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Literature summary for 3.4.22.59 extracted from

  • Tubeleviciute-Aydin, A.; Beautrait, A.; Lynham, J.; Sharma, G.; Gorelik, A.; Deny, L.J.; Soya, N.; Lukacs, G.L.; Nagar, B.; Marinier, A.; LeBlanc, A.C.
    Identification of allosteric inhibitors against active caspase-6 (2019), Sci. Rep., 9, 5504 .
    View publication on PubMedView publication on EuropePMC
Search for more literature for 3.4.22.59

Application

Application Comment Organism
medicine caspase-6 inhibition is a promising strategy to stop early stage neurodegenerative events Homo sapiens

Cloned(Commentary)

Cloned (Comment) Organism
wild-type enzyme and variants are expressed in Escherichia coli Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
-
 Homo sapiens

Protein Variants

Protein Variants Comment Organism
A109T missense rare variants with amino acid substitution located remotely from Casp6 active site. Activity with the substrate Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin is comparable to that of wild-type enzyme. No significant changes in kinetic parameters, KM, and kcat, for Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin Homo sapiens
A34E missense rare variants with amino acid substitution located remotely from Casp6 active site. Lower activity than wild-type enzyme with the substrate Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin. No significant changes in kinetic parameters, KM, and kcat, for Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin Homo sapiens
E35K missense rare variants with amino acid substitution located remotely from Casp6 active site. Lower activity than wild-type enzyme with the substrate Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin. Slightly reduced kcat and about 2fold reduced catalytic efficiency kcat/KM Homo sapiens
G66R natural variant with significantly impaired activity Homo sapiens
R65W natural variant with significantly impaired activity Homo sapiens
T182S missense rare variants with amino acid substitution located remotely from Casp6 active site. Lower activity than wild-type enzyme with the substrate Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin. No significant changes in kinetic parameters, KM, and kcat, for Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(5Z)-1-(furan-2-ylmethyl)-5-([1-[2-(2-methylpiperidin-1-yl)-2-oxoethyl]-1H-indol-3-yl]methylidene)pyrimidine-2,4,6(1H,3H,5H)-trione
-
 Homo sapiens
(5Z)-1-(furan-2-ylmethyl)-5-([1-[2-(morpholin-4-yl)-2-oxoethyl]-1H-indol-3-yl]methylidene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione
-
 Homo sapiens
(5Z)-1-(furan-2-ylmethyl)-5-([1-[2-(morpholin-4-yl)-2-oxoethyl]-1H-indol-3-yl]methylidene)pyrimidine-2,4,6(1H,3H,5H)-trione
-
 Homo sapiens
(5Z)-1-(furan-2-ylmethyl)-5-([1-[2-oxo-2-(piperidin-1-yl)ethyl]-1H-indol-3-yl]methylidene)pyrimidine-2,4,6(1H,3H,5H)-trione
-
 Homo sapiens
(5Z)-1-(furan-2-ylmethyl)-5-([1-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1H-indol-3-yl]methylidene)pyrimidine-2,4,6(1H,3H,5H)-trione
-
 Homo sapiens
2-(3-[(E)-[1-(furan-2-ylmethyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)-N-(2-methoxyethyl)acetamide
-
 Homo sapiens
2-(3-[(E)-[1-(furan-2-ylmethyl)-4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)-N-(2-methoxyethyl)acetamide
-
 Homo sapiens
2-(3-[(Z)-[1-(furan-2-ylmethyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)-N-(3-methoxypropyl)acetamide
-
 Homo sapiens
2-(3-[(Z)-[1-(furan-2-ylmethyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)acetamide
-
 Homo sapiens
2-(3-[(Z)-[1-(furan-2-ylmethyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)acetamide
-
 Homo sapiens
2-(3-[(Z)-[1-(furan-2-ylmethyl)-4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)acetamide
-
 Homo sapiens
2-([[(6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl)sulfanyl]acetyl]amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide
-
 Homo sapiens
2-([[1-(4-chlorophenyl)-1H-tetrazol-5-yl]sulfanyl]methyl)quinazolin-4(1H)-one
-
 Homo sapiens
2-amino-7-[4-[(3-fluorobenzyl)oxy]phenyl]-6,7-dihydro[1,3]thiazolo[4,5-b]pyridin-5(4H)-one
-
 Homo sapiens
2-[(4-methylquinazolin-2-yl)amino]-6-[(pyridin-2-ylsulfanyl)methyl]pyrimidin-4(3H)-one
-
 Homo sapiens
2-[1-(2-chloro-4-fluorobenzyl)-3-oxopiperazin-2-yl]-N-cyclooctylacetamide
-
 Homo sapiens
2-[1-(3-methoxybenzyl)-3-oxopiperazin-2-yl]-N-[[1-(2-methylphenyl)-1H-pyrazol-4-yl]methyl]acetamide
-
 Homo sapiens
3-[(5E)-5-(2-chlorobenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]-N-(adamantan-1-yl)propanamide
-
 Homo sapiens
6-amino-4-[3-(benzyloxy)phenyl]-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
-
 Homo sapiens
methyl 3-(aminomethyl)-5-[(furan-2-ylcarbonyl)amino]benzoate
-
 Homo sapiens
methyl 3-([[(2,3-dimethyl-1H-indol-7-yl)carbonyl]amino]methyl)-5-[(furan-2-ylcarbonyl)amino]benzoate
-
 Homo sapiens
methyl 3-[(furan-2-ylcarbonyl)amino]-5-([[(5-methyl-3-phenyl-1,2-oxazol-4-yl)carbonyl]amino]methyl)benzoate
-
 Homo sapiens
methyl 3-[([[1-(4-chlorophenyl)cyclobutyl]carbonyl]amino)methyl]-5-[(furan-2-ylcarbonyl)amino]benzoate
-
 Homo sapiens
methyl 3-[[(2,2-dimethylpropanoyl)amino]methyl]-5-[(furan-2-ylcarbonyl)amino]benzoate
-
 Homo sapiens
methyl 3-[[(2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]methyl]-5-[(furan-2-ylcarbonyl)amino]benzoate
-
 Homo sapiens
methyl 3-[[(2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]methyl]-5-[(phenylacetyl)amino]benzoate
-
 Homo sapiens
methyl 3-[[(3,5-dimethylbenzoyl)amino]methyl]-5-[(furan-2-ylcarbonyl)amino]benzoate
-
 Homo sapiens
N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-3-methyl-1-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
-
 Homo sapiens
N-(furan-2-ylmethyl)-2-(3-[(Z)-[1-(furan-2-ylmethyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)acetamide
-
 Homo sapiens
N-(furan-2-ylmethyl)-2-[3-(phenoxyacetyl)-1H-indol-1-yl]acetamide
-
 Homo sapiens

KM Value [mM]

KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
0.0227
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme A34E Homo sapiens
0.0312
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7., wild-type enzyme Homo sapiens
0.0326
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme K284A Homo sapiens
0.0333
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme T182S Homo sapiens
0.0345
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme A109T Homo sapiens
0.0371
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme E35K Homo sapiens
0.315
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme L200A Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin + H2O Homo sapiens
-
 Ac-Val-Glu-Ile-Asp + 7-amino-4-trifluoromethylcoumarin
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens P55212
-
-

Purification (Commentary)

Purification (Comment) Organism
-
 Homo sapiens

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin + H2O
-
 Homo sapiens Ac-Val-Glu-Ile-Asp + 7-amino-4-trifluoromethylcoumarin
-
 ?

Turnover Number [1/s]

Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
0.05
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme L200A Homo sapiens
1.71
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme E35K Homo sapiens
2
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme K284A Homo sapiens
2.04
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme A34E Homo sapiens
2.27
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, wild-type enzyme Homo sapiens
2.42
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme T182S Homo sapiens
2.51
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme A109T Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0042
-
 37°C, pH 6.8 Homo sapiens N-(furan-2-ylmethyl)-2-(3-[(Z)-[1-(furan-2-ylmethyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)acetamide
0.0044
-
 37°C, pH 6.8 Homo sapiens 2-(3-[(Z)-[1-(furan-2-ylmethyl)-4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)acetamide
0.0076
-
 37°C, pH 6.8 Homo sapiens (5Z)-1-(furan-2-ylmethyl)-5-([1-[2-(morpholin-4-yl)-2-oxoethyl]-1H-indol-3-yl]methylidene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione
0.0098
-
 37°C, pH 6.8 Homo sapiens (5Z)-1-(furan-2-ylmethyl)-5-([1-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1H-indol-3-yl]methylidene)pyrimidine-2,4,6(1H,3H,5H)-trione
0.0105
-
 37°C, pH 6.8 Homo sapiens 2-(3-[(Z)-[1-(furan-2-ylmethyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)acetamide
0.011
-
 37°C, pH 6.8 Homo sapiens (5Z)-1-(furan-2-ylmethyl)-5-([1-[2-oxo-2-(piperidin-1-yl)ethyl]-1H-indol-3-yl]methylidene)pyrimidine-2,4,6(1H,3H,5H)-trione
0.0128
-
 37°C, pH 6.8 Homo sapiens (5Z)-1-(furan-2-ylmethyl)-5-([1-[2-(morpholin-4-yl)-2-oxoethyl]-1H-indol-3-yl]methylidene)pyrimidine-2,4,6(1H,3H,5H)-trione
0.0129
-
 37°C, pH 6.8 Homo sapiens 2-(3-[(Z)-[1-(furan-2-ylmethyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)-N-(3-methoxypropyl)acetamide
0.0132
-
 37°C, pH 6.8 Homo sapiens methyl 3-[[(2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]methyl]-5-[(furan-2-ylcarbonyl)amino]benzoate
0.0164
-
 37°C, pH 6.8 Homo sapiens (5Z)-1-(furan-2-ylmethyl)-5-([1-[2-(2-methylpiperidin-1-yl)-2-oxoethyl]-1H-indol-3-yl]methylidene)pyrimidine-2,4,6(1H,3H,5H)-trione
0.0165
-
 37°C, pH 6.8 Homo sapiens 2-(3-[(E)-[1-(furan-2-ylmethyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)-N-(2-methoxyethyl)acetamide
0.0168
-
 37°C, pH 6.8 Homo sapiens 2-(3-[(E)-[1-(furan-2-ylmethyl)-4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)-N-(2-methoxyethyl)acetamide
0.0215
-
 37°C, pH 6.8 Homo sapiens methyl 3-[[(3,5-dimethylbenzoyl)amino]methyl]-5-[(furan-2-ylcarbonyl)amino]benzoate
0.027
-
 37°C, pH 6.8 Homo sapiens methyl 3-[([[1-(4-chlorophenyl)cyclobutyl]carbonyl]amino)methyl]-5-[(furan-2-ylcarbonyl)amino]benzoate
0.0302
-
 37°C, pH 6.8 Homo sapiens 2-(3-[(Z)-[1-(furan-2-ylmethyl)-2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene]methyl]-1H-indol-1-yl)-N-(tetrahydrofuran-2-ylmethyl)acetamide
0.0441
-
 37°C, pH 6.8 Homo sapiens 2-[1-(3-methoxybenzyl)-3-oxopiperazin-2-yl]-N-[[1-(2-methylphenyl)-1H-pyrazol-4-yl]methyl]acetamide
0.0464
-
 37°C, pH 6.8 Homo sapiens 2-[1-(2-chloro-4-fluorobenzyl)-3-oxopiperazin-2-yl]-N-cyclooctylacetamide
0.0799
-
 37°C, pH 6.8 Homo sapiens N-(furan-2-ylmethyl)-2-[3-(phenoxyacetyl)-1H-indol-1-yl]acetamide
0.09
-
 37°C, pH 6.8 Homo sapiens N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-3-methyl-1-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
0.1095
-
 37°C, pH 6.8 Homo sapiens 2-([[(6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl)sulfanyl]acetyl]amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide
0.123
-
 37°C, pH 6.8 Homo sapiens 3-[(5E)-5-(2-chlorobenzylidene)-4-oxo-2-thioxo-1,3-thiazolidin-3-yl]-N-(adamantan-1-yl)propanamide
0.1418
-
 37°C, pH 6.8 Homo sapiens 2-([[1-(4-chlorophenyl)-1H-tetrazol-5-yl]sulfanyl]methyl)quinazolin-4(1H)-one
0.159
-
 37°C, pH 6.8 Homo sapiens 6-amino-4-[3-(benzyloxy)phenyl]-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
0.2334
-
 37°C, pH 6.8 Homo sapiens 2-[(4-methylquinazolin-2-yl)amino]-6-[(pyridin-2-ylsulfanyl)methyl]pyrimidin-4(3H)-one
0.289
-
 37°C, pH 6.8 Homo sapiens 2-amino-7-[4-[(3-fluorobenzyl)oxy]phenyl]-6,7-dihydro[1,3]thiazolo[4,5-b]pyridin-5(4H)-one
0.719
-
 37°C, pH 6.8 Homo sapiens methyl 3-([[(2,3-dimethyl-1H-indol-7-yl)carbonyl]amino]methyl)-5-[(furan-2-ylcarbonyl)amino]benzoate
1.545
-
 37°C, pH 6.8 Homo sapiens methyl 3-[[(2,3-dihydro-1-benzofuran-2-ylcarbonyl)amino]methyl]-5-[(phenylacetyl)amino]benzoate
1.922
-
 37°C, pH 6.8 Homo sapiens methyl 3-(aminomethyl)-5-[(furan-2-ylcarbonyl)amino]benzoate
2.047
-
 37°C, pH 6.8 Homo sapiens methyl 3-[(furan-2-ylcarbonyl)amino]-5-([[(5-methyl-3-phenyl-1,2-oxazol-4-yl)carbonyl]amino]methyl)benzoate
3.37
-
 37°C, pH 6.8 Homo sapiens methyl 3-[[(2,2-dimethylpropanoyl)amino]methyl]-5-[(furan-2-ylcarbonyl)amino]benzoate

General Information

General Information Comment Organism
malfunction the excess neuronal activity of Caspase-6 is associated with Alzheimer disease neuropathology and age-dependent cognitive impairment Homo sapiens
physiological function the enzyme plays essential roles in programmed cell death, axonal degeneration, and development Homo sapiens

kcat/KM [mM/s]

kcat/KM Value [1/mMs-1] kcat/KM Value Maximum [1/mMs-1] Substrate Comment Organism Structure
0.15
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme L200A Homo sapiens
46.833
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme E35K Homo sapiens
58.65
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme K284A Homo sapiens
72.65
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme T182S Homo sapiens
72.68
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme A109T Homo sapiens
76
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7., wild-type enzyme Homo sapiens
89.8
-
 Ac-Val-Glu-Ile-Asp-7-amido-4-trifluoromethylcoumarin 37°C, pH 7.2, mutant enzyme A34E Homo sapiens