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
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neprilysin
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abeta
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hippocampus
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dementia
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mellitus
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cerebral
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morris
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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
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enzyme-1
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b-chains
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analysis
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ad-like
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anti-ide
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exosite
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beta-peptide
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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 (Inhibitors
Inhibitors on EC 3.4.24.56 - insulysin
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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
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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 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
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(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
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(benzyl-(((S)-2-(1H-imidazol-4-yl)-1-methylcarbamoylethylcarbamoyl)-methyl)-amino)-acetic acid
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(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
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(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
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(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
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(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
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(S)-2-(2-(benzyl-carboxymethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid tert-butyl ester
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(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
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(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
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(S)-2-(2-(benzyl-hydroxycarbamoylmethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
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(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
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(S)-2-(2-(carboxymethyl-(2-(1H-indol-3-yl)-ethyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
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(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
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(S)-2-(2-(carboxymethyl-(3-phenyl-propyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid tert-butyl ester
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(S)-2-(2-(carboxymethyl-(4-fluoro-benzyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
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(S)-2-(2-(carboxymethyl-(4-methyl-benzyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
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(S)-2-(2-(carboxymethyl-(4-phenyl-butyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
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(S)-2-(2-(carboxymethyl-(4-trifluoromethyl-benzyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
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(S)-2-(2-(carboxymethyl-(n-hexyl)-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
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(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
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(S)-2-(2-(carboxymethyl-phenethyl-amino)-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
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(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
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(S)-2-(2-benzylamino-acetylamino)-3-(1H-imidazol-4-yl)-propionic acid methyl ester
less than 10% inhibition at 0.1 mM
(S)-4-fluoro-N-((1-(4-(hydroxyamino)-1-(naphthalen-2-yl)-4-oxobutan-2-yl)-1H-1,2,3-triazol-4-yl)methyl)benzamide
i.e. BDM44768, catalytic site inhibitor, designed by kinetic target-guided synthesis. Selectively inhibits insulin-degrading enzyme. Crystallographic and small angle X-ray scattering analyses show that it locks insulin-degrading enzyme in a closed conformation. Acute treatment of mice with BDM44768 increases insulin signalling and impairs glucose tolerance in an insulin-degrading enzyme-dependent manner. The results casts doubt on the general usefulness of the inhibition of insulin-degrading enzyme catalytic activity to treat diabetes
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
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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
adrenocorticotropic hormone
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competitive inhibition of amylin degradation
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amylin
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excess amylin inhibits amylin degradation, competitive inhibition
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cholesterol
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membranes isolated from mouse brain with endogenous reduced levels of cholesterol due to targeted deletion of one seladin-I allele show a reduced amount of IDE
glutathione
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oxidized glutathione inhibits IDE through glutathionylation, which is reversible by dithiothreitol but not by ascorbic acid
InsL3
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competitively inhibits the degradation of insulin, and crosslinking of insulin to IDE
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insulin-like peptide 3
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IDE degrades insulin quickly, and addition of INSL3 significantly decreases insulin degradation, competitive inhibition
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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
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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
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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
Natural inhibitor of MW 67000 or 80000-120000 MW
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reduces activity reversibly, nonprogressively, and noncompetitively with respect to insulin
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o-phenanthroline
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0.1 mM, wild-type, 73% residual activity, mutants H112D, H112Q, less than 2.5% residual activity
QSLPWCYPHCVT-NH2
the substrate contains two cysteine residues, which are predicted to form a disulfide bond that cyclizes the peptide, together with 2 proline residues. By virtue of its potency, stability, specificity for insulin-degrading enzyme, low cost of synthesis, and demonstrated ability to potentiate insulin-induced processes involved in wound healing and skin health, the inhibitor holds significant therapeutic and cosmetic potential for topical applications
relaxin
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competitively inhibits the degradation of insulin, and crosslinking of insulin to IDE
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relaxin-3
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competitively inhibits the degradation of insulin, and crosslinking of insulin to IDE
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S-nitroso-N-acetylpenicillamine
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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
sodium nitroprusside
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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
[(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
[(Z)-1-[N-3-aminopropyl]-N-(n-propyl)amino]diazen-1-ium-1,2-dolate
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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
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Zn2+, Co2+, Mn2+ and to a smaller extent Cd2+ and Fe2+ are capable of preventing the inhibition
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
ATP
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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
ATP
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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
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the activation of IDE disappears upon inactivation by EDTA, which chelates the catalytic Zn2+ ion
EDTA
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0.1 mM, wild-type, 91% residual activity, mutants H112D, H112Q, less than 2.5% residual activity
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
Inhibitor from rat liver homogenate
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purification of endogenous inhibitor from rat liver
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Inhibitor from rat liver homogenate
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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
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Insulin
-
inhibits amylin degradation, excess insulin inhibits insulin degradation
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nestin
-
insulin degradation activity of IDE is suppressed by about 50% by either nestin or phosphorylated vimentin, while the cleavage of bradykinin-mimetic peptide by IDE is increased 2 to 3fold
-
nestin
-
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
-
nitric oxide
-
amyloid beta peptide degradation by IDE is inhibited by NO donor Sin-1
nitric oxide
-
incubation with NO donor Sin-1 results in a strong reduction of IDE activity. In vivo the activity of insulin-degrading enzyme is lowered in APP/PS1 mice, but not in APP/PS1/NOS2(-/-) mice
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
-
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
-
S-nitrosoglutathione
-
potent inhibition at physiologically relevant concentrations
S-nitrosoglutathione
-
the oxidative burst of BV-2 microglial cells leads nitrosylation of secreted IDE at Cys residues, e.g. Cys819, Cys110, Cys257, and Cys178, leading to the reduced activity versus amyloid beta degradation, increases IDE oligomerization, and decreases IDE thermostability. This inhibitory response of IDE is substrate-dependent, biphasic for amyloid beta degradation but monophasic for a shorter bradykinin-mimetic substrate, mutational analysis, overview. Only Cys819 modification plays a prominant role in the change of enzyme properties
S-nitrosoglutathione
-
inhibits IDE-mediated degradation of two IDE substrates, insulin and amyloid beta
sulfhydryl-modifying reagents
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Drosophila, human and rat enzyme inhibited, bacterial enzyme not
-
sulfhydryl-modifying reagents
-
Drosophila, human and rat enzyme inhibited, bacterial enzyme not
-
sulfhydryl-modifying reagents
-
Drosophila, human and rat enzyme inhibited, bacterial enzyme not
-
additional information
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not: the enzyme is inhibited by cysteine protease inhibitors as well as metalloprotease inhibitors
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additional information
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not: aprotinin; not: pancreatic trypsin inhibitor
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additional information
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not: phenylmethanesulfonyl fluoride; not: phosphoramidon
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additional information
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not: the enzyme is inhibited by cysteine protease inhibitors as well as metalloprotease inhibitors
-
additional information
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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
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additional information
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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
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not: the enzyme is inhibited by cysteine protease inhibitors as well as metalloprotease inhibitors
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additional information
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not: antipain; not: bestatine; not: chymostatin; not: elastatinal; not: leupeptin; not: pepstatin; not: phosphoramidon
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additional information
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not: overview: various amino acid derivatives, small polypeptides, indole and quinoline derivatives, dyes and dye derivatives
-
additional information
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pepstatin-A, leupeptin, and calpains are ineffective as inhibitors, no competitive inhibition with EGF or insulin C-peptide
-
additional information
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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
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additional information
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not: benzamidine; not: bestatine; not: phenylmethanesulfonyl fluoride
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