Literature summary for 3.4.22.56 extracted from

Wang, Z.; Watt, W.; Brooks, N.A.; Harris, M.S.; Urban, J.; Boatman, D.; McMillan, M.; Kahn, M.; Heinrikson, R.L.; Finzel, B.C.; Wittwer, A.J.; Blinn, J.; Kamtekar, S.; Tomasselli, A.G.
Kinetic and structural characterization of caspase-3 and caspase-8 inhibition by a novel class of irreversible inhibitors (2010), Biochim. Biophys. Acta, 1804, 1817-1831.

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Application

Application	Comment	Organism
drug development	caspase-3 ia a target for structure-based drug design approach	Homo sapiens

Crystallization (Commentary)

Crystallization (Comment)	Organism
caspase-3 in complex with beta-strand urazole ring-containing irreversible peptidomimetic inhibitor compound-1, vapor diffusion, at 4°C, from 0.005 ml drops containing equal volumes of 16% ethanol, 0.1 M Tris buffer, pH 7.8, and the protein complex solution, X-ray diffraction structure determination and analysis at 2.0 A resolution, molecular replacement	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism	Structure
(3S)-3-([[2-(3-carboxypropyl)-1,3-dioxo-8-(2-phenylethyl)-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl]amino)-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid	-	Homo sapiens
(3S)-3-([[2-(3-carboxypropyl)-1,3-dioxo-8-(pyridin-3-yl)-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl]amino)-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid	-	Homo sapiens
(3S)-3-([[2-(3-carboxypropyl)-1,3-dioxo-8-[2-[(thiophen-2-ylacetyl)amino]ethyl]-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl]amino)-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid	-	Homo sapiens
(3S)-3-([[2-(3-carboxypropyl)-8-(2-[[(4-chlorophenyl)acetyl]amino]ethyl)-1,3-dioxo-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl]amino)-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid	-	Homo sapiens
(3S)-3-([[2-[2-[(1H-benzimidazol-6-ylcarbonyl)amino]ethyl]-7-(cyclohexylmethyl)-1,3-dioxo-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl]amino)-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid	-	Homo sapiens
(3S)-3-([[2-[2-[(cyclohexylcarbonyl)amino]ethyl]-7-(cyclohexylmethyl)-1,3-dioxo-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl]amino)-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid	-	Homo sapiens
(3S)-3-[[(2-[4-carboxy-2-[(phenylacetyl)amino]butyl]-1,3-dioxo-2,3,5,7,8,9,10,10a-octahydro-1H-[1,2,4]triazolo[1,2-a]cinnolin-5-yl)carbonyl]amino]-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid	-	Homo sapiens
(3S)-5-[(2,6-dichlorobenzoyl)oxy]-3-[([1,3-dioxo-2-[2-(1H-tetrazol-5-yl)ethyl]-2,3,5,7,8,9,10,10a-octahydro-1H-[1,2,4]triazolo[1,2-a]cinnolin-5-yl]carbonyl)amino]-4-oxopentanoic acid	-	Homo sapiens
4-[5-([(3S)-1-[(2,6-dichlorobenzoyl)oxy]-2,5-dioxohexan-3-yl]carbamoyl)-1,3-dioxo-8-(thiophen-2-yl)-5,8-dihydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl]butanoic acid	-	Homo sapiens
additional information	structure-based drug design approach, synthesis of beta-strand urazole ring-containing irreversible peptidomimetic compounds. Z-VAD-fmk and the peptidomimetic inhibitors inhibit caspase-3 via a three-step kinetic mechanism, i.e. two rapid equilibrium steps followed by a relatively fast inactivation step, caspase-inhibitor interactions, overview	Homo sapiens
N-benzyloxycarbonyl-VAD-fluoromethylketone	a irreversible caspase inhibitor	Homo sapiens

KM Value [mM]

KM Value [mM]	KM Value Maximum [mM]	Substrate	Comment	Organism	Structure
additional information	-	additional information	stopped-flow and steady-state kinetic kinetics	Homo sapiens
0.0337	-	Ac-DEVD-4-methylcoumarin 7-amide	pH 7.5, 25°C	Homo sapiens

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	-	-	-

Posttranslational Modification

Posttranslational Modification	Comment	Organism
proteolytic modification	upon purification and activation, caspase-3 subunits A and B are processed to yield the sequences S29GIS...IETD175 and S176GVDYFYH277-(H)7	Homo sapiens

Purification (Commentary)

Purification (Comment)	Organism
upon purification and activation, caspase-3 subunits A and B are processed to yield the sequences S29GIS...IETD175 and S176GVDYFYH277-(H)7, the purified enzyme shows 90% of maximum activity	Homo sapiens

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
Ac-DEVD-4-methylcoumarin 7-amide + H2O	an artificial caspase-3 substrate	Homo sapiens	Ac-DEVD + 7-amino-4-methylcoumarin	-	?

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
25	-	assay at	Homo sapiens

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
7.5	-	assay at	Homo sapiens

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism	Structure
additional information	-	additional information	inhibition kinetics, first-order inhibition kinetics and two-step irreversible inhibition mechanism	Homo sapiens

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor	Structure
0.00066	-	pH 7.5, 25°C	Homo sapiens	(3S)-3-([[2-(3-carboxypropyl)-1,3-dioxo-8-(2-phenylethyl)-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl]amino)-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid
0.00203	-	pH 7.5, 25°C	Homo sapiens	(3S)-5-[(2,6-dichlorobenzoyl)oxy]-3-[([1,3-dioxo-2-[2-(1H-tetrazol-5-yl)ethyl]-2,3,5,7,8,9,10,10a-octahydro-1H-[1,2,4]triazolo[1,2-a]cinnolin-5-yl]carbonyl)amino]-4-oxopentanoic acid
0.00505	-	pH 7.5, 25°C	Homo sapiens	(3S)-3-([[2-(3-carboxypropyl)-8-(2-[[(4-chlorophenyl)acetyl]amino]ethyl)-1,3-dioxo-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl]amino)-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid
0.00524	-	pH 7.5, 25°C	Homo sapiens	(3S)-3-([[2-(3-carboxypropyl)-1,3-dioxo-8-[2-[(thiophen-2-ylacetyl)amino]ethyl]-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl]amino)-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid
0.00681	-	pH 7.5, 25°C	Homo sapiens	(3S)-3-([[2-(3-carboxypropyl)-1,3-dioxo-8-(pyridin-3-yl)-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl]amino)-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid
0.00754	-	pH 7.5, 25°C	Homo sapiens	(3S)-3-([[2-[2-[(cyclohexylcarbonyl)amino]ethyl]-7-(cyclohexylmethyl)-1,3-dioxo-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl]amino)-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid
0.00913	-	pH 7.5, 25°C	Homo sapiens	4-[5-([(3S)-1-[(2,6-dichlorobenzoyl)oxy]-2,5-dioxohexan-3-yl]carbamoyl)-1,3-dioxo-8-(thiophen-2-yl)-5,8-dihydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl]butanoic acid
0.0134	-	pH 7.5, 25°C	Homo sapiens	(3S)-3-[[(2-[4-carboxy-2-[(phenylacetyl)amino]butyl]-1,3-dioxo-2,3,5,7,8,9,10,10a-octahydro-1H-[1,2,4]triazolo[1,2-a]cinnolin-5-yl)carbonyl]amino]-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid
0.0172	-	pH 7.5, 25°C	Homo sapiens	(3S)-3-([[2-[2-[(1H-benzimidazol-6-ylcarbonyl)amino]ethyl]-7-(cyclohexylmethyl)-1,3-dioxo-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl]carbonyl]amino)-5-[(2,6-dichlorobenzoyl)oxy]-4-oxopentanoic acid

General Information

General Information	Comment	Organism
evolution	caspase-3 is an executioner caspase	Homo sapiens

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Release 2023.1 (January 2023)