Information on EC 3.4.22.61 - caspase-8 and Organism(s) Homo sapiens

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The taxonomic range for the selected organisms is: Homo sapiens

The enzyme appears in selected viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.4.22.61
-
RECOMMENDED NAME
GeneOntology No.
caspase-8
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY hide
179241-78-2
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
Ac-IEPD-7-amido-4-methylcoumarin + H2O
Ac-IEPD + 7-amino-4-methylcoumarin
show the reaction diagram
-
37°C
-
-
?
Ac-IEPD-AMC + H2O
Ac-IEPD + AMC
show the reaction diagram
-
37°C
-
-
?
Ac-IETD-4-methylcoumarin 7-amide + H2O
Ac-IETD + 7-amino-4-methylcoumarin
show the reaction diagram
-
an artificial caspase-8 substrate
-
-
?
acetyl-DEVD-4-nitroanilide + H2O
acetyl-DEVD + 4-nitroaniline
show the reaction diagram
-
-
-
-
?
acetyl-DEVD-7-amido-4-methylcoumarin + H2O
acetyl-DEVD + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
-
?
acetyl-IETD-4-nitroanilide + H2O
acetyl-IETD + 4-nitroaniline
show the reaction diagram
-
-
-
-
?
acetyl-IETD-7-amido-4-fluoromethylcoumarin + H2O
acetyl-IETD + 7-amino-4-fluoromethylcoumarin
show the reaction diagram
-
-
-
-
?
acetyl-Ile-Glu(OMe)-Thr-Asp(OMe)-7-amido-4-trifluoromethylcoumarin + H2O
acetyl-Ile-Glu(OMe)-Thr-Asp(OMe) + 7-amino-4-trifluoromethylcoumarin
show the reaction diagram
-
-
-
-
?
acetyl-Ile-Glu-Thr-Asp-7-amino-4-fluoromethylcoumarin + H2O
Ac-IETD + 7-amino-4-fluoromethylcoumarin
show the reaction diagram
-
37°C, pH 7.4
-
-
?
alpha-fodrin + H2O
?
show the reaction diagram
-
-
-
-
?
Atg3 protein + H2O
?
show the reaction diagram
-
-
-
-
?
BAP31 + H2O
?
show the reaction diagram
-
cleavage results in a proapoptotic p20 fragment
-
-
?
Bcl-2 protein Bid + H2O
?
show the reaction diagram
-
cleavage results in a proapoptotic p15 tBid fragment
-
-
?
BID + H2O
?
show the reaction diagram
Bid + H2O
tBid + ?
show the reaction diagram
Bid peptide + H2O
?
show the reaction diagram
Bid peptide + H2O
truncated Bid peptide + ?
show the reaction diagram
-
-
-
-
?
Bid protein + H2O
?
show the reaction diagram
-
-
-
-
?
Bid protein + H2O
cleaved Bid protein
show the reaction diagram
-
i.e. BH3 interacting domain death agonist protein
-
-
?
Ca2+/calmodulin-dependent protein kinase-like kinase + H2O
?
show the reaction diagram
-
cleavage generates a 43 kDa C-terminal fragment and a small N-terminal fragment with proapoptotic activity
-
-
?
carbonic anhydrase XIV + H2O
?
show the reaction diagram
-
cleaved at Asp53
-
-
?
caspase-3 + H2O
?
show the reaction diagram
-
-
-
-
?
cellular inhibitor of apoptosis 1 + H2O
?
show the reaction diagram
CYLD + H2O
CYLDp25 + ?
show the reaction diagram
evolutionarily related interleukin-1beta converting enzyme + H2O
?
show the reaction diagram
-
ERICE i.e. evolutionarily related interleukin-1beta converting enzyme, cleavage at LEED289-/-, processing leads to the generation of two subunits
-
-
?
FLICE2 + H2O
?
show the reaction diagram
-
-
-
?
FLIPL protein + H2O
?
show the reaction diagram
glutaredoxin-1 + H2O
?
show the reaction diagram
-
murine or human protein substrate, the putative cleavage site of caspase-8, amino acids 43-46 EFVD and 56-59 AIQD, which has predicted affiffinity toward glutamic and aspartic acid residues
cleavage produces a 8 kDA fragment
-
?
HER-2 + H2O
?
show the reaction diagram
IEPD-7-amido-4-methylcoumarin + H2O
IEPD + 7-amino-4-methylcoumarin
show the reaction diagram
-
-
-
-
?
IETD-4-nitroanilide + H2O
IETD + 4-nitroaniline
show the reaction diagram
-
-
-
-
?
IETD-7-amido-4-trifluoromethylcoumarin + H2O
IETD + 7-amino-4-trifluoromethylcoumarin
show the reaction diagram
-
-
-
-
?
Ile-Glu-Thr-Asp-4-nitroanilide + H2O
Ile-Glu-Thr-Asp + 4-nitroaniline
show the reaction diagram
-
-
-
-
?
interleukin-21 + H2O
?
show the reaction diagram
LAP3 + H2O
?
show the reaction diagram
-
-
-
?
LAP6 + H2O
?
show the reaction diagram
-
-
-
?
N-acetyl-IETD-4-trifluoromethylcoumarin 7-amide + H2O
N-acetyl-IETD + 7-amino-4-trifluoromethylcoumarin
show the reaction diagram
-
-
-
-
?
nuclear export signal-LQTDG + H2O
?
show the reaction diagram
-
-
-
-
?
p21-activated kinase 2 + H2O
?
show the reaction diagram
-
separates the N-terminal regulatory domain from the C-terminal catalytic domain
-
-
?
parkin + H2O
?
show the reaction diagram
pro-caspase-3 + H2O
caspase-3 + ?
show the reaction diagram
procaspase-3 + H2O
?
show the reaction diagram
procaspase-3 + H2O
caspase-3 + ?
show the reaction diagram
procaspase-6 + H2O
caspase-6 + ?
show the reaction diagram
procaspase-8 + H2O
caspase-8 + ?
show the reaction diagram
-
caspase-8 is initially synthesized as a single-chain zymogen, procaspase-8, and activated by autocleavage at proteolytic sites Asp126, Asp216, Asp374, and Asp384 after recruitment to DISCs by N-terminal two tandem DEDs of procaspase-8. The proximity-driven dimerization of procaspase-8 is attributable to initiate autocleavage of procaspase-8 involving intra-dimeric and inter-dimeric attack. Dimerized procaspase-8 which achieves enzymatical competency specifically processes one another, while mature caspase-8 can cleave effector caspases and some other substrates. Dramatical conformation changes of the linker region undergo in order to bring cleavage sites, Asp374 and Asp384, to the vicinity of catalytic residue Cys283 from other protomer during dimerization of procaspase-8. Separation of the large and small subunit after intra-dimeric cleavage in the linker region between the large and small subunit renders the linker region between the large subunit and the prodomain of caspase-8 susceptible for the further inter-dimeric cleavage
the C- and N-terminal end, of linker region are released with cleavage at Asp374 and Asp384 before separation of the large and small subunit
-
?
receptor-indicating protein + H2O
?
show the reaction diagram
-
separates the N-terminal kinase from the C-terminal death domain
-
-
?
RIPK1 + H2O
?
show the reaction diagram
Tx + H2O
?
show the reaction diagram
-
-
-
?
vezatin + H2O
?
show the reaction diagram
-
cleaved at Asp655
-
-
?
Yama + H2O
?
show the reaction diagram
-
-
-
?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
alpha-fodrin + H2O
?
show the reaction diagram
-
-
-
-
?
Atg3 protein + H2O
?
show the reaction diagram
-
-
-
-
?
BID + H2O
?
show the reaction diagram
-
a 15000 Da C-terminal frament and a 14000 Da N-terminal fragment are generated by caspase-8 cleavage at T58-/-D59. While full-length BID is localized in cytosol, truncated BID translocates to mitochondria and thus transduces apoptotic signals from cytoplasmic membrane to mitochondria. BID is a mediator of mitochondrial damage induced by Casp8
-
-
?
Bid + H2O
tBid + ?
show the reaction diagram
Bid peptide + H2O
?
show the reaction diagram
Bid peptide + H2O
truncated Bid peptide + ?
show the reaction diagram
-
-
-
-
?
Bid protein + H2O
?
show the reaction diagram
-
-
-
-
?
Bid protein + H2O
cleaved Bid protein
show the reaction diagram
-
i.e. BH3 interacting domain death agonist protein
-
-
?
caspase-3 + H2O
?
show the reaction diagram
-
-
-
-
?
cellular inhibitor of apoptosis 1 + H2O
?
show the reaction diagram
-
i.e. cIAP-1, TRAIL-induced degradation of cIAP-1 requires caspase 8 activity, and it is, at least in part, due to direct cleavage of cIAP-1 by caspase 8
-
-
?
CYLD + H2O
CYLDp25 + ?
show the reaction diagram
-
key substrate processed by caspase 8 to block necrosis, CYLD is a key requirement for necrosis
-
-
?
FLIPL protein + H2O
?
show the reaction diagram
HER-2 + H2O
?
show the reaction diagram
-
-
-
-
?
interleukin-21 + H2O
?
show the reaction diagram
-
-
the CASP8-cleaved form of IL21R does not induce phosphorylation at Tyr705 of STAT3
-
?
parkin + H2O
?
show the reaction diagram
-
cleavage at Asp126-Ser127. Caspase-1 and caspase-8 dependent parkin cleavage in sporadic Parkinson‘s disease may play an important role in the degenerative process by initiating a vicious circle that leads to the accumulation of toxic parkin substrates, e.g. alpha-synuclein
-
-
?
pro-caspase-3 + H2O
caspase-3 + ?
show the reaction diagram
-
caspase-3 is activated through caspase-8 during H2O2-induced apoptosis in HeLa cells
-
-
?
procaspase-3 + H2O
?
show the reaction diagram
-
caspase-8 induces apoptosis by directly activating caspase-3, which in turn causes the characteristic features of apoptosis, including DNA fragmentation and cell death
-
-
?
procaspase-3 + H2O
caspase-3 + ?
show the reaction diagram
procaspase-6 + H2O
caspase-6 + ?
show the reaction diagram
-
cleavage of caspases 3 and 6 by caspase-8 results in apoptosis
-
-
?
procaspase-8 + H2O
caspase-8 + ?
show the reaction diagram
-
caspase-8 is initially synthesized as a single-chain zymogen, procaspase-8, and activated by autocleavage at proteolytic sites Asp126, Asp216, Asp374, and Asp384 after recruitment to DISCs by N-terminal two tandem DEDs of procaspase-8. The proximity-driven dimerization of procaspase-8 is attributable to initiate autocleavage of procaspase-8 involving intra-dimeric and inter-dimeric attack. Dimerized procaspase-8 which achieves enzymatical competency specifically processes one another, while mature caspase-8 can cleave effector caspases and some other substrates. Dramatical conformation changes of the linker region undergo in order to bring cleavage sites, Asp374 and Asp384, to the vicinity of catalytic residue Cys283 from other protomer during dimerization of procaspase-8. Separation of the large and small subunit after intra-dimeric cleavage in the linker region between the large and small subunit renders the linker region between the large subunit and the prodomain of caspase-8 susceptible for the further inter-dimeric cleavage
the C- and N-terminal end, of linker region are released with cleavage at Asp374 and Asp384 before separation of the large and small subunit
-
?
RIPK1 + H2O
?
show the reaction diagram
-
Lys63-linked RIPK1 ubiquitylation is required to render RIPK1 susceptible to caspase 8-mediated cleavage, the mechanism by which RIPK1 signalling is suppressed in this context
-
-
?
vezatin + H2O
?
show the reaction diagram
-
cleaved at Asp655
-
-
?
additional information
?
-
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(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
-
-
(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
-
-
(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
-
-
(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
-
compound-4 is binding to caspase-8 in a pocket far from the active site
(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
-
-
(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
-
-
(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
-
-
(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
-
-
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
-
-
Ac-IETD-CHO
-
-
acetyl-AEVD-aldehyde
-
-
acetyl-DEVD-aldehyde
-
-
acetyl-IETD-aldehyde
acetyl-WEHD-aldehyde
-
-
acetyl-YVAD-aldehyde
-
-
benzyloxycarbonyl-DEVD-aldehyde
-
the inhibitor interacts favourably with the enzyme in subsite S4
benzyloxycarbonyl-IETD-fluoromethyl ketone
-
-
benzyloxycarbonyl-IETD-fluoromethylketone
benzyloxycarbonyl-Ile-Glu-Thr-Asp-fluoromethylketone
-
-
benzyloxycarbonyl-L-Asp-2,6-dichlorobenzoyloxymethylketone
-
pan-caspase inhibitor
benzyloxycarbonyl-LEHD-fluoromethylketone
-
a caspase-9 inhibitor, partial inhibition of caspase-8 activation in lung carcinoma cells
benzyloxycarbonyl-VAD-fluoromethylketone
benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone
-
-
benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone
-
t1/2 at 0.001 mM: 2.5 s
biotin-conjugated valine-alanine-aspartate-fluoromethylketone
-
c-FLIP
-
-
-
carboxyfluorescein-labeled-LETD-fluoromethylketone
-
-
cellular FLICE inhibitory protein
-
-
-
cFLIP
-
cowpox serpin CrmA
-
CrmA
-
FAM-LETD-FMK
-
-
Fas-associated death domain-like interleukin 1-converting enzyme-inhibitory proteins
-
FLIPs, natural inhibitor
-
FLIPL protein
-
IETD-fluoromethyl ketone
-
a caspase-8-specific inhibitor
IETD-fluoromethylketone
-
-
IETD-fmk
-
-
Ile-Glu-Thr-Asp-[O-methyl]-fluoromethylketone
-
-
N-acetyl-IETD-aldehyde
-
-
N-benzyloxycarbonyl-VAD-fluoromethyl ketone
-
a general caspase inhibitor
N-benzyloxycarbonyl-VAD-fluoromethylketone
-
an irreversible caspase inhibitor
N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone
-
-
N-carbobenzyloxy-IETD-fluoromethyl ketone
N-carbobenzyloxy-VAD-fluoromethyl ketone
p35
-
p35 protein from baculovirus inhibits in the active site through a covalent thioester linkage to p35. The p35 protein undergoes dramatic conformational changes on cleavage by the caspase. The repositioning of the amino terminus of p35 into the active site of the caspase eliminates solvent accessibility of the catalytic dyad
-
Q-VD-OPH
-
pan-caspase inhibitor
tert-butyloxycarbonyl-IETD-aldehyde
-
-
triptolide
-
a diterpenoid triepoxide derived from the herb Tripterygium wilfordii that is used as a natural medicine in China, activates caspase-8 4-6fold in pituitary adenoma cancer cells within 2 days, overview
Z-EVD-chloromethylketone
-
-
Z-IETD
Z-IETD-fluoromethylketone
Z-VAD
-
pan-caspase inhibitor
Z-VAD-fluoromethylketone
-
-
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
actinomycin D
-
significantly activates caspase-8
CD95
-
FLICE is the first in a cascade of ICE-like proteases activated by CD95. This activation requires a functional CD95 disc
-
complement factor 5a
-
increases caspase-8 activity and expression level of procaspase-8, and increases caspase 8 homologue FLICE-inhibitory protein, cFLIP, activation, C5a stimulation initiated cFLIP cleavage, which increased the 43 kDa active fragment, overview
-
edelfosine
-
i.e. 1-O-octadecyl-2-O-methyl-racglycero-3-phosphocholine, an anti-tumor drug, induces activation of procaspase-8 in T-cell leukemia, specific inhibition of caspase-8 prevents the apoptotic response triggered by edelfosine, overview. The compound induces the generation of the so-called death-inducing signaling complex, DISC, made up of Fas/CD95, FADD, and procaspase-8, in lipid rafts
Fas death domain
-
FADD, activating caspase-8 via its death-effector domain, DED. FADD dimerizes on binding to Fas, a crucial event that greatly enhances both the FADD-Fas interaction and caspase-8 activation
-
Fas-associated death domain protein-like interleukin-1-beta-converting enzyme-like inhibitory protein, long form
-
FLIP L, results in a heterodimeric enzyme
-
FLIPL protein
-
a catalytically defective caspase-8 paralogue, can interact with caspase-8 to activate its catalytic function
-
harmol
-
i.e. 1-methyl-9H-beta-carbolin-7-ol, a natural beta-carboline plant alkaloid, induces caspase-8 activation
homocysteine
-
induces the enzyme activation 3.5fold in endothelial progenitor cells at 0.2 mM
interferon-alpha
-
increases caspase-8 transcription
-
justicidin A
-
-
lithium/SB-415286
-
two GSK-3 inhibitor, enhance caspase-8 activity in hepatoma cells, but not in healthy hepatocyte, and increase the sensitivity of the cells to tumor necrosis factor-related apoptosis-inducing ligand, i.e. TRAIL, or CH-11, a CD95 agonistic antibody, which leads to increased apoptosis, the agents have no effect alone, mechanism, overview, 1.5-2.1fold activation of CH-11-induced apoptosis at 20 mM LiCl and 0.025 mM SB-415286
-
NPI-0052
-
the chemotherapeutic agent, i.e. salinosporamide A, a proteasome inhibitor, activates the caspase-8-dependent apoptosis pathway in multiple myeloma cells, it potentiates the apoptosis induced by TNF-alpha, bortezomib, and thalidomide, regulation, overview
radiation
-
increases caspase-8 expression and activity
-
resveratrol
-
causes activation of caspase-8, which in turn results in modulation of mitochondrial apoptotic machinery to promote apoptosis of rheumatoid arthritis fibroblast-like synoviocytes
Sodium citrate
-
enhances activity
Tumor necrosis factor alpha
-
-
-
additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0045
Ac-IETD-4-methylcoumarin 7-amide
-
pH 7.2, 25°C
0.0206 - 0.0552
Ac-IETD-fluoromethylcoumarin
0.004 - 0.007
acetyl-DEVD-7-amido-4-methylcoumarin
0.066
acetyl-IETD-4-nitroanilide
-
pH 7.5, 37°C
additional information
additional information
-
stopped-flow and steady-state kinetics
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.65 - 1.25
Ac-IETD-fluoromethylcoumarin
0.37
acetyl-DEVD-7-amido-4-methylcoumarin
-
pH 7.0 or pH 7.5
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0000016
acetyl-AEVD-aldehyde
-
pH 7.5, 25°C
0.00000092
acetyl-DEVD-aldehyde
-
pH 7.5, 25°C
0.00000105
acetyl-IETD-aldehyde
-
pH 7.5, 25°C
0.0000211
acetyl-WEHD-aldehyde
-
pH 7.5, 25°C
0.000352
acetyl-YVAD-aldehyde
-
pH 7.5, 25°C
0.000002
benzyloxycarbonyl-DEVD-aldehyde
-
-
0.000001
tert-butyloxycarbonyl-IETD-aldehyde
-
-
additional information
additional information
-
inhibition kinetics, first-order inhibition kinetics, and two-step irreversible inhibition mechanism
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00354
(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;
-
pH 7.2, 25°C
0.0031
(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;
-
pH 7.2, 25°C
0.00152
(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;
-
pH 7.2, 25°C
0.00132
(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;
-
pH 7.2, 25°C
0.00644
(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;
-
pH 7.2, 25°C
0.00357
(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;
-
pH 7.2, 25°C
0.00927
(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;
-
pH 7.2, 25°C
0.00363
(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;
-
pH 7.2, 25°C
0.00033
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;
-
pH 7.2, 25°C
0.00005
acetyl-IETD-aldehyde
Homo sapiens;
-
IC50: 50 nM, covalently modifies the active site C360
0.00045
N-benzyloxycarbonyl-VAD-fluoromethylketone
Homo sapiens;
-
pH 7.2, 25°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.5 - 7.5
-
reaction with acetyl-DEVD-7-amido-4-methylcoumari
7.2
-
assay at
7.5
-
assay at
8
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
-
assay at room temperature
25
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
no change in activity after irradiation
Manually annotated by BRENDA team
-
healthy and Parkinson disease brains, caspase-8 is selectively activated in brain tissue from patients with LRRK2 Parkinson disease
Manually annotated by BRENDA team
-
recombinant enzyme
Manually annotated by BRENDA team
-
OCUM-2M, OCUM-1, OCUM-8, OCUM-9, NUGC3, NIGC4, MKN45, MKN74, FU97, MKN7
Manually annotated by BRENDA team
-
NCH421K_SCG, NCH441_SCG, NCH421K_NSCG; NCH441_SCG, NCH421K_SCG, NCH421K_NSCG
Manually annotated by BRENDA team
-
caspase-8 is the most important factor that controls interferon and 5-fluorouracil-induced apoptosis in hepatoma cell lines
Manually annotated by BRENDA team
-
a oral squamous cell carcinoma cell line
Manually annotated by BRENDA team
-
a oral squamous cell carcinoma cell line
Manually annotated by BRENDA team
-
express low levels of caspase-8
Manually annotated by BRENDA team
-
expression patterns of the major caspases, CASP3, 6, 7, 8, 9, and 10, and inhibitor of apoptosis proteins, survivin, CIAP1, CIAP2, XIAP, and livin, overview
Manually annotated by BRENDA team
-
expression patterns of the major caspases, CASP3, 6, 7, 8, 9, and 10, and inhibitor of apoptosis proteins, survivin, CIAP1, CIAP2, XIAP, and livin, overview
Manually annotated by BRENDA team
-
caspase-8 interacts with the p85 subunit of phosphatidylinositol 3-kinase to regulate cell adhesion and motility
Manually annotated by BRENDA team
-
caspase-8L is generated by the alternative splicing of human caspase-8
Manually annotated by BRENDA team
-
caspase-8 is the most important factor that controls interferon and 5-fluorouracil-induced apoptosis in hepatoma cell lines
Manually annotated by BRENDA team
-
activation of caspase-8 is essential for triggering resveratrol-induced apoptotic signalling via the involvement of the mitochondrial pathway in rheumatoid arthritis fibroblast-like synoviocytes. Resveratrol causes activation of caspase-8, which in turn results in modulation of mitochondrial apoptotic machinery to promote apoptosis of rheumatoid arthritis fibroblast-like synoviocytes
Manually annotated by BRENDA team
-
increase in caspase-8 transcript levels and activity after irradiation
Manually annotated by BRENDA team
-
increase in caspase-8 transcript levels and activity after irradiation
Manually annotated by BRENDA team
-
no change in activity after irradiation
Manually annotated by BRENDA team
additional information
-
constitutive pro-caspase-8 protein expression
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
-
in addition to its cytosolic distribution, caspase 8 is recruited to lamella of migrating cells
Manually annotated by BRENDA team
-
nuclear colocalization of caspase-8 and Fas-associated death domain, FADD
Manually annotated by BRENDA team
-
caspase-8 is significantly more active at the plasma membrane than within the cytosol upon CD95 activation
Manually annotated by BRENDA team
additional information
PDB
SCOP
CATH
UNIPROT
ORGANISM
Homo sapiens;
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
11000
-
alpha2beta2, 2 * 18000 + 2 * 11000, crystallographic data
28000
-
activated heterodimer, gel filtration
31000
-
monomer, non-cleavable caspase-8, SDS-PAGE
41000
-
x * 41000 + x * 43000, cleaved caspase-8, SDS-PAGE
54000
-
monomer, pro-caspase-8, SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
-
x * 41000 + x * 43000, cleaved caspase-8, SDS-PAGE
monomer
tetramer
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
proteolytic modification
side-chain modification
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
caspase-8 in complex with beta-strand urazole ring-containing irreversible peptidomimetic inhibitor compounds 4 and 9, vapour diffusion, at 4°C, mixing of 0.002 ml inhibitor solution, containing 100 mM inhibitor, with 0.1 ml protein solution containing 8.4 mg/ml caspase-8, 20 mM Tris, 100 mM DTT, pH 8.0, incubation for 60 min, mixing of 0.0025 ml of protein complex solution with 0.0025 ml of reservoir solution containing 1.0-1.1 M citrate, 0.1 M HEPES or PIPES, pH 6.5, 4°C, X-ray diffraction structure determination and analysis at 1.8 A resolution, molecular replacement
-
crystal structure of a complex of the activated caspase-8 proteolytic domain with the irreversible peptidic inhibitor benzyloxycarbonyl-EVD-dichloromethylketone, vapour diffusion method
-
crystallization of caspase-8 in complex with p35 protein from baculovirus, at 20°C by hanging-drop vapour diffusion
-
crystallization of the enzyme covalently modified with acetyl-IETD-aldehyde, hanging- and sitting-drop vapor diffusion
-
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
caspase-8 polyubiquitination by the E3 ligase cullin-3 and its subsequent p62-dependent aggregation stabilises active caspase-8 |
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
to near homogeneity
-
upon refolding and purification, mature caspase-8 yields the sequences S18PRE-VETD181 and L192SSP-FPSD286, for subunits A and B, respectively, the purified enzyme shows 85% of maximum activity
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
CASP8, expression analysis in melanoma cells
-
determination of hypermethylation of CASP8 promoter in stem-cell-like glioma cells, whereas non-stem-cell-like glioma cells exhibit a non-methylated CASP8 promoter, expression analysis, overview; gene CASP8, expression analysis, analysis of promoter methylation status, hypermethylation of the CASP8 promoter in stem-cell-like glioma cells
-
expressed in HeLa cells
-
expressed in Neuro-2A and HeLa cells
-
expression analysis of caspase-8 in absence and presence of poly(ADP-ribose) polymerase 1, PARP-1, expression, the caspase-8 expression is not influenced
-
expression analysis of caspase-8 in B-cell chronic lymphocytic leukemia compared to healthy B-cells, overview
-
expression in COS-7 cells
-
expression in Escherichia coli
-
expression in HEK293T cells
gene CASP8, located at chromosome 2q33-q34, DNA and amino acid sequence determination and analysis, quantitative expression analysis in neuroblastoma cells by RT-PCR, determination of methylation status of a CpG island located between exons 2 and 3 of caspase 8 in neuroblastomas, methylation inactivates the geneoverview
-
proMch5 lacking the two N-terminal FADD-like domains are subcloned in the bacterial expression vector pET21b in frame with an N-terminal T7 tag and a C-terminal His6tag. Bacterial expression generates a mature enzyme composed of two subunits, which are derived from the precursor by processing at Asp227, Asp233, Asp391 and Asp401
-
transient coexpression of caspase wild-type parkin in HEK-293 cells identifies caspase-1, caspase-3 and caspase-8 as efficient inducers of parkin cleavage
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
30 h after treatment with ionizing radiation (20 Gy), there is an activation of caspase 8
-
4 mM butyrate and propionate but not acetate can induce non-activated and lipopolysaccharide- or tumor necrosis factor-alpha-activated neutrophil apoptosis by caspase-8 pathway
-
a significant downregulation in CASP8 expression is observed after cell activation in multiple sclerosis patients homozygotes for the protective (ACT/ACT) and risk haplotypes (GCA/GCA)
-
after cecropin A treatment for 24 h at concentrations of 0.03 or 0.04 mM, the activity of caspase-8 does not increase
-
caspase-8 activity remains low when human gingival epithelial cells are incubated with 50 ng/ml H2S in air containing 5% CO2 for 24, 48 or 72 h
-
caspase-8 is activated by arsenic trioxide during neutrophil apoptosis, after 3 h a slight caspase-8 activity is observed only in arsenic trioxide-induced neutrophils
-
Dryopteris crassirhizoma extract (0.1 mg/ml for 24-48 h) causes the cleavage of pro-caspase-8 in PC3-MM2 cells, indicating the increased activity of this caspase
-
eosinophil cationic protein induces caspase-8 activation through mitochondria-independent pathway
-
expression, nuclear fragmentation and caspase-8 activation are not decreased significantly in R393E mutant C-terminal pseudo death effector domain of HIPPI-cells in comparison to that obtained with wild type C-terminal pseudo death effector domain of HIPPI-cells
-
extracellular signal-regulated kinase activity induces caspase-8 activation
-
genistein triggers the receptor-mediated apoptotic pathway through activation of caspase-8, the highest activation of caspase-8 occurs after treatment with the combination of Bcl-2 siRNA and genistein (0.01 mM)
-
histone deacetylase inhibition leads to transcriptional suppression of cellular FLIP, which negatively regulates extrinsic apoptosis by preventing the recruitment of caspase-8 to the death-inducing signaling complex
-
in cells exposed to 0.5 mM UDP for 4.5 h, the activation of caspase-8 increases about 3fold
-
inactivation of protein-associated splicing factor by siRNA significantly decreases the level of caspase-8 in macrophages, significant suppression of caspase-8 activation is observed in both macrophages infected with wild type Mycobacterium tuberculosis H37Rv and with the complemented 31G12 strain containing the pLD31G12-3 construct
-
no change in caspase-8 expressions is observed in ischemic preconditioning livers
-
NPI-0052 plus lenalidomide-induced apoptosis is associated with activation of caspase-8
-
procaspase-8 is cleaved after evodiamine treatment (0.001 and 0.01 mM) for 36 h and increases significantly at 60 h
-
processing of caspase-8 and its enzymatic activity is reduced in Chlamydia trachomatis-infected cells and coincides with a decrease in Bid truncation, caspase-8 inhibition by Chlamydia is dependent on cFlip
-
recombinant tumor necrosis actor-alpha-treated and Mycobacterium tuberculosis 31G12-infected macrophages show caspase-8 activation
-
simvastatin does not induce caspase-8 activity
-
sperm samples of Robertsonian translocation carrier patients show a higher proportion of spermatozoa with activated caspase-8 than those from fertile donors
-
staurosporine-induced apoptosis induces caspase-8 activation
-
the majority (78.3%) of HeLa cells reveals an activated caspase-8 after 8 h of coculture with adipose-derived-mesenchymal stromal/stem cell tumor necrosis factor-related apoptosis-inducing ligand
-
there is an increase in active caspase-8 within 4 h of Helicobacter pylori infection in APE-1-downregulated cells relative to the control cells
-
there is no significant increase of caspase-8 activity in 0.05 mM goniothalamin treatment from 2 up to 12 h
-
transient expression of GFP-Hippi in cells with reduced Huntingtin interacting protein-1 significantly decreases nuclear fragmentation and caspase-8 activation
-
treatment with 0.05 mM (2R,3S)-3',4',5,7-tetrahydroxyflavan-3-yl decanoate (catechin-C10) increases caspase-8 activity after 4 and 6 h
-
tumor necrosis factor–related apoptosis-inducing ligand, TRAIL, signaling induces caspase 8
-
[Me(2)Ga(S-imi)](2) causes apoptosis by upregulation of caspases 8
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C360S
-
a caspase-8 inactive mutant, shows no LRRK2-induced neuronal death, knockdown of caspase-8 by siRNA blocks LRRK2-induced neurotoxicity and neurodegeneration
D210A/D216A
-
cannot be cleaved to release death effector domains, overexpression inhibits the endothelial cell leukocyte adhesion molecule 1 promoter activation induced by Fas-associated death domain and receptor-interacting protein 1
E396A
diminishes TRAF6 binding capacity
E417A
diminishes TRAF6 binding capacity
additional information
Renatured/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
upon refolding and purification, mature caspase-8 yields the sequences S18PRE-VETD181 and L192SSP-FPSD286, for subunits A and B, respectively, the purified enzyme shows 85% of maximum activity
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
medicine