3.4.24.56: insulysin
This is an abbreviated version!
For detailed information about insulysin, go to the full flat file.
Word Map on EC 3.4.24.56
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3.4.24.56
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alzheimer
-
neprilysin
-
abeta
-
hippocampus
-
dementia
-
mellitus
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cerebral
-
morris
-
amyloid-beta
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metalloprotease
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maze
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neuroprotective
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amyloidogenic
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tau
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beta-amyloid
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neurodegenerative
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presenilin
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endothelin-converting
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senile
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gamma-secretase
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beta-protein
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125i-insulin
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abeta-degrading
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hyperinsulinemia
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metalloendopeptidase
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bacitracin
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beta-secretase
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late-onset
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amylin
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microglia
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medicine
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adam10
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non-amyloidogenic
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glutathione-insulin
-
enzyme-1
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b-chains
-
analysis
-
ad-like
-
anti-ide
-
exosite
-
beta-peptide
-
abeta1-40
- 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
Reaction
Degradation of insulin, glucagon and other polypeptides. No action on proteins =
Synonyms
ADE, amyloid degrading enzyme, cgd6_5510, EC 3.4.22.11, EC 3.4.99.10, EC 3.4.99.45, gamma-endorphin-generating enzyme, IDE, INS20-19, insulin degrading enzyme, Insulin protease, Insulin proteinase, Insulin-degrading enzyme, Insulin-degrading neutral proteinase, Insulin-glucagon protease, Insulin-specific protease, Insulinase, Insulysin, Metalloinsulinase, More, pitrilysin metallopeptidase 1, Pitrm1
ECTree
3.4.24.56 insulysinAdvanced search results
results (
results (Substrates Products
Substrates Products on EC 3.4.24.56 - insulysin
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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-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-QKLVFFAEDVK(2,4-dinitrophenyl)-OH + H2O
?
-
-
-
?
(7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK(2,4-dinitrophenyl)-OH + H2O
?
-
-
-
?
(7-methoxycoumarin-4-yl)acetyl-VEALYLVCGEK(2,4-dinitrophenyl)-OH + H2O
?
-
-
-
?
2-amino-benzoyl-GGFLRKAGQ-ethylenediamine-2,4-dinitrophenyl + H2O
?
-
-
-
?
2-amino-benzoyl-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl + H2O
?
-
-
-
?
2-amino-benzoyl-GGFLRKMGQ-ethylenediamine-2,4-dinitrophenyl + H2O
?
-
-
-
?
2-aminobenzoyl-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl + H2O
2-aminobenzoyl-GGFLR + KHGQ-ethylenediamine-2,4-dinitrophenyl
-
-
-
-
?
7-methoxycoumarin-4-yl-acetyl-RPPGF-SAFK-2,4-dinitrophenyl + H2O
?
-
-
-
?
Abz-SEKKDNYIIKGV-nitroY-OH + H2O
?
-
a substrate based on the polypeptide sequence of the yeast P2 a-factor mating propheromone
-
-
?
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 1-42 + H2O
?
-
cleavage occurs at peptide bonds Phe19-Phe20, Phe20-Ala21, and Leu34-Met35, with the latter cleavage site being the initial and principal one
-
?
amyloid peptide + H2O
?
-
23 amino acid peptide resulting from internal proteolysis of wild-type type 2 transmembrane protein BRI2
-
-
?
amyloid peptide ABri + H2O
?
-
34 amino acid peptide resulting from internal proteolysis of genetically defect type 2 transmembrane protein BRI2 in patients with familial British dementia. Enzymic degradation of peptide is more efficient with monomeric peptide than with aggregated peptide
-
-
?
amyloid peptide ADan + H2O
?
-
34 amino acid peptide resulting from internal proteolysis of genetically defect type 2 transmembrane protein BRI2 in patients with familial Danish dementia
-
-
?
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
-
-
?
Fragment of cytochrome c + H2O
Hydrolyzed fragment of cytochrome c
-
Ile81-Glu108
cleavage at Tyr97-Leu98 bond
?
insulin-like growth factor-II + H2O
insulin-like growth factor-II peptide fragments
-
identification of cleavage sites by mass spectrometry and NMR
-
-
?
o-aminobenzoic acid-GGFLRKHGQ-ethylenediamine-2,4-dinitrophenyl + H2O
?
-
-
-
?
peptide containing the mitochondrial targeting sequence of E1alpha subunit of human pyruvate dehydrogenase + H2O
?
-
hydrolysis occurs at several sites
-
-
?
Porcine proinsulin intermediates + H2O
?
-
cleaved proinsulin, desdipeptide-proinsulin, desnonapeptide-proinsulin, destridecapeptide-proinsulin, desalanine-insulin, monoarginine-insulin and diarginine-proinsulin are degraded at 19.8%, 25.6%, 63.5%, 73.7%, 101.5%, 98% and 98% of the activity of insulin, respectively
-
-
?
Proinsulin + H2O
Hydrolyzed proinsulin
-
15fold greater rate of insulin destruction over that for proinsulin
-
-
?
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
-
-
?
Tryptic fragment of bovine serum albumin + H2O
Hydrolyzed tryptic fragment of bovine serum albumin
-
Leu503-Lys518
cleaved at Phe506-His507
?
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
-
-
?
[(7-methoxycoumarin-4-yl)acetyl]-RPPGFSAFK(Dnp)-OH + H2O
[(7-methoxycoumarin-4-yl)acetyl]-RPPGF + SAFK(Dnp)-OH
(7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK-2,4-dinitrophenyl + H2O
?
-
-
-
-
?
(7-methoxycoumarin-4-yl)acetyl-RPPGFSAFK-2,4-dinitrophenyl + H2O
?
-
-
-
?
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) + H2O
?
-
-
-
-
?
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) + H2O
?
-
-
-
-
?
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
-
-
?
Abz-GGFLRKHGQ-EDDnp + H2O
Abz-GGFLR + KHGQ-EDDnp
-
substrate or small peptide activation occurs through a cis effect
-
-
?
Abz-GGFLRKHGQ-EDDnp + H2O
Abz-GGFLR + KHGQ-EDDnp
-
synthetic fluorogenic substrate
-
-
?
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 + H2O
?
role of insulin-degrading enzyme in the intracytosolic clearance of amyloid beta and other amyloid-like peptides
-
-
?
amyloid beta + H2O
amyloid beta peptide fragments
-
-
-
-
?
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, IDE has no effect on the secreted ectodomain of the amyloid precursor protein derivative generated by alpha-secretase
-
-
?
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
-
-
?
amyloid beta-peptide + H2O
?
-
degradation, role for insulysin in regulating amyloid beta peptide levels in the brain
-
-
?
amyloid beta-peptide + H2O
?
-
IDE is involved in clearance of amyloid-beta pepetide in the brain, enzyme deficiency may participate in the progression of Alzheimer's disease
-
-
?
amyloid beta-peptide + H2O
?
-
degradation, role for insulysin in regulating amyloid beta peptide levels in the brain
-
-
?
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 1-40 + H2O
?
-
76 kDa and 56 kDa fragments of IDE, derived from cleavage with proteinase K, exhibit a low level of catalytic activity but retain the ability to bind the substrate with a similar affinity as the full-length enzyme, and they retain the regulatory cationic binding site that binds ATP
-
-
?
amyloid 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
-
-
?
ATP + H2O
ADP + phosphate
-
insulin-binding and degradation are dependent on ATP concentration, however, insulin does not modify the ATPase activity of IDE
-
-
?
ATP + H2O
ADP + phosphate
-
the enzyme contains one ATP binding site per enzyme molecule
-
-
?
beta-endorphin + H2O
?
-
76 kDa and 56 kDa fragments of IDE, derived from cleavage with proteinase K, exhibit a low level of catalytic activity but retain the ability to bind the substrate with a similar affinity as the full-length enzyme, and they retain the regulatory cationic binding site that binds ATP
-
-
?
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
-
-
?
Glucagon + H2O
Hydrolyzed glucagon
-
-
appearance of: tyrosine, leucine, lysine, alanine and phenylalanine
?
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 + 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
?
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
-
-
?
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, reduced insulin degradation leads to type 2 diabetes, regulation, overview
-
-
?
insulin + H2O
?
the enzyme plays a critical role in both the proteolytic degradation and inactivation of insulin
-
-
?
insulin + H2O
?
-
insulin degrading enzyme is unlikely to be the relevant enzyme for endosomal proteolysis of internalized insulin in liver parenchyma
-
-
?
insulin + H2O
?
-
stepwise degradation occurs in vivo, an early step in the process is the cleavage of the B-chain between Tyr16 and Leu17, that renders the molecule susceptible to further degradation by nonspecific proteases
-
-
?
insulin + H2O
?
-
seems to be implicated in insulin metabolism to terminate the response of cells to hormone, as well as in other biological functions, including muscle differentiation, regulation of growth factor levels and antigen processing
-
-
?
insulin + H2O
?
-
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-binding and degradation are dependent on ATP concentration, however, insulin does not modify the ATPase activity of IDE
-
-
?
insulin + H2O
?
-
degradation, reduced insulin degradation leads to type 2 diabetes, regulation, overview
-
-
?
insulin + H2O
?
-
degradation, type 2 diabetic GK rats exhibit defects in both insulin action and insulin degradation mainly due to mutation H18R and A890V in the insulysin protein
-
-
?
insulin + H2O
?
-
76 kDa and 56 kDa fragments of IDE, derived from cleavage with proteinase K, exhibit a low level of catalytic activity but retain the ability to bind the substrate with a similar affinity as the full-length enzyme, and they retain the regulatory cationic binding site that binds ATP
-
-
?
insulin + H2O
?
-
investigation of activity of IDE regarding cleavage site's preferentiality upon modification of environmental factors by atmospheric pressure/laser desorption ionization-mass spectrometry. The first insulin fragments produced by IDE are mainly [A (1-13) + B (1-9)], [A (1-14) + B (1-9)] and [A (1-14) + B (1-10)]. A second set of insulin fragments involving the C-terminal residues of the insulin A chain [A (14-21) and A (15-21)] and the fragments B (17-24) and B (17-25) are then produced, confirming a delayed action of IDE on these cleavage sites. A third set of insulin fragments at lower and higher m/z values start to appear soon after and their intensity increases as the intensity of the middle fragments intensity decreases
-
-
?
Insulin + H2O
Hydrolyzed insulin
-
not: individual A and B-chains of insulin
-
-
?
Insulin + H2O
Hydrolyzed insulin
-
Drosophila and rat enzyme cleave the A-chain of intact insulin between residues A13-A14 and A14-A15
-
?
Insulin + H2O
Hydrolyzed insulin
-
the Drosophila enzyme cleaves the B-chain of intact insulin at B10-B11, B14-B15, B16-B17 and B25-B26
-
?
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
Hydrolyzed insulin
-
-
31312, 31313, 31315, 31317, 31318, 31320, 31321, 31322, 31323, 31324, 31325, 31326, 31327, 31328, 31330, 31331, 31333, 31337, 31339, 31340
-
-
?
Insulin + H2O
Hydrolyzed insulin
-
Drosophila and rat enzyme cleave the A-chain of intact insulin between residues A13-A14 and A14-A15
-
?
Insulin + H2O
Hydrolyzed insulin
-
degradation of 4 monoiodoinsulin isomers
-
?
Insulin + H2O
Hydrolyzed insulin
-
specific for insulin
stepwise degradation occurs in vivo, an early step in the process is the cleavage of the B-chain at Tyr16-Leu17
?
Insulin + H2O
Hydrolyzed insulin
-
the insulin protease appears to first degrade insulin to multiple products with molecular sizes slightly smaller than insulin and subsequently to small peptides (e.g. containing tyrosine A-19) and amino acids (e.g. tyrosine A-14, B-16 and B-26)
-
?
insulin + H2O
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 + 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 + 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 growth factor I + H2O
insulin-like growth factor I peptide fragments
-
-
-
-
?
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
-
-
-
-
?
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
-
-
?
islet amyloid polypeptide + H2O
?
degradation of islet amyloid polypeptide in beta-cells
-
-
?
islet amyloid polypeptide + H2O
?
degradation of monomeric, but not oligomeric islet amyloid polypeptide in vitro
-
-
?
peptide V + H2O
?
-
a bradykinin-mimetic fluorogenic peptide substrate V
-
-
?
peptide V + H2O
?
-
a bradykinin-mimetic fluorogenic peptide substrate V
-
-
?
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]-RPPGFSAFK(Dnp)-OH + H2O
[(7-methoxycoumarin-4-yl)acetyl]-RPPGF + SAFK(Dnp)-OH
-
-
-
ir
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
?
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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
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regulation of enzyme expression in the liver, overview
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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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the insulin-degrading enzyme is genetically associated with Alzheimer's disease in the Finnish population, overview
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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
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the enzyme is a neutral thiol metalloprotease with the active site sequence HEXXH
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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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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
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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
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the putative ATP-binding domain is a key modulator of IDE proteolytic activity
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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
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the enzyme selectively degrades biologically important substrates associated with type 2 diabetes and Alzheimer's disease
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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
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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
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hyperinsulinemia is probably elevated through insulin's competition with amyloid beta-peptide for the enzyme, IDE deficiency might be involved in development of Alzheimer's disease, regulation, overview
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additional information
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the enzyme is a neutral thiol metalloprotease with the active site sequence HEXXH
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additional information
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the substrates often possess disulfide bonds that are involved in enzyme-substrate interactions, e.g. insulin possesses three disulfide bonds. The exosite interaction serves as a molecular tether allowing the proper positioning of the C-terminal end of the substrate to the catalytic site, exosite binding ligands can activate the enzyme, the exosite has regulatory function. IDE is an allosteric enzyme
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requirement for optimal substrate activity is the deblocking of the amino end of the A-chain
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human growth hormone is not appreciably degraded
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EGF and insulin C-peptide are no substrates
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gamma-endorphin, Leu-Arg, and Leu-enkephalin are not significantly cleaved
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enzyme may participate in prostatic and uterine growth
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hyperinsulinemia is probably elevated through insulin's competition with amyloid beta-peptide for the enzyme, IDE deficiency might be involved in development of Alzheimer's disease, regulation, overview
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additional information
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the enzyme is a neutral thiol metalloprotease with the active site sequence HEXXH
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additional information
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IDE interacts with vimentin and with nestin during mitosis, vimentin binds IDE with a higher affinity than nestin in vitro. The interaction between vimentin and IDE is enhanced by vimentin phosphorylation at Ser55, the interaction between nestin and IDE is phosphorylation-independent. Nestin-mediated disassembly of vimentin IFs generates a structure capable of sequestering and modulating the activity of IDE, overview
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additional information
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the substrates often possess disulfide bonds that are involved in enzyme-substrate interactions, e.g. insulin possesses three disulfide bonds. The exosite interaction serves as a molecular tether allowing the proper positioning of the C-terminal end of the substrate to the catalytic site, exosite binding ligands can activate the enzyme, the exosite has regulatory function. Regulatory mechanism, overview. IDE is an allosteric enzyme
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additional information
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IDE interacts with vimentin and nestin, vimentin binds IDE with a higher affinity than nestin in vitro. A nestin tail fragment interacts with insulin-degrading enzyme in Xenopus egg extracts, overview. The interaction between vimentin and IDE is enhanced by vimentin phosphorylation at Ser55, the interaction between nestin and IDE is phosphorylation-independent. Nestin-mediated disassembly of vimentin IFs generates a structure capable of sequestering and modulating the activity of IDE, overview
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