutant Y609F IDE:IDE mutant H112Q/Y609F
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, 37°C, 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, 37°C
0.0001
Insulin
-
pH not specified in the publication, temperature not specified in the publication
-
additional information
additional information
-
amyloid beta degradation kinetics in presence or absence of activators
-
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
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.23
(7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK(2,4-dinitrophenyl)-OH
37°C, pH not specified in the publication
0.028
(7-methoxycoumarin-4-yl)acetyl-NPPGFSAFK-2,4-dinitrophenyl
-
pH not specified in the publication, 37°C
0.0022
amyloid beta-peptide 1-40
pH not specified in the publication, temperature not specified in the publication
-
0.0004
amyloid beta-peptide 1-42
pH not specified in the publication, temperature not specified in the publication
-
61 - 62.7
Dabcyl-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Glu(EDANS)-NH2
0.29
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F820Y
0.298
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme Y150K
0.33
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme 141A
0.338
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme Y150F
0.45
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme Y150W
0.53
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F202D
0.57
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme W199Y
0.57
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, wild-type enzyme
0.625
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme 141W
0.72
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F115Y
0.725
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F115A
0.73
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F115W
0.735
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F202Y
0.78
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme 141Y
0.803
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F202W
0.85
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F820W
1.1
(7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme Y150F
0.088
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme W199K
0.095
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme Y150K
0.097
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F202D
0.097
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F202K
0.1
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F141W
0.108
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F820Y
0.123
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F141N
0.143
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme Y150W
0.148
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F202W
0.16
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F820W
0.16
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme W199Y
0.17
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F202N
0.177
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme W199N
0.178
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F141Y
0.18
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme W199A
0.198
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, wild-type enzyme
0.2
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F115Y
0.22
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F141A
0.22
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme Y150F
0.24
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme F202Y
0.24
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH
pH 7.3, 37°C, mutant enzyme W199F
20
amyloid beta-peptide1-40
recombinant mutant D426C/K899C, pH 7.4, 37°C
-
1.2
(7-methoxycoumarin-4-yl)acetyl-KLVFFAEDK(Dnp)-OH
pH 7.0, 37°C, mutant enzyme R183Q
7.5
(7-methoxycoumarin-4-yl)acetyl-KLVFFAEDK(Dnp)-OH
pH 7.0, 37°C, wild-type enzyme
1.2
7-methoxycoumarin-4-yl-acetyl-RPPGFSAFK-2,4-dinitrophenyl
pH 7.0, 37°C, mutant enzyme R183Q
6.5
7-methoxycoumarin-4-yl-acetyl-RPPGFSAFK-2,4-dinitrophenyl
pH 7.0, 37°C, wild-type enzyme
0.003
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37°C, mutant Y609F IDE:IDE mutant E111F/Y609F
0.06
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, 37°C, mutant Y609F IDE:IDE mutant H112Q/Y609F
61
Dabcyl-Tyr-Glu-Val-His-His-Gln-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Glu(EDANS)-NH2
-
pH 7.3, 37°C, 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, 37°C
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
23.4
(7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK(2,4-dinitrophenyl)-OH
37°C, pH not specified in the publication
0.803
amyloid beta-peptide 1-40
pH not specified in the publication, temperature not specified in the publication
-
0.178
amyloid beta-peptide 1-42
pH not specified in the publication, temperature not specified in the publication
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0004
((((S)-1-benzylcarbamoyl-2-(1H-imidazol-4-yl)-ethylcarbamoyl)-methyl)-(3-phenyl-propyl)-amino)-acetic acid
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0005
((((S)-2-(1H-imidazol-4-yl)-1-(3-methyl-(1,2,4)oxadiazol-5-yl)-ethylcarbamoyl)-methyl)-(3-phenyl-propyl)-amino)-acetic acid
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0001
((((S)-2-(1H-imidazol-4-yl)-1-methylcarbamoylethylcarbamoyl)-methyl)-(3-phenyl-propyl)-amino)-acetic acid
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0016
((((S)-2-hydroxy-1-(1H-imidazol-4-ylmethyl)-ethylcarbamoyl)-methyl)-(3-phenyl-propyl)-amino)-acetic acid
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0014
(benzyl-(((S)-1-benzylcarbamoyl-2-(1H-imidazol-4-yl)-ethylcarbamoyl)-methyl)-amino)-acetic acid
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0014
(benzyl-(((S)-1-carbamoyl-2-(1H-imidazol-4-yl)-ethylcarbamoyl)-methyl)-amino)-acetic acid
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0069
(benzyl-(((S)-1-dimethylcarbamoyl-2-(1H-imidazol-4-yl)-ethylcarbamoyl)-methyl)-amino)-acetic acid
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0006
(benzyl-(((S)-2-(1H-imidazol-4-yl)-1-methylcarbamoylethylcarbamoyl)-methyl)-amino)-acetic acid
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0041
(benzyl-(((S)-2-hydroxy-1-(1H-imidazol-4-ylmethyl)-ethylcarbamoyl)-methyl)-amino)-acetic acid
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0029
(S)-2-(2-((4-tert-butyl-benzyl)-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0125
(S)-2-(2-(benzyl-(2-hydroxy-3,4-dioxo-cyclobut-1-enyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0003
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid isopropyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0029
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0008
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid tert-butyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0006
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-(3H-imidazol-4-yl)-propionic acid isobutyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0363
(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-5-guanidino-pentanoic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0032
(S)-2-(2-(benzyl-hydroxycarbamoylmethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0006
(S)-2-(2-(carboxymethyl-(1-methyl-3-phenyl-propyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0012
(S)-2-(2-(carboxymethyl-(2-(1H-indol-3-yl)-ethyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.001
(S)-2-(2-(carboxymethyl-(3-phenyl-propyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0004
(S)-2-(2-(carboxymethyl-(3-phenyl-propyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid tert-butyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0025
(S)-2-(2-(carboxymethyl-(4-fluoro-benzyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0017
(S)-2-(2-(carboxymethyl-(4-methyl-benzyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0006
(S)-2-(2-(carboxymethyl-(4-phenyl-butyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.002
(S)-2-(2-(carboxymethyl-(4-trifluoromethyl-benzyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0004
(S)-2-(2-(carboxymethyl-(n-hexyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0012
(S)-2-(2-(carboxymethyl-naphthalen-2-ylmethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0014
(S)-2-(2-(carboxymethyl-phenethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0063
(S)-2-(2-(carboxymethyl-pyridin-4-ylmethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.0036
3-(((S)-1-methoxy-1-oxo-3-imidazol-2-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-2-ethanoic acid
Homo sapiens
in HEPES 50 mM, NaCl 100 mM, pH 7.4, at 37°C
0.000018
methyl [(2S)-2-(5-[5-[4-([(2S)-2-[(3S)-3-amino-2-oxopiperidin-1-yl]-2-cyclohexylacetyl]amino)phenyl]pentyl]-2-fluorophenyl)-3-(quinolin-3-yl)propyl]carbamate
Homo sapiens
37°C, pH 7.5
0.000015
methyl [(2S)-2-[4-([5-[4-([(2S)-2-[(3S)-3-amino-2-oxopiperidin-1-yl]-2-cyclohexylacetyl]amino)phenyl]pentyl]oxy)phenyl]-3-(quinolin-3-yl)butyl]carbamate
Homo sapiens
37°C, pH 7.5
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
cytosolic IDE and membrane-bound IDE activity, and clinical dementia scores, 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
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.3
assay at, substrate (7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK-2,4-dinitrophenyl
7.4
assay at, substrates amyloid beta-peptide and o-aminobenzoic acid-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22
assay at, substrate o-aminobenzoic acid-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl
37
37
assay at, substrates amyloid beta-peptide and (7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK-2,4-dinitrophenyl
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
683651, 707526, 733513, 733788, 734222, 735168, 752373, 752656, 752772, 752782, 752806, 753039, 753246, 753340, 753552, 754114, 754821
UniProt
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
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
in Alzheimer's disease patients the protein level of insulin-degrading enzyme is decreased compared to control. However, mRNA of insulin-degrading enzyme is higher in cortex of Alzheimer's disease patients
in Alzheimer's disease patients the protein level of insulin-degrading enzyme is decreased compared to control
-
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
-
endothelium of the cerebrovascular blood vessel, expression of enzyme
-
post-mortal samples, regional and cellular distribution pattern, immunohistochemic analysis, overview
additional information
-
endothelium of the cerebrovascular blood vessel, expression of enzyme
-
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
-
post-mortal brains, regional and cellular distribution pattern, immunohistochemic analysis, overview
-
left and right dorsolateral prefrontal cortex, expression of IDE protein in postmortem brains of healthy subjects and patients with schizophrenia, immunohistochemic analysis, overview
-
cells express enzyme and respond to exposure to low levels of amyloid beta-protein by upregulation of enzyme expression
-
cerebrovascular, the this cell surface form is the major form of insulysin responsible for degrading amyloid beta-peptides
-
insulysin is reduced in the hippocampus of Alzheimer's disease patients with an apolipoprotein E-4 allele
additional information
-
insulin occurs only in grade 3 tumors, whereas grade 2 carcinomas and the normal mammary gland are each insulin-negative, overview
additional information
-
tissue expression pattern in wild-type mice, tissue-specific regulation, overview
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
LOCALIZATION
ORGANISM
UNIPROT
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
additional information
-
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
-
associated to plasma membrane, mainly at basolateral cell surface
-
-
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
-
-
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
-
a form of the enzyme derived from an alternative translational start site that can localize to mitochondria
-
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
additional information
-
cellular distribution patterns in different tissues and brain regions, immunohistochemic analysis, overview
-
additional information
-
interplay between retinoblastoma tumor suppressor protein and IDE within the proteasome that may have important growth-regulatory consequences
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
malfunction
metabolism
physiological function
additional information
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
enzyme downregulation impairs SHSY5Y cell proliferation and triggers cell death. Enzyme inhibition is accompanied by a decrease of the poly-ubiquitinated protein content and co-immunoprecipitates with proteasome and ubiquitin in SHSY5Y cells
metabolism
ATP regulates insulin-degrading enzyme-dependent degradation of insulin, but the addition of Mg2+ abolishes the regulation
metabolism
the enzyme activates ubiquitin and promotes the formation of K48 and K63 diubiquitin
metabolism
the enzyme modulates blood glucose levels by cleaving insulin, a hormone that promotes glucose clearance. It also degrades glucagon, a hormone that elevates glucose levels and opposes the effect of insulin
physiological function
insulin-degrading enzyme selectively degrades the monomer of amyloidogenic peptides and contributes to clearance of amyloid-beta. Thus, the enzyme retards the progression of Alzheimers disease
physiological function
role of insulin-degrading enzyme in the intracytosolic clearance of amyloid beta and other amyloid-like peptides
physiological function
the enzyme has a minimal role in insulin metabolism in vivo. It may be more important in helping regulate amylin clearance
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
-
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
-
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
-
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 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 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 key role in degrading both amyloid beta and insulin
physiological function
-
IDE plays a primary role in insulin degradation and cellular insulin processing
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
-
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
physiological function
beta-site amyloid precursor protein-cleaving enzyme BACE2 overexpression in cultured cells lowers net amyloid beta levels with comparable effectiveness to insulin degrading enzyme
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
-
interplay between retinoblastoma tumor suppressor protein and IDE within the proteasome that may have important growth-regulatory consequences
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). IDE_HUMAN
1019
0
117968
Swiss-Prot
Mitochondrion (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
110000
113000
2 * 113000, homodimer or heterodimer of isoforms 15a-IDE and 15b-IDE, SDS-PAGE
110000
113000
-
x * 113000, native enzyme, x * 56000, isolated C-terminal domain IDE-C, 1 * 60000, isolated N-terminal domain IDE-N, SDS-PAGE
56000
-
x * 113000, native enzyme, x * 56000, isolated C-terminal domain IDE-C, 1 * 60000, isolated N-terminal domain IDE-N, SDS-PAGE
60000
-
x * 113000, native enzyme, x * 56000, isolated C-terminal domain IDE-C, 1 * 60000, isolated N-terminal domain IDE-N, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
monomer
oligomer
-
monomeric IDE is composed of two domains, N- and C-terminal domain, of about 55000 Da, can occur as tetramer or dimer
additional information
dimer
2 * 113000, homodimer or heterodimer of isoforms 15a-IDE and 15b-IDE, SDS-PAGE
?
-
x * 113000, native enzyme, x * 56000, isolated C-terminal domain IDE-C, 1 * 60000, isolated N-terminal domain IDE-N, SDS-PAGE
additional information
-
human enzyme partially exists as homodimer or heterodimer
additional information
-
enzyme interacts with Varicella zoster virus glycoprotein E through its extracellular domain
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
-
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
-
the enzyme is probably part of a multienzyme complex and co-isolates with the multicatalytic proteinase
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
COMMENTARY
LITERATURE
proteolytic modification
-
for the mitochondrial isoform, mitochondrial targeting sequence of 41 amino acids is probably removed upon import into mitochondria
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging drop vapor diffusion method, using 0.1 M sodium cacodylate (pH 6.5), 0.2 M MgCl2, and 10% (w/v) PEG-3000 at 18°C
hanging drop vapor diffusion method, X-ray co-crystal structures, including an insulin-degrading enzyme-ligand-glucagon ternary complex, reveal substrate-dependent interactions that enable these inhibitors to potently block insulin binding while allowing glucagon cleavage, even at saturating inhibitor concentrations
mutant E111Q, in complex with inhibitors, hanging drop vapor-diffusion method, using 10-13% (w/v) PEG MME 5000, 100 mM HEPES pH 7.0, 4-14% (w/v) tacsimate, 10% (v/v) dioxane
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
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, 18°C, 3-5 days, X-ray diffraction structure determination and analysis at 2.6-2.8 A resolution, molecular replacement
-
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
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A140D
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
A140F
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
A140K
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
A140N
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
A140W
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
A140Y
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
D426C/K899C
site-directed mutagenesis, hyperactive IDE mutation, the mutant shows increased activity, but reduced activationby ATP compared to the wild-type enzyme
E111Q
F530A
the mutation renders the enzyme hyperactive, with up to a 20fold enhancement in degrading activity
K898A
P286G
the mutation results in a significant reduction of enzyme catalysis
Y831A
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
Y831D
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
Y831F
Y831K
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
Y831N
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
Y831W
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
C819A
-
thiol-directed modification of C819 likely causes local structure perturbation to reduce substrate binding and catalysis
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
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
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
R183a
about 35% of the activity compared to wild-type enzyme with the substrate
R183D
less than 5% of the activity compared to wild-type enzyme with the substrate (7-methoxycoumarin-4-yl)acetyl-KLVFFAEDK(Dnp)-OH
R183E
about less than 5% of the activity compared to wild-type enzyme with the substrate (7-methoxycoumarin-4-yl)acetyl-KLVFFAEDK(Dnp)-OH
R183K
about 30% of the activity compared to wild-type enzyme with the substrate (7-methoxycoumarin-4-yl)acetyl-KLVFFAEDK(Dnp)-OH
R183N
about 10% of the activity compared to wild-type enzyme with the substrate (7-methoxycoumarin-4-yl)acetyl-KLVFFAEDK(Dnp)-OH
R183Q
mutant Pitrm1 R183Q is implicated in inherited amyloidogenic neuropathy. Recombinant R183Q mutant is less active than the recombinant wild-type enzyme against recombinant amyloid beta-peptide (Abeta1-40). R183Q mutant enzyme exhibits significantly decreased rate of fluorogenic peptide hydrolysis ((7-methoxycoumarin-4-yl)acetyl-KLVFFAEDK(Dnp)-OH), yet retains similar binding affinity by comparison with the wild-type enzyme. Residue R183 is positioned within an N-terminal strand-loop-strand motif that is essential for enzyme function. A requirement for charged residues within 4.5 A of residue R183 is demonstrated. The R183Q mutant enzyme exhibits increased sensitivity to heat inactivation
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
additional information
E111Q
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
Y831F
site-directed mutagenesis, the mutant shows catalytic activity similar to the wild-type enzyme
Y831F
specific activity with the substrates (7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH and (7-methoxycoumarin-4-yl)acetyl-QKLVFFAEDVK(2,4-dinitrophenyl)-OH is below 1 nmol/min*mg
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
additional information
-
chromosome 10-linked Alzheimer disease families show decreased enzyme activity
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
-
enzyme deficiency leads to development of either Alzheimer's disease and type 2 diabetes, overview
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
-
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
-
no correlation of single nucleotide polymorphisms and IDE haplotypes with the risk of dementia, overview
additional information
-
overexpression of insulysin in human amyloid precursor protein transgenic mice leads to a decrease in amyloid beta peptide levels
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
-
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
-
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
-
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
-
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%
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
3 - 5
at very low pH (less than 5.0) the enzyme loses its capability to bind insulin at the catalytic site, so that the substrate is quickly released
733513
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
LITERATURE
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni-NTA column chromatography, Source Q column chromatography, and Superdex 200 gel filtration
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
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
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
glutathione S-transferase-tagged human insulin-degrading enzyme in pGEX-6p-1 vector is transformed into Escherichia coli BL21-CodonPlus (DE3) competent cells
wild-type and E111Q glutathione S-transferase tagged human insulin-degrading enzyme are expressed in Escherichia coli BL21 (DE3) codon plus competent cells
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
-
expressed in and isolated from Escherichia coli as C-terminal polyhistidine tagged fusion partners lacking N-terminal mitochondrial targeting sequence
expression of His-tagged wild-type and mutant IDEs in Escherichia coli strain Rosetta (DE3)
-
expression of the enzyme in transgenic mice under control of the H1 CMV promoter
-
genetic linkage and association of Alzheimer disease on chromosome 10q23-24 in the region harboring the IDE gene
-
IDE gene is localized on chromosome 10q24, genotyping of IDE in the Finnish population, overview
-
IDE genotyping, expression of promoter constructs in Hela cells and SH-SY5Y cells
-
polyhistidine- and haemagglutinin-tagged recombinant wild-type and catalytically inactive mutants expressed in bacteria
-
the gene encoding IDE is located on chromosome 10q23-q25, a gene locus linked to schizophrenia
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
all-trans retinoic acid treatment down-regulates enzyme expression in neuroblastoma cells
enzyme expression is stress-inducible (heat shock at 48°C for 15 and 30 min, increasing concentrations of H2O2, and serum starvation for 60 min) and up-regulated in some central nervous system tumors
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
-
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
-
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
-
reduced neuronal expression of insulin-degrading enzyme in the dorsolateral prefrontal cortex of patients with haloperidol-treated, chronic schizophrenia
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
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
medicine
the enzyme modulates blood glucose levels by cleaving insulin, a hormone that promotes glucose clearance. It also degrades glucagon, a hormone that elevates glucose levels and opposes the effect of insulin. Insulin-degrading enzyme inhibitors to treat diabetes, therefore, should prevent insulin-degrading enzyme-mediated insulin degradation, but not glucagon degradation. Using a high-throughput screen for non-active-site ligands, potent and highly specific small-molecule inhibitors are discovered that alter substrate selectivity of insulin-degrading enzyme. X-ray co-crystal structures, including an insulin-degrading enzyme-ligand-glucagon ternary complex, reveal substrate-dependent interactions that enable these inhibitors to potently block insulin binding while allowing glucagon cleavage, even at saturating inhibitor concentrations
medicine
therapeutic and/or preventative approaches combining resveratrol and insulin-degrading enzyme may hold promise for sporadic 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
-
substrate amyloid beta-protein is an essential factor in the pathogenesis of Alzheimer's disease
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 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
-
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
beta-site amyloid precursor protein-cleaving enzyme BACE2 overexpression in cultured cells lowers net amyloid beta levels to a greater extent than multiple, well-established amyloid beta-degrading proteases, including neprilysin and endothelinconverting enzyme-1, while showing comparable effectiveness to insulin degrading enzyme
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ding, L.; Becker, A.B.; Suzuki, A.; Roth, R.A.
Comparison of the enzymatic and biochemical properties of human insulin-degrading enzyme and Escherichia coli protease III
J. Biol. Chem.
267
2414-2420
1992
Homo sapiens
Affholter, J.A.; Fried, V.A.; Roth, R.A.
Human insulin-degrading enzyme shares structural and functional homologies with E. coli protease III
Science
242
1415-1418
1988
Homo sapiens
Duckworth, W.C.; Hamel, F.G.; Bennett, R.; Ryan, M.P.; Roth, R.A.
Human red blood cell insulin-degrading enzyme and rat skeletal muscle insulin protease share antigenic sites and generate identical products from insulin
J. Biol. Chem.
265
2984-2987
1990
Homo sapiens, Rattus norvegicus
Becker, A.B.; Roth, R.A.
Insulysin and pitrilysin: insulin-degrading enzymes of mammals and bacteria
Methods Enzymol.
248
693-703
1995
Drosophila melanogaster, Homo sapiens, Mammalia, Rattus norvegicus
Rawlings, N.D.; Barrett, A.J.
Homologues of insulinase, a new superfamily of metalloendopeptidases
Biochem. J.
275
389-391
1991
Homo sapiens
Kolb, H.J.; Standl, E.
Purification to homogeneity of an insulin-degrading enzyme from human erythrocytes
Hoppe-Seyler's Z. Physiol. Chem.
361
1029-1039
1980
Homo sapiens
Ebrahim, A.; Hamel, F.G.; Bennett, R.G.; Duckworth, W.C.
Identification of the metal associated with the insulin degrading enzyme
Biochem. Biophys. Res. Commun.
181
1398-1406
1991
Homo sapiens, Rattus norvegicus
Perlman, R.K.; Gehm, B.D.; Kuo, W.L.; Rosner, M.R.
Functional analysis of conserved residues in the active site of insulin-degrading enzyme
J. Biol. Chem.
268
21538-21544
1993
Drosophila melanogaster, Homo sapiens, Rattus norvegicus
Authier, F.; Rachubinski, R.A.; Posner, B.I.; Bergeron, J.M.
Endosomal proteolysis of insulin by an acidic thiol metalloprotease unrelated to insulin degrading enzyme
J. Biol. Chem.
269
3010-3016
1994
Drosophila melanogaster, Homo sapiens, Rattus norvegicus
Chesneau, V.; Vekrellis, K.; Rosner, M.R.; Selkoe, D.J.
Purified recombinant insulin-degrading enzyme degrades amyloid beta-protein but does not promote its oligomerization
Biochem. J.
351
509-516
2000
Homo sapiens
Kurochkin, I.V.
Insulin-degrading enzyme: embarking on amyloid destruction
Trends Biochem. Sci.
26
421-425
2001
Drosophila melanogaster, Homo sapiens, Rattus norvegicus
Morelli, L.; Llovera, R.E.; Alonso, L.G.; Frangione, B.; de Prat-Gay, G.; Ghiso, J.; Castano, E.M.
Insulin-degrading enzyme degrades amyloid peptides associated with British and Danish familial dementia
Biochem. Biophys. Res. Commun.
332
808-816
2005
Homo sapiens, Rattus norvegicus
Li, P.; Kuo, W.L.; Yousef, M.; Rosner, M.R.; Tang, W.J.
The C-terminal domain of human insulin degrading enzyme is required for dimerization and substrate recognition
Biochem. Biophys. Res. Commun.
343
1032-1037
2006
Homo sapiens
Leissring, M.A.; Farris, W.; Wu, X.; Christodoulou, D.C.; Haigis, M.C.; Guarente, L.; Selkoe, D.J.
Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria
Biochem. J.
383
439-446
2004
Homo sapiens
Farris, W.; Leissring, M.A.; Hemming, M.L.; Chang, A.Y.; Selkoe, D.J.
Alternative splicing of human insulin-degrading enzyme yields a novel isoform with a decreased ability to degrade insulin and amyloid beta-protein
Biochemistry
44
6513-6525
2005
Homo sapiens (P14735), Homo sapiens
Li, Q.; Ali, M.A.; Cohen, J.I.
Insulin degrading enzyme is a cellular receptor mediating Varicella-zoster virus infection and cell-to-cell spread
Cell
127
305-316
2006
Homo sapiens
Duckworth, W.C.; Fawcett, J.; Reddy, S.; Page, J.C.
Insulin-degrading activity in wound fluid
J. Clin. Endocrinol. Metab.
89
847-851
2004
Homo sapiens
Lynch, J.A.; George, A.M.; Eisenhauer, P.B.; Conn, K.; Gao, W.; Carreras, I.; Wells, J.M.; McKee, A.; Ullman, M.D.; Fine, R.E.
Insulin degrading enzyme is localized predominantly at the cell surface of polarized and unpolarized human cerebrovascular endothelial cell cultures
J. Neurosci. Res.
83
1262-1270
2006
Homo sapiens
Shen, Y.; Joachimiak, A.; Rosner, M.R.; Tang, W.J.
Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism
Nature
443
870-874
2006
Homo sapiens
Gao, W.; Eisenhauer, P.B.; Conn, K.; Lynch, J.A.; Wells, J.M.; Ullman, M.D.; McKee, A.; Thatte, H.S.; Fine, R.E.
Insulin degrading enzyme is expressed in the human cerebrovascular endothelium and in cultured human cerebrovascular endothelial cells
Neurosci. Lett.
371
6-11
2004
Homo sapiens
Fawcett, J.; Permana, P.A.; Levy, J.L.; Duckworth, W.C.
Regulation of protein degradation by insulin-degrading enzyme: analysis by small interfering RNA-mediated gene silencing
Arch. Biochem. Biophys.
468
128-133
2007
Homo sapiens
Hersh, L.B.
The insulysin (insulin degrading enzyme) enigma
Cell. Mol. Life Sci.
63
2432-2434
2006
Homo sapiens, Mus musculus, Rattus norvegicus
Hwang, D.Y.; Seo, S.; Kim, Y.; Kim, C.; Shim, S.; Jee, S.; Lee, S.; Sin, J.; Cho, J.; Kang, B.; Jang, I.; Cho, J.
Significant change in insulin production, glucose tolerance and ER stress signaling in transgenic mice coexpressing insulin-siRNA and human IDE
Int. J. Mol. Med.
19
65-73
2007
Homo sapiens
Jee, S.; Hwang, D.; Seo, S.; Kim, Y.; Kim, C.; Kim, B.; Shim, S.; Lee, S.; Sin, J.; Bae, C.; Lee, B.; Jang, M.; Kim, M.; Yim, S.; Jang, I.; Cho, J.; Chae, K.
Microarray analysis of insulin-regulated gene expression in the liver: the use of transgenic mice co-expressing insulin-siRNA and human IDE as an animal model
Int. J. Mol. Med.
20
829-835
2007
Homo sapiens
Radulescu, R.T.; Hufnagel, C.; Luppa, P.; Hellebrand, H.; Kuo, W.L.; Rosner, M.R.; Harbeck, N.; Giersig, C.; Meindl, A.; Schmitt, M.; Weirich, G.
Immunohistochemical demonstration of the zinc metalloprotease insulin-degrading enzyme in normal and malignant human breast: correlation with tissue insulin levels
Int. J. Oncol.
30
73-80
2007
Homo sapiens
Im, H.; Manolopoulou, M.; Malito, E.; Shen, Y.; Zhao, J.; Neant-Fery, M.; Sun, C.Y.; Meredith, S.C.; Sisodia, S.S.; Leissring, M.A.; Tang, W.J.
Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE
J. Biol. Chem.
282
25453-25463
2007
Homo sapiens (P14735), Homo sapiens
Kim, M.; Hersh, L.B.; Leissring, M.A.; Ingelsson, M.; Matsui, T.; Farris, W.; Lu, A.; Hyman, B.T.; Selkoe, D.J.; Bertram, L.; Tanzi, R.E.
Decreased catalytic activity of the insulin-degrading enzyme in chromosome 10-linked Alzheimer disease families
J. Biol. Chem.
282
7825-7832
2007
Homo sapiens
Bernstein, H.G.; Lendeckel, U.; Bukowska, A.; Ansorge, S.; Ernst, T.; Stauch, R.; Truebner, K.; Steiner, J.; Dobrowolny, H.; Bogerts, B.
Regional and cellular distribution patterns of insulin-degrading enzyme in the adult human brain and pituitary
J. Chem. Neuroanat.
35
216-224
2008
Homo sapiens
Grasso, G.; Rizzarelli, E.; Spoto, G.
AP/MALDI-MS complete characterization of the proteolytic fragments produced by the interaction of insulin degrading enzyme with bovine insulin
J. Mass Spectrom.
42
1590-1598
2007
Homo sapiens
Vepsaelaeinen, S.; Parkinson, M.; Helisalmi, S.; Mannermaa, A.; Soininen, H.; Tanzi, R.E.; Bertram, L.; Hiltunen, M.
Insulin-degrading enzyme is genetically associated with Alzheimers disease in the Finnish population
J. Med. Genet.
44
606-608
2007
Homo sapiens
Li, Q.; Krogmann, T.; Ali, M.A.; Tang, W.J.; Cohen, J.I.
The amino terminus of varicella-zoster virus (VZV) glycoprotein E is required for binding to insulin-degrading enzyme, a VZV receptor
J. Virol.
81
8525-8532
2007
Homo sapiens
Qiu, W.Q.; Folstein, M.F.
Insulin, insulin-degrading enzyme and amyloid beta-peptide in Alzheimers disease: review and hypothesis
Neurobiol. Aging
27
190-198
2006
Homo sapiens, Mus musculus, Rattus norvegicus
Zhao, Z.; Xiang, Z.; Haroutunian, V.; Buxbaum, J.D.; Stetka, B.; Pasinetti, G.M.
Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimers disease
Neurobiol. Aging
28
824-830
2007
Homo sapiens
Marlowe, L.; Peila, R.; Benke, K.S.; Hardy, J.; White, L.R.; Launer, L.J.; Myers, A.
Insulin-degrading enzyme haplotypes affect insulin levels but not dementia risk
Neurodegener. Dis.
3
320-326
2006
Homo sapiens
Malito, E.; Ralat, L.A.; Manolopoulou, M.; Tsay, J.L.; Wadlington, N.L.; Tang, W.J.
Molecular bases for the recognition of short peptide substrates and cysteine-directed modifications of human insulin-degrading enzyme
Biochemistry
47
12822-12834
2008
Homo sapiens
Weirich, G.; Mengele, K.; Yfanti, C.; Gkazepis, A.; Hellmann, D.; Welk, A.; Giersig, C.; Kuo, W.L.; Rosner, M.R.; Tang, W.J.; Schmitt, M.
Immunohistochemical evidence of ubiquitous distribution of the metalloendoprotease insulin-degrading enzyme (IDE; insulysin) in human non-malignant tissues and tumor cell lines
Biol. Chem.
389
1441-1445
2008
Homo sapiens
Qin, W.; Jia, J.
Down-regulation of insulin-degrading enzyme by presenilin 1 V97L mutant potentially underlies increased levels of amyloid beta 42
Eur. J. Neurosci.
27
2425-2432
2008
Homo sapiens
Ciaccio, C.; Tundo, G.R.; Grasso, G.; Spoto, G.; Marasco, D.; Ruvo, M.; Gioia, M.; Rizzarelli, E.; Coletta, M.
Somatostatin: a novel substrate and a modulator of insulin-degrading enzyme activity
J. Mol. Biol.
385
1556-1567
2009
Homo sapiens
Miners, J.S.; Kehoe, P.G.; Love, S.
Immunocapture-based fluorometric assay for the measurement of insulin-degrading enzyme activity in brain tissue homogenates
J. Neurosci. Methods
169
177-181
2008
Homo sapiens
Zhao, J.; Li, L.; Leissring, M.A.
Insulin-degrading enzyme is exported via an unconventional protein secretion pathway
Mol. Neurodegener.
4
04
2009
Homo sapiens, Mus musculus
Dorfman, V.B.; Pasquini, L.; Riudavets, M.; Lopez-Costa, J.J.; Villegas, A.; Troncoso, J.C.; Lopera, F.; Castano, E.M.; Morelli, L.
Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer's disease
Neurobiol. Aging
31
1743-1757
2010
Homo sapiens
Du, J.; Zhang, L.; Liu, S.; Zhang, C.; Huang, X.; Li, J.; Zhao, N.; Wang, Z.
PPARgamma transcriptionally regulates the expression of insulin-degrading enzyme in primary neurons
Biochem. Biophys. Res. Commun.
383
485-490
2009
Homo sapiens, Rattus norvegicus
Radulescu, R.T.; Duckworth, W.C.; Levy, J.L.; Fawcett, J.
Retinoblastoma protein co-purifies with proteasomal insulin-degrading enzyme: implications for cell proliferation control
Biochem. Biophys. Res. Commun.
395
196-199
2010
Homo sapiens
Bora, R.P.; Prabhakar, R.
Elucidation of interactions of Alzheimer amyloid beta peptides (Abeta40 and Abeta42) with insulin degrading enzyme: a molecular dynamics study
Biochemistry
49
3947-3956
2010
Homo sapiens (P14735)
Zuo, X.; Jia, J.
Promoter polymorphisms which modulate insulin degrading enzyme expression may increase susceptibility to Alzheimer's disease
Brain Res.
1249
1-8
2009
Homo sapiens
Wang, R.; Wang, S.; Malter, J.S.; Wang, D.S.
Effects of 4-hydroxy-nonenal and Amyloid-beta on expression and activity of endothelin converting enzyme and insulin degrading enzyme in SH-SY5Y cells
J. Alzheimers Dis.
17
489-501
2009
Homo sapiens
Amata, O.; Marino, T.; Russo, N.; Toscano, M.
Human insulin-degrading enzyme working mechanism
J. Am. Chem. Soc.
131
14804-14811
2009
Homo sapiens
Manolopoulou, M.; Guo, Q.; Malito, E.; Schilling, A.B.; Tang, W.J.
Molecular basis of catalytic chamber-assisted unfolding and cleavage of human insulin by human insulin-degrading enzyme
J. Biol. Chem.
284
14177-14188
2009
Homo sapiens
Ralat, L.A.; Ren, M.; Schilling, A.B.; Tang, W.J.
Protective role of Cys-178 against the inactivation and oligomerization of human insulin-degrading enzyme by oxidation and nitrosylation
J. Biol. Chem.
284
34005-34018
2009
Homo sapiens
Guo, Q.; Manolopoulou, M.; Bian, Y.; Schilling, A.B.; Tang, W.J.
Molecular basis for the recognition and cleavages of IGF-II, TGF-alpha, and amylin by human insulin-degrading enzyme
J. Mol. Biol.
395
430-443
2010
Homo sapiens
Bernstein, H.G.; Ernst, T.; Lendeckel, U.; Bukowska, A.; Ansorge, S.; Stauch, R.; Have, S.T.; Steiner, J.; Dobrowolny, H.; Bogerts, B.
Reduced neuronal expression of insulin-degrading enzyme in the dorsolateral prefrontal cortex of patients with haloperidol-treated, chronic schizophrenia
J. Psychiatr. Res.
43
1095-1105
2009
Homo sapiens, Rattus norvegicus
Lu, X.; Huang, Y.; Liu, Y.; Wu, X.; Shi, X.
Variants in the insulin-degrading enzyme gene are associated with metabolic syndrome in Chinese elders
Metab. Clin. Exp.
58
1465-1469
2009
Homo sapiens
Cabrol, C.; Huzarska, M.A.; Dinolfo, C.; Rodriguez, M.C.; Reinstatler, L.; Ni, J.; Yeh, L.A.; Cuny, G.D.; Stein, R.L.; Selkoe, D.J.; Leissring, M.A.
Small-molecule activators of insulin-degrading enzyme discovered through high-throughput compound screening
PLoS ONE
4
e5274
2009
Homo sapiens
Carrasquillo, M.M.; Belbin, O.; Zou, F.; Allen, M.; Ertekin-Taner, N.; Ansari, M.; Wilcox, S.L.; Kashino, M.R.; Ma, L.; Younkin, L.H.; Younkin, S.G.; Younkin, C.S.; Dincman, T.A.; Howard, M.E.; Howell, C.C.; Stanton, C.M.; Watson, C.M.; Crump, M.; Vitart, V.; Hayward, C.; Hastie, N.D.; Rudan, I.; Campbell, H.; , P.
Concordant association of insulin degrading enzyme gene (IDE) variants with IDE mRNA, Abeta, and Alzheimers disease
PLoS ONE
5
e8764
2010
Homo sapiens
Zhang, W.J.; Luo, X.; Guo, Z.Y.
In vitro degradation of insulin-like peptide 3 by insulin-degrading enzyme
Protein J.
29
93-98
2010
Homo sapiens
Hulse, R.E.; Ralat, L.A.; Wei-Jen, T.
Structure, function, and regulation of insulin-degrading enzyme
Vitam. Horm.
80
635-648
2009
Homo sapiens, Mus musculus, Rattus norvegicus
Song, E.; Rodgers, D.; Hersh, L.
Mixed dimers of insulin-degrading enzyme reveal a cis activation mechanism
J. Biol. Chem.
286
13853-13858
2011
Homo sapiens
Ralat, L.A.; Guo, Q.; Ren, M.; Funke, T.; Dickey, D.M.; Potter, L.R.; Tang, W.J.
Insulin-degrading enzyme modulates the natriuretic peptide-mediated signaling response
J. Biol. Chem.
286
4670-4679
2011
Homo sapiens
Bora, R.; Ozbil, M.; Prabhakar, R.
Elucidation of insulin degrading enzyme catalyzed site specific hydrolytic cleavage of amyloid beta peptide: A comparative density functional theory study
J. Biol. Inorg. Chem.
15
485-495
2010
Homo sapiens
Ralat, L.A.; Kalas, V.; Zheng, Z.; Goldman, R.D.; Sosnick, T.R.; Tang, W.J.
Ubiquitin is a novel substrate for human insulin-degrading enzyme
J. Mol. Biol.
406
454-466
2011
Homo sapiens
Kummer, M.P.; Huelsmann, C.; Hermes, M.; Axt, D.; Heneka, M.T.
Nitric Oxide Decreases the Enzymatic Activity of Insulin Degrading Enzyme in APP/PS1 Mice
J. Neuroimmune Pharmacol.
7
165-172
2012
Homo sapiens, Mus musculus
Grasso, G.; Satriano, C.; Milardi, D.
A neglected modulator of insulin-degrading enzyme activity and conformation: The pH
Biophys. Chem.
203-204
33-40
2015
Homo sapiens (P14735)
Charton, J.; Gauriot, M.; Totobenazara, J.; Hennuyer, N.; Dumont, J.; Bosc, D.; Marechal, X.; Elbakali, J.; Herledan, A.; Wen, X.; Ronco, C.; Gras-Masse, H.; Heninot, A.; Pottiez, V.; Landry, V.; Staels, B.; Liang, W.; Leroux, F.; Tang, W.; Deprez, B.; De
Structure-activity relationships of imidazole-derived 2-[N -carbamoylmethyl-alkylamino]acetic acids, dual binders of human insulin-degrading enzyme
Eur. J. Med. Chem.
90
547-567
2014
Homo sapiens (P14735), Homo sapiens
Tundo, G.; Sbardella, D.; Ciaccio, C.; Bianculli, A.; Orlandi, A.; Desimio, M.; Arcuri, G.; Coletta, M.; Marini, S.
Insulin-degrading enzyme (IDE): A novel heat shock-like protein
J. Biol. Chem.
288
2281-2289
2013
Homo sapiens (P14735), Homo sapiens
Abdul-Hay, S.O.; Sahara, T.; McBride, M.; Kang, D.; Leissring, M.A.
Identification of BACE2 as an avid beta-amyloid-degrading protease
Mol. Neurodegener.
7
46
2012
Homo sapiens (Q9Y5Z0)
McCord, L.; Liang, W.; Dowdell, E.; Kalas, V.; Hoey, R.; Koide, A.; Koide, S.; Tang, W.
Conformational states and recognition of amyloidogenic peptides of human insulin-degrading enzyme
Proc. Natl. Acad. Sci. USA
110
13827-13832
2013
Homo sapiens (P14735), Homo sapiens
Krasinski, C.A.; Ivancic, V.A.; Zheng, Q.; Spratt, D.E.; Lazo, N.D.
Resveratrol sustains insulin-degrading enzyme activity toward Abeta42
ACS Omega
3
13275-13282
2018
Homo sapiens (P14735)
Sharma, S.K.; Chorell, E.; Wittung-Stafshede, P.
Insulin-degrading enzyme is activated by the C-terminus of alpha-synuclein
Biochem. Biophys. Res. Commun.
466
192-195
2015
Homo sapiens (P14735)
Kurochkin, I.V.; Guarnera, E.; Wong, J.H.; Eisenhaber, F.; Berezovsky, I.N.
Toward allosterically increased catalytic activity of insulin-degrading enzyme against amyloid peptides
Biochemistry
56
228-239
2017
Homo sapiens (P14735), Homo sapiens
Stefanidis, L.; Fusco, N.D.; Cooper, S.E.; Smith-Carpenter, J.E.; Alper, B.J.
Molecular determinants of substrate specificity in human insulin-degrading enzyme
Biochemistry
57
4903-4914
2018
Homo sapiens (P14735), Homo sapiens
Hubin, E.; Cioffi, F.; Rozenski, J.; van Nuland, N.A.; Broersen, K.
Characterization of insulin-degrading enzyme-mediated cleavage of Abeta in distinct aggregation states
Biochim. Biophys. Acta
1860
1281-1290
2016
Homo sapiens (P14735), Homo sapiens
Ivancic, V.A.; Krasinski, C.A.; Zheng, Q.; Meservier, R.J.; Spratt, D.E.; Lazo, N.D.
Enzyme kinetics from circular dichroism of insulin reveals mechanistic insights into the regulation of insulin-degrading enzyme
Biosci. Rep.
38
BSR20181416
2018
Homo sapiens (P14735)
Grasso, G.; Lanza, V.; Malgieri, G.; Fattorusso, R.; Pietropaolo, A.; Rizzarelli, E.; Milardi, D.
The insulin degrading enzyme activates ubiquitin and promotes the formation of K48 and K63 diubiquitin
Chem. Commun. (Camb.)
51
15724-15727
2015
Homo sapiens (P14735)
Zhang, H.; Liu, D.; Huang, H.; Zhao, Y.; Zhou, H.
Characteristics of insulin-degrading enzyme in Alzheimers Disease a meta-analysis
Curr. Alzheimer Res.
15
610-617
2018
Homo sapiens (P14735), Homo sapiens
Tundo, G.R.; Di Muzio, E.; Ciaccio, C.; Sbardella, D.; Di Pierro, D.; Polticelli, F.; Coletta, M.; Marini, S.
Multiple allosteric sites are involved in the modulation of insulin-degrading-enzyme activity by somatostatin
FEBS J.
283
3755-3770
2016
Homo sapiens (P14735)
Durham, T.B.; Toth, J.L.; Klimkowski, V.J.; Cao, J.X.; Siesky, A.M.; Alexander-Chacko, J.; Wu, G.Y.; Dixon, J.T.; McGee, J.E.; Wang, Y.; Guo, S.Y.; Cavitt, R.N.; Schindler, J.; Thibodeaux, S.J.; Calvert, N.A.; Coghlan, M.J.; Sindelar, D.K.; Christe, M.; Kiselyov, V.V.; Michael, M.D.; Sloop, K.W.
Dual exosite-binding inhibitors of insulin-degrading enzyme challenge its role as the primary mediator of insulin clearance in vivo
J. Biol. Chem.
290
20044-20059
2015
Homo sapiens (P14735), Mus musculus (Q9JHR7)
Maianti, J.P.; Tan, G.A.; Vetere, A.; Welsh, A.J.; Wagner, B.K.; Seeliger, M.A.; Liu, D.R.
Substrate-selective inhibitors that reprogram the activity of insulin-degrading enzyme
Nat. Chem. Biol.
15
565-574
2019
Homo sapiens (P14735)
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