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Information on EC 3.4.24.56 - insulysin and Organism(s) Rattus norvegicus and UniProt Accession P35559
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3.4.24.56 insulysinSpecify your search results
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- 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: Rattus norvegicus
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 protease
Insulin proteinase
-
-
-
-
Insulin-degrading enzyme
Insulin-degrading neutral proteinase
-
-
-
-
Insulin-glucagon protease
-
-
-
-
Insulin-specific protease
-
-
-
-
Insulinase
Insulysin
Metalloinsulinase
-
-
-
-
additional information
IDE
-
-
-
-
IDE
-
-
Insulin protease
-
-
-
-
Insulin-degrading enzyme
-
-
-
-
Insulin-degrading enzyme
-
-
Insulinase
-
-
-
-
Insulysin
-
-
-
-
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
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-(N-(2,4-dinitrophenyl)ethylenediamine) + H2O
?
-
-
-
-
?
Abz-SEKKDNYIIKGV-nitroY-OH + H2O
?
-
a substrate based on the polypeptide sequence of the yeast P2 a-factor mating propheromone
-
-
?
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
-
-
?
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
-
-
-
-
?
peptide V + H2O
?
-
a bradykinin-mimetic fluorogenic peptide substrate V
-
-
?
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
-
-
?
Abz-GGFLRKHGQ-EDDnp + H2O
Abz-GGFLR + KHGQ-EDDnp
-
synthetic fluorogenic substrate
-
-
?
amyloid beta-peptide + H2O
?
-
degradation, role for insulysin in regulating amyloid beta peptide levels in the brain
-
-
?
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
-
-
?
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
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
?
-
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
-
-
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
-
IDE uses the size and charge distribution of the catalytic chamber and structural flexibility of the substrates to selectively recognize and degrade insulin
-
-
?
additional information
?
-
-
requirement for optimal substrate activity is the deblocking of the amino end of the A-chain
-
-
?
additional information
?
-
-
human growth hormone is not appreciably degraded
-
-
?
additional information
?
-
-
EGF and insulin C-peptide are no substrates
-
?
additional information
?
-
-
gamma-endorphin, Leu-Arg, and Leu-enkephalin are not significantly cleaved
-
?
additional information
?
-
-
enzyme may participate in prostatic and uterine growth
-
-
?
additional information
?
-
-
hyperinsulinemia is probably elevated through insulin's competition with amyloid beta-peptide for the enzyme, IDE deficiency might be involved in development of Alzheimer's disease, regulation, overview
-
-
?
additional information
?
-
-
the enzyme is a neutral thiol metalloprotease with the active site sequence HEXXH
-
-
?
additional information
?
-
-
IDE interacts with vimentin and with nestin during mitosis, vimentin binds IDE with a higher affinity than nestin in vitro. The interaction between vimentin and IDE is enhanced by vimentin phosphorylation at Ser55, the interaction between nestin and IDE is phosphorylation-independent. Nestin-mediated disassembly of vimentin IFs generates a structure capable of sequestering and modulating the activity of IDE, overview
-
-
?
additional information
?
-
-
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
-
-
?
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
ATP + H2O
ADP + phosphate
-
insulin-binding and degradation are dependent on ATP concentration, however, insulin does not modify the ATPase activity of IDE
-
-
?
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
-
-
-
-
?
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
?
-
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
-
-
?
additional information
?
-
-
enzyme may participate in prostatic and uterine growth
-
-
?
additional information
?
-
-
hyperinsulinemia is probably elevated through insulin's competition with amyloid beta-peptide for the enzyme, IDE deficiency might be involved in development of Alzheimer's disease, regulation, overview
-
-
?
additional information
?
-
-
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
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
Mg2+
Mn2+
thiol
-
the enzyme is a neutral thiol metalloprotease requiring both free thiol and divalent cations for activity
Zinc
-
zinc and manganese are associated with the enzyme, with approximately 10times more zinc than manganese being present, one or both of these two metals are endogenously associated with this enzyme
Zn2+
additional information
Mg2+
-
activates at concentration up to 0.05 mM, less active than Mn2+, inhibitory at above 0.05 mM
Mn2+
-
zinc and manganese are associated with the enzyme, with approximately 10times more zinc than manganese being present, one or both of these two metals are endogenously associated with this enzyme
Mn2+
-
activates, best at 1 mM, preferred divalent cation for both insulin degradation and ATP hydrolysis
Zn2+
-
one Zn2+ bound at the active site, with the zinc-binding motif HXXEH
Zn2+
-
the enzyme is a neutral thiol metalloprotease requiring both free thiol and divalent cations for activity
additional information
-
metalloenzyme, removal of the protein-bound metal(s) results in nearly total and irreversible loss of activity
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
adrenocorticotropic hormone
-
competitive inhibition of amylin degradation
-
amylin
-
excess amylin inhibits amylin degradation, competitive inhibition
-
glutathione
-
oxidized glutathione inhibits IDE through glutathionylation, which is reversible by dithiothreitol but not by ascorbic acid
InsL3
-
competitively inhibits the degradation of insulin, and crosslinking of insulin to IDE
-
Natural inhibitor of MW 67000 or 80000-120000 MW
-
reduces activity reversibly, nonprogressively, and noncompetitively with respect to insulin
-
nestin
-
insulin degradation activity of IDE is suppressed by about 50% by either nestin or phosphorylated vimentin, while the cleavage of bradykinin-mimetic peptide by IDE is increased 2 to 3fold
-
o-phenanthroline
-
0.1 mM, wild-type, 73% residual activity, mutants H112D, H112Q, less than 2.5% residual activity
phosphorylated vimentin
-
insulin degradation activity of IDE is suppressed by about 50% by either nestin or phosphorylated vimentin, while the cleavage of bradykinin-mimetic peptide by IDE is increased 2 to 3fold
-
relaxin
-
competitively inhibits the degradation of insulin, and crosslinking of insulin to IDE
-
relaxin-3
-
competitively inhibits the degradation of insulin, and crosslinking of insulin to IDE
-
S-nitroso-N-acetylpenicillamine
-
nitric oxide donors decrease both insulin and amyloid beta degrading activities of insulysin. Insulin-degrading activity is more sensitive to nitric oxide inhibition than amyloid beta degrading activity. Insulysin-mediated regulation of proteasome activity is affected similarly to insulin-degrading activity. S-nitrosylation of enzyme does not affect the insulin degradation products produced by the enzyme, nor does nitric oxide affect insulin binding to insulysin. Inhibition is noncompetitive
S-nitrosoglutathione
-
inhibits IDE-mediated degradation of two IDE substrates, insulin and amyloid beta
sodium nitroprusside
-
nitric oxide donors decrease both insulin and amyloid beta degrading activities of insulysin. Insulin-degrading activity is more sensitive to nitric oxide inhibition than amyloid beta degrading activity. Insulysin-mediated regulation of proteasome activity is affected similarly to insulin-degrading activity. S-nitrosylation of enzyme does not affect the insulin degradation products produced by the enzyme, nor does nitric oxide affect insulin binding to insulysin. Inhibition is noncompetitive
sulfhydryl-modifying reagents
-
Drosophila, human and rat enzyme inhibited, bacterial enzyme not
-
[(Z)-1-[N-3-aminopropyl]-N-(n-propyl)amino]diazen-1-ium-1,2-dolate
-
nitric oxide donors decrease both insulin and amyloid beta degrading activities of insulysin. Insulin-degrading activity is more sensitive to nitric oxide inhibition than amyloid beta degrading activity. Insulysin-mediated regulation of proteasome activity is affected similarly to insulin-degrading activity. S-nitrosylation of enzyme does not affect the insulin degradation products produced by the enzyme, nor does nitric oxide affect insulin binding to insulysin. Inhibition is noncompetitive
1,10-phenanthroline
-
Zn2+, Co2+, Mn2+ and to a smaller extent Cd2+ and Fe2+ are capable of preventing the inhibition
ATP
-
ATP hydrolysis is a mechanism for reversion of this inhibition, however, insulin does not modify the ATPase activity of IDE
ATP
-
interacts via the phosphate moiety, inhibits IDE and shifts the oligomeric equilibrium promoting the transition from tetramer to dimer and from closed to open state
EDTA
-
0.1 mM, wild-type, 91% residual activity, mutants H112D, H112Q, less than 2.5% residual activity
Inhibitor from rat liver homogenate
-
purification of endogenous inhibitor from rat liver
-
Inhibitor from rat liver homogenate
-
low-molecular-weight protein, order of greatest to least activity: pancreas, liver, kidney, testes, adrenal, lung, spleen, diaphragm, heart, muscle, brain, epididymal fad pad, skin
-
Insulin
-
inhibits amylin degradation, excess insulin inhibits insulin degradation
-
additional information
-
not: the enzyme is inhibited by cysteine protease inhibitors as well as metalloprotease inhibitors
-
additional information
-
not: overview: various amino acid derivatives, small polypeptides, indole and quinoline derivatives, dyes and dye derivatives
-
additional information
-
pepstatin-A, leupeptin, and calpains are ineffective as inhibitors, no competitive inhibition with EGF or insulin C-peptide
-
additional information
-
IDE is inhibited by metal chelators, thiol modifiers, inhibitors of cysteine protease activity and insulin, no inhibition by GTP and DMSO, poor inhibition by ATP
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-diphosphoinositol pentakisphosphate
activates, maximal 79.7fold activation
5-diphosphoinositol pentakisphosphate
activates, maximal 94.7fold activation
myoinositol 1,2,3,4,5,6-hexakisphosphate
i.e. phytic acid, maximal 72fold activation
myoinositol 1,3,4,5,6-pentakisphosphate
activates, maximal 83.3fold activation
myoinositol 1,3,4,5-tetrakisphosphate
activates, maximal 58.6fold activation
myoinositol 1,3,5-trisphosphate
activates, maximal 12.9fold activation
myoinositol 1,4,5-trisphosphate
activates, maximal 30.6fold activation
2',3'-O-(2,4,6-trinitrophenyl)adenosine triphosphate
-
about 15fold activation, 50% activation at o.0016 mM, activation is inhibited by Mg2+
2'-O-(2,4,6-trinitrophenyl) adenosine triphosphate
-
ATP-derivative TNP-ATP
3'-O-(2,4,6-trinitrophenyl) adenosine triphosphate
-
ATP-derivative TNP-ATP
AMP
-
in Tris buffer, activation for substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine). Activation in decreasing order: ATP, triphosphate, ADP, AMP
nestin
-
insulin degradation activity of IDE is suppressed by about 50% by either nestin or phosphorylated vimentin, while the cleavage of bradykinin-mimetic peptide by IDE is increased 2 to 3fold
-
phosphorylated vimentin
-
insulin degradation activity of IDE is suppressed by about 50% by either nestin or phosphorylated vimentin, while the cleavage of bradykinin-mimetic peptide by IDE is increased 2 to 3fold
-
ADP
-
in Tris buffer, activation for substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine). Activation in decreasing order: ATP, triphosphate, ADP, AMP
ADP
-
inhibition of binding of 2,3-O-(2,4,6-trinitrophenyl)adenosine triphosphate with Ki-value 2.2 mM
ATP
-
50% activation at 1.4 mM, activation is inhibited by Mg2+. Inhibition of binding of 2,3-O-(2,4,6-trinitrophenyl)adenosine triphosphate with Ki-value 1.3 mM
ATP
-
in Tris buffer, up to 20fold activation for substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine), noncompetitive activator. Activation in decreasing order: ATP, triphosphate, ADP, AMP. Up to 10fold activation with substrates bradykinin, dynorphin B-9. No activation with substrates insulin or amyloid beta-protein
ATP
-
regulatory cationic binding site, 76 kDa and 56 kDa fragments of IDE, derived from cleavage with proteinase K, retain the ability to bind ATP, 4fold activation at 4 mM of 56 kDa fragment, poor activation of the 76 kDa enzyme fragment, overview
Triphosphate
-
in Tris buffer, up to 20fold activation for substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine), noncompetitive activator. Activation in decreasing order: ATP, triphosphate, ADP, AMP. Up to 10fold activation with substrates bradykinin, dynorphin B-9. No activation with substrates insulin or amyloid beta-protein
Triphosphate
-
inhibition of binding of 2,3-O-(2,4,6-trinitrophenyl)adenosine triphosphate with Ki-value 0.9 mM
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0111
Abz-Gly-Gly-Leu-Arg-Lys-His-Gly-Gln-EDDnp
37°C, pH 7.4, without activator
additional information
additional information
-
no relation between Km and the chemical dissimilarity between bovine insulin and endogenous insulin of the species
-
0.014
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111L, pH 7.3
0.0156
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111V, pH 7.3
0.0274
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111F, pH 7.3
0.0287
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
wild-type, K0.5-value, pH 7.3
0.083
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant H112D, pH 7.3
0.158
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant H112Q, pH 7.3
0.204
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111A, pH 7.3
0.0066
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, mutant DELTAC lacking the C-terminal region
0.0068
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, mutant T609F, Vmax: 2.6 nmol/min/mg
0.0085
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, mutant I374S, Vmax: 3.45 nmol/min/mg
0.00861
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, mutant V360S, Vmax: 2 nmol/min/mg
0.01587
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, wild-type, Vmax: 35.5 nmol/min/mg
0.0215
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, wild-type
9.6
Abz-GGFLRKHGQ-EDDnp
-
wild-type, pH 7.4, temperature not specified in the publication
17.3
Abz-GGFLRKHGQ-EDDnp
-
mutant K898A/K899A/S901A, pH 7.4, temperature not specified in the publication
21.3
Abz-GGFLRKHGQ-EDDnp
-
mutant R429S, pH 7.4, temperature not specified in the publication
0.0059
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37°C, 56 kDa detagged fragment of recombinant His6-tagged enzyme
0.0075
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37°C, 76 kDa detagged fragment of recombinant His6-tagged enzyme
0.0254
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37°C, recombinant His6-tagged full-length enzyme
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2 - 3.7
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant H112D, pH 7.3
2.4
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111V, pH 7.3
6.5
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111L, pH 7.3
11.4
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111F, pH 7.3
17.5
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant E111A, pH 7.3
1953
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
mutant H112Q, pH 7.3
162600
2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine)
-
wild-type, pH 7.3
0.01
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, mutant DELTAC lacking the C-terminal region
0.043
Abz-GGFLRKHGQ-EDDnp
-
pH 7.4, temperature not specified in the publication, wild-type
0.078
Abz-GGFLRKHGQ-EDDnp
-
mutant R429S, pH 7.4, temperature not specified in the publication
0.086
Abz-GGFLRKHGQ-EDDnp
-
wild-type, pH 7.4, temperature not specified in the publication
0.258
Abz-GGFLRKHGQ-EDDnp
-
mutant K898A/K899A/S901A, pH and temperature not specified in the publication
0.72
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37°C, 56 kDa detagged fragment of recombinant His6-tagged enzyme
0.77
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37°C, 76 kDa detagged fragment of recombinant His6-tagged enzyme
93.17
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37°C, recombinant His6-tagged full-length enzyme
104
Abz-GGFLRKHGQEDDnp
-
pH 7.4, 37°C, recombinant His6-tagged full-length enzyme
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0000444
InsL3
Rattus norvegicus
-
pH not specified in the publication, temperature not specified in the publication
-
0.000182
relaxin
Rattus norvegicus
-
pH not specified in the publication, temperature not specified in the publication
-
0.0000537
relaxin-3
Rattus norvegicus
-
pH not specified in the publication, temperature not specified in the publication
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.22
-
pH 9.2, 37°C, purified recombinant His-tagged enzyme, substrate Abz-SEKKDNYIIKGV-nitroY-OH
additional information
additional information
-
activities of recombinant His-tagged full-length enzyme and detagged recombinant enzyme fragments with different substrates, overview
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
activity and amount of enzyme decrease in the cytosolic fraction with castration and increase with testpsterone treatment
-
activity and amount of enzyme decrease during metestrus and increase with estradiol treatment and proestrus
additional information
-
high expression level, increased expression level during development
-
native enzyme, insulysin is able to form a stable complex with amyloid beta
-
left and right dorsolateral prefrontal cortex, immunohistochemic IDE expression analysis, overview
-
-
31317, 31318, 31322, 31326, 31327, 31333, 31336, 31339, 31340, 31341, 696135, 707150, 710682, 720820
-
high expression level, increased expression level during development
additional information
-
IDE activity levels in decreasing order in liver, pancreas, kidney, testis, adrenal gland, spleen, ovary, lung, heart, muscle, brain, and adipose tissue
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
binding to phosphatdidylinositol phosphates facilitates its localization to endosomes
-
cytosolic enzyme shows a longer half-life compared with the detergent-resistant membrane-associated form. The detergent-resistant membrane-associated enzyme co-localizes with amyloid beta. Distribution and activity is sensitive to manipulation of lipid composition in vitro and in vivo
-
-
-
cytosolic enzyme shows a longer half-life compared with the detergent-resistant membrane-associated form
-
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
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
-
palmitic acid and docosahexaenoic acid opposingly regulate the expression of insulin-degrading enzyme in neurons
physiological function
additional information
-
IDE activity protects against Alzheimer's disease, IDE suppression of IDE induces the pathology
malfunction
-
reduced neuronal expression of insulin-degrading enzyme in the left and right dorsolateral prefrontal cortex, but not in other brain areas investigated, of haloperidol-treated rats
malfunction
-
susceptibility of Goto-Kakizaki rats to diabetes due to IDE polymorphisms
physiological function
-
IDE is a ubiquitously expressed metalloproteinase responsible for the intracellular degradation of insulin, but possibly also for the cellular proteolysis of relaxin, InsL3 and relaxin-3
physiological function
-
IDE is an important protease responsible for the degradation of amyloid-beta in neural cells
physiological function
-
IDE is important in maintaining insulin levels and in insulin catabolism
physiological function
-
IDE plays a key role in degrading both amyloid beta and insulin
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_RAT
1019
0
117710
Swiss-Prot
Mitochondrion (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
110000
300000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
monomer
-
mutant with a deleted putative dimer interface in the C-terminal region is created, which results in a monomeric variant. Monomeric IDE retains 25% of the wild type activity substrate (Abz-GGFLRKHGQ-EDDnp). With the peptide substrates beta-endorphin and amyloid beta peptide, monomeric IDE retains 1 to 0.25% of wild type activity. No activation through bradykinin or dynorphin B-9. Monomeric IDE is not activated by polyphosphates
additional information
-
the protease is a complex of rather easily dissociating units, which severly complicates its purification
additional information
-
sedimentation analysis shows that enzyme in Tris buffers mainly consists of monomers and dimers, in phosphate buffer there are monomers, dimers and tetramers. Tris buffer supplemented with 4 mM triphosphate contains enzyme as monomer and high oligomers, but without dimers
additional information
-
both recombinant and brain enzyme are able to form a stable complex with amyloid beta that resists dissociation after treatment with strong denaturants. Amyloid beta sequence 17-27 is sufficient to form a stable complex with IDE. Monomeric as opposed to aggregated amyloid beta is competent to associate irreversibly with IDE following a very slow kinetics. Partial denaturation of IDE as well as preincubation with a 10fold molar excess of insulin prevent complex formation. Amyloid beta remains bound to a 25 kDa N-terminal fragment of IDE in an SDS-resistant manner
additional information
-
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
-
treatment of the recombinant N-terminally His6-tagged IDE with proteinase K leads to the initial cleavage of the His tag and linker region, followed by C-terminal cleavages resulting in intermediate fragments of 95 and 76 kDa and finally a relatively stable 56 kDa fragment, overview
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H18R/A890V
plus silent mutation at codon 934, naturally occuring missense mutations occuring in a rat model of type 2 diabetes mellitus, resulting in decreased catalytic efficiency and 15-30% deficit in degradation of both insulin and insulin Abeta. Endogenously secreted insulin Abeta40 and Abeta42 are significantly elevated in primnary neuronal cultures from mutant animals
K898A/K899A/S901A
variant with mutations in the polyanion-binding site shows reduced activation by myoinositol 1,4,5-trisphosphate and phytic acid
Y609F
activation by myoinositol 1,4,5-trisphosphate and phytic acid is decreased in the mutant enzyme
E111A
-
change in the substrate response from sigmoidal to hyperbolic. Activating effect of ATP or triphosphate with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) on wild-type is dampened. Mutant recognizes additional cleavage sites in substrate beta-endorphin
E111F
E111L
-
change in the substrate response from sigmoidal to hyperbolic. Activating effect of ATP or triphosphate with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) on wild-type is dampened. Mutant recognizes additional cleavage sites in substrate beta-endorphin
E111V
-
change in the substrate response from sigmoidal to hyperbolic. Activating effect of ATP or triphosphate with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) on wild-type is dampened. Mutant recognizes additional cleavage sites in substrate beta-endorphin
H112D
-
change in the substrate response from sigmoidal to hyperbolic. Activating effect of ATP or triphosphate with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) on wild-type is changed to inhibition. Affinity to Zn2+ is lower than in wild-type
H112Q
-
change in the substrate response from sigmoidal to hyperbolic. Activating effect of ATP or triphosphate with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) on wild-type is changed to inhibition. Affinity to Zn2+ is lower than in wild-type
H18R/A890V
-
naturally occuring mutations in the insulysin gene in GK rats causing 30% reduced enzyme activity and type 2 diabetes as well as increased amyloid beta peptide levels , the rats exhibit defects in both insulin action and insulin degradation, the increased amyloid beta-peptide levels do not lead to increased steady-state levels of its activity due to compensatory degradative mechanisms in the brain
I374S
-
mutation in the distal site eliminates allosterism, Vmax decreased approximately 10fold compared to wild-type, Km (Abz-GGFLRKHGQ-EDDnp) roughly similar to wild-type, no heterotropic activation with bradykinin, no significant activation through ATP
K898A/K899A/S901A
-
mutant shows greatly decreased activation by the polyphosphate anions ATP and PPP, mutant is also deficient in activation by small peptides and has reduced intracellular function relative to unmodified IDE. Km and kcat (Abz-GGFLRKHGQ-EDDnp) higher than wild-type
R429S
-
mutant shows greatly decreased activation by the polyphosphate anions ATP and PPP. kcat (Abz-GGFLRKHGQ-EDDnp) comparable to wild-type and Km (Abz-GGFLRKHGQ-EDDnp) higher than wild-type
V360S
-
mutation in the distal site eliminates allosterism, Vmax decreased approximately 10fold compared to wild-type, Km (Abz-GGFLRKHGQ-EDDnp) roughly similar to wild-type, no heterotropic activation with bradykinin, ATP activation is reduced to 8fold
Y609F
-
mutation in the distal site eliminates allosterism, Vmax decreased approximately 10fold compared to wild-type, Km (Abz-GGFLRKHGQ-EDDnp) roughly similar to wild-type, no heterotropic activation with bradykinin, no significant activation through ATP
additional information
E111F
-
change in the substrate response from sigmoidal to hyperbolic. Activating effect of ATP or triphosphate with substrate 2-aminobenzoyl-GGFLRKHGQ-(N-(2,4-dinitrophenyl)ethylenediamine) on wild-type is dampened. Mutant recognizes additional cleavage sites in substrate beta-endorphin
E111F
-
crystal structure of a catalytically compromised E111F mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2
additional information
-
heterologous expression in Saccharomyces cerevisiae, enzyme can promote the in vivo production of yeast a-factor mating pheromone, but cannot substitue for other fuctions of yeast Axl1p. Enzyme requires an intact C-terminus for optimal activity
additional information
-
construction of transgenic mice with increased enzyme levels show that the enzyme prevents and treats Alzheimer's disease formation
additional information
-
mutant with a deleted putative dimer interface in the C-terminal region is created, which results in a monomeric variant. Monomeric IDE retains enzymatic activity. Monomeric IDE retains, 25% of the wild type activity substrate (Abz-GGFLRKHGQ-EDDnp). With the peptide substrates beta-endorphin and amyloid beta peptide 1-40, monomeric IDE retains 1 to 0.25% of wild type activity. No activation through bradykinin or dynorphin B-9. Monomeric IDE is not activated by polyphosphates
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
IDE is associated with other cellular proteins in its freshly isolated state and co-purifies to a variable degree with other proteins including multicatalytic proteinase
-
native enzyme from skeletal muscle by anion exchange chromatography and chromatofocusing to homogeneity
-
recombinant His6-tagged IDE from Escherichia coli strain BL21(DE3) by nickel affinity chromatography and gel filtration
-
the protease is a complex of rather easily dissociating units, which severly complicates its purification
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
a form of the enzyme derived from an alternative translational start site that can localize to mitochondria instead of the cytosol
-
cloning from C6 glioma cells, expression of recombinant GST-tagged wild-type IDE, and of recombinant IDE mutant E111Q
-
expression of the N-terminally His6-tagged enzyme in Spodopterafrugiperda Sf9 cells using the baculovirus transfection system
-
recombinant expression of His6-tagged IDE in Escherichia coli strain BL21(DE3)
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
docosahexaenoic acid induces the expression of IDE in primary hippocampal neurons and prevents Alzheimer's disease
-
palmitic acid suppresses the expression of IDE and induces Alzheimer's disease
-
peroxisome proliferator-activated receptor gamma, PPARgamma, increases IDE levels acting as a positive regulator. PPARgamma participates in the insulin-induced IDE expression in neurons, it binds to the IDE gene promoter flanking a functional PPRE in primary neurons
-
reduced neuronal expression of insulin-degrading enzyme in the left and right dorsolateral prefrontal cortex, but not in other brain areas investigated, of haloperidol-treated rats
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
IDE represents a target for the development of a new class of drugs for the treatment of Alzheimer's disease that lowers amyloid beta-peptide levels by increasing ist rate of catabolism
medicine
-
enzyme is capable of cleavage of the 34 amino acid peptides resulting from internal proteolysis of genetically defect type 2 transmembrane protein BRI2 in patients with familial British dementia or familial Danish dementia. Enzymic degradation of peptide is more efficient with monomeric peptide than with aggregated peptide. Proteolysis of monomeric soluble peptide precursors by enzyme may delay peptide ABri and ADan aggregation in vivo
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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
Ryan, M.P.; Duckworth, W.C.
Partial characterization of an endogenous inhibitor of a calcium-dependent form of insulin protease
Biochem. Biophys. Res. Commun.
116
195-203
1983
Rattus norvegicus
Brush, J.S.; Nascimento, C.G.
Studies of the properties of the insulin protease of rat liver
Biochim. Biophys. Acta
704
398-402
1982
Rattus norvegicus
Chowdhary, B.K.; Smith, G.D.; Peters, T.J.
Subcellular localization and partial characterization of insulin proteolytic activity in rat liver
Biochim. Biophys. Acta
840
180-186
1985
Rattus norvegicus
Duckworth, W.C.; Stentz, F.B.; Heinemann, M.; Kitabchi, A.E.
Initial site of insulin cleavage by insulin protease
Proc. Natl. Acad. Sci. USA
76
635-639
1979
Rattus norvegicus
Duckworth, W.C.; Heinemann, M.A.; Kitabchi, A.E.
Purification of insulin-specific protease by affinity chromatography
Proc. Natl. Acad. Sci. USA
69
3698-3702
1972
Rattus norvegicus
Baskin, F.K.; Kitachi, A.E.
Substrate studies for insulin-specific protease
Eur. J. Biochem.
37
489-496
1973
Rattus norvegicus
Brush, J.S.; Shah, R.J.
Purification and characterization of inhibitors of insulin specific protease in human serum
Biochem. Biophys. Res. Commun.
53
894-903
1973
Rattus norvegicus
Baskin, F.K.; Duckworth, W.C.; Kitabchi, A.E.
Sites of cleavage of glucagon by insulin-glucagon protease
Biochem. Biophys. Res. Commun.
67
163-169
1975
Rattus norvegicus
Bennett, R.G.; Hamel, F.G.; Duckworth, W.C.
Identification and isolation of a cytosolic proteolytic complex containing insulin degrading enzyme and the multicatalytic proteinase
Biochem. Biophys. Res. Commun.
202
1047-1053
1994
Rattus norvegicus
Werlen, R.C.; Offord, R.E.; Rose, K.
Preparation and characterization of novel substrates of insulin proteinase (EC 3.4.99.45)
Biochem. J.
302
907-911
1994
Rattus norvegicus, Sus scrofa
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
Rawlings, N.D.; Barrett, A.J.
Potential metal ligands in the insulinase superfamily of endopeptidases
Biochem. Soc. Trans.
19
289S
1991
Drosophila melanogaster, Rattus norvegicus
Ogawa, W.; Shii, K.; Yonezawa, K.; Baba, S.; Yokono, K.
Affinity purification of insulin-degrading enzyme and its endogenous inhibitor from rat liver
J. Biol. Chem.
267
1310-1316
1992
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
McKenzie, R.A.; Burghen, G.A.
Partial purification and characterization of insulin protease and its intracellular inhibitor from rat liver
Arch. Biochem. Biophys.
229
604-611
1984
Rattus norvegicus
Duckworth, W.C.; Garcia, J.V.; Liepnieks, J.J.; Hamel, F.G.; Hermodson, M.A.; Frank, B.H.; Rosner, M.R.
Drosophila insulin degrading enzyme and rat skeletal muscle insulin protease cleave insulin at similar sites
Biochemistry
28
2471-2477
1989
Drosophila melanogaster, Rattus norvegicus
Ansorge, S.; Bohley, P.; Kirschke, H.; Langner, J.; Wiederanders, B.
The insulin and glucagon degrading proteinase of rat liver: a metal-dependent enzyme
Biomed. Biochim. Acta
43
39-46
1984
Rattus norvegicus
Mannor, G.; Movsas, B.; Yalow, R.S.
Characterization of insulinase from mammalian and non-mammalian livers
Life Sci.
34
1341-1345
1984
Canis lupus familiaris, Cavia porcellus, Oryctolagus cuniculus, Frog, Rattus norvegicus, Sus scrofa
Brush, J.S.
Studies on inhibitors of the insulin protease of rat liver
Biochem. Pharmacol.
26
2349-2354
1977
Rattus norvegicus
Burghen, G.A.; Kitabchi, A.E.; Brush, J.S.
Characterization of a rat liver protease with specificity for insulin
Endocrinology
91
633-642
1972
Rattus norvegicus
Brush, J.S.; Sonne, O.; Gliemann, J.
Degradation of the four monoiodoinsulin isomers by the insulin protease of rat liver
Biochim. Biophys. Acta
757
269-273
1983
Rattus norvegicus
Camberos, M.C.; Perez, A.A.; Udrisar, D.P.; Wanderley, M.I.; Cresto, J.C.
ATP inhibits insulin-degrading enzyme activity
Exp. Biol. Med.
226
334-341
2001
Rattus norvegicus, Rattus norvegicus Wistar
Bennett, R.G.; Duckworth, W.C.; Hamel, F.G.
Degradation of amylin by insulin-degrading enzyme
J. Biol. Chem.
275
36621-36625
2000
Rattus norvegicus
Edbauer, D.; Willem, M.; Lammich, S.; Steiner, H.; Haass, C.
Insulin-degrading enzyme rapidly removes the beta-amyloid precursor protein intracellular domain (AICD)
J. Biol. Chem.
277
13389-13393
2002
Rattus norvegicus
Song, E.S.; Juliano, M.A.; Juliano, L.; Hersh, L.B.
Substrate activation of insulin-degrading enzyme (insulysin). A potential target for drug development
J. Biol. Chem.
278
49789-49794
2003
Rattus norvegicus
Miller, B.C.; Eckman, E.A.; Sambamurti, K.; Dobbs, N.; Chow, K.M.; Eckman, C.B.; Hersh, L.B.; Thiele, D.L.
Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo
Proc. Natl. Acad. Sci. USA
100
6221-6226
2003
Rattus norvegicus, Mus musculus (Q8CGB9), Mus musculus
Kurochkin, I.V.
Insulin-degrading enzyme: embarking on amyloid destruction
Trends Biochem. Sci.
26
421-425
2001
Drosophila melanogaster, Homo sapiens, Rattus norvegicus
Farris, W.; Mansourian, S.; Leissring, M.A.; Eckman, E.A.; Bertram, L.; Eckman, C.B.; Tanzi, R.E.; Selkoe, D.J.
Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein
Am. J. Pathol.
164
1425-1434
2004
Rattus norvegicus (P35559)
Yao, H.; Hersh, L.B.
Characterization of the binding of the fluorescent ATP analog TNP-ATP to insulysin
Arch. Biochem. Biophys.
451
175-181
2006
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
Udrisar, D.P.; Wanderley, M.I.; Porto, R.C.; Cardoso, C.L.; Barbosa, M.C.; Camberos, M.C.; Cresto, J.C.
Androgen- and estrogen-dependent regulation of insulin-degrading enzyme in subcellular fractions of rat prostate and uterus
Exp. Biol. Med.
230
479-486
2005
Rattus norvegicus
Song, E.S.; Juliano, M.A.; Juliano, L.; Fried, M.G.; Wagner, S.L.; Hersh, L.B.
ATP effects on insulin-degrading enzyme are mediated primarily through its triphosphate moiety
J. Biol. Chem.
279
54216-54220
2004
Rattus norvegicus
Song, E.S.; Daily, A.; Fried, M.G.; Juliano, M.A.; Juliano, L.; Hersh, L.B.
Mutation of active site residues of insulin-degrading enzyme alters allosteric interactions
J. Biol. Chem.
280
17701-17706
2005
Rattus norvegicus
Kim, S.; Lapham, A.N.; Freedman, C.G.; Reed, T.L.; Schmidt, W.K.
Yeast as a tractable genetic system for functional studies of the insulin-degrading enzyme
J. Biol. Chem.
280
27481-27490
2005
Rattus norvegicus
Song, E.S.; Cady, C.; Fried, M.G.; Hersh, L.B.
Proteolytic fragments of insulysin (IDE) retain substrate binding but lose allosteric regulation
Biochemistry
45
15085-15091
2006
Rattus norvegicus
Hersh, L.B.
The insulysin (insulin degrading enzyme) enigma
Cell. Mol. Life Sci.
63
2432-2434
2006
Homo sapiens, Mus musculus, Rattus norvegicus
Camberos, M.d.; Cresto, J.C.
Insulin-degrading enzyme hydrolyzes ATP
Exp. Biol. Med.
232
281-292
2007
Rattus norvegicus
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
Cordes, C.M.; Bennett, R.G.; Siford, G.L.; Hamel, F.G.
Nitric oxide inhibits insulin-degrading enzyme activity and function through S-nitrosylation
Biochem. Pharmacol.
77
1064-1073
2009
Rattus norvegicus
Llovera, R.E.; de Tullio, M.; Alonso, L.G.; Leissring, M.A.; Kaufman, S.B.; Roher, A.E.; de Prat Gay, G.; Morelli, L.; Castano, E.M.
The catalytic domain of insulin-degrading enzyme forms a denaturant-resistant complex with amyloid beta peptide: implications for Alzheimer disease pathogenesis
J. Biol. Chem.
283
17039-17048
2008
Rattus norvegicus
Grasso, G.; Rizzarelli, E.; Spoto, G.
The proteolytic activity of insulin-degrading enzyme: a mass spectrometry study
J. Mass Spectrom.
44
735-741
2009
Rattus norvegicus
Bulloj, A.; Leal, M.C.; Surace, E.I.; Zhang, X.; Xu, H.; Ledesma, M.D.; Castano, E.M.; Morelli, L.
Detergent resistant membrane-associated IDE in brain tissue and cultured cells: relevance to Abeta and insulin degradation
Mol. Neurodegener.
3
22
2008
Mus musculus, Rattus norvegicus
Bennett, R.G.; Heimann, D.G.; Hamel, F.G.
Degradation of relaxin family peptides by insulin-degrading enzyme
Ann. N. Y. Acad. Sci.
1160
38-41
2009
Rattus norvegicus
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
Chou, Y.H.; Kuo, W.L.; Rosner, M.R.; Tang, W.J.; Goldman, R.D.
Structural changes in intermediate filament networks alter the activity of insulin-degrading enzyme
FASEB J.
23
3734-3742
2009
Rattus norvegicus, Xenopus laevis
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
Du, J.; Zhang, L.; Liu, S.; Wang, Z.
Palmitic acid and docosahexaenoic acid opposingly regulate the expression of insulin-degrading enzyme in neurons
Pharmazie
65
231-232
2010
Rattus norvegicus
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
Alper, B.J.; Rowse, J.W.; Schmidt, W.K.
Yeast Ste23p shares functional similarities with mammalian insulin-degrading enzymes
Yeast
26
595-610
2009
Rattus norvegicus
Noinaj, N.; Song, E.S.; Bhasin, S.; Alper, B.J.; Schmidt, W.K.; Hersh, L.B.; Rodgers, D.W.
Anion activation site of insulin-degrading enzyme
J. Biol. Chem.
287
48-57
2012
Rattus norvegicus
Song, E.; Rodgers, D.; Hersh, L.
A monomeric variant of insulin degrading enzyme (IDE) loses its regulatory properties
PLoS ONE
5
e9719
2010
Rattus norvegicus
Cordes, C.; Bennett, R.; Siford, G.; Hamel, F.
Redox regulation of insulin degradation by insulin-degrading enzyme
PLoS ONE
6
e18138
2011
Rattus norvegicus
Noinaj, N.; Bhasin, S.K.; Song, E.S.; Scoggin, K.E.; Juliano, M.A.; Juliano, L.; Hersh, L.B.; Rodgers, D.W.
Identification of the allosteric regulatory site of insulysin
PLoS ONE
6
e20864
2011
Rattus norvegicus
Song, E.S.; Jang, H.; Guo, H.F.; Juliano, M.A.; Juliano, L.; Morris, A.J.; Galperin, E.; Rodgers, D.W.; Hersh, L.B.
Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes
Proc. Natl. Acad. Sci. USA
114
E2826-E2835
2017
Rattus norvegicus (P35559)
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