Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human gamma interferon produced by recombinant Escherichia coli was degraded by endogenous protease after cell disruption. Specific cleavages took place at the center of two pairs of basic amino acids (Lys-131-Arg-132 and Arg-142-Arg-143) in the C-terminal region, giving rise to products with molecular weights of 17,500 and 16,000. The proteolytic activity was associated with the outer membrane of E. coli. It was insensitive to the protease inhibitors diisopropylfluorophosphate, phenylmethylsulfonyl fluoride, tosyl-L-lysine chloro-methyl ketone, EDTA, and p-chloromercuribenzoate. Benzamidine and the bivalent cations Zn2+ and Cu2+ inhibited the activity. Dynorphin A(1-13) (Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys) was a good substrate and was preferentially cleaved at the center of Arg-6-Arg-7. Neither the amino nor carboxyl sides of Arg-9 and Lys-11 were digested. These results indicate that the protease specifically cleaves the peptide bond between consecutive basic residues and therefore is different from the known membrane enzymes, proteases IV, V, and VI. We have designated this new enzyme protease VII.
 ...
PMID:A novel outer-membrane-associated protease in Escherichia coli. 313 44

Protease A of Bitis arietans venom is probably a metalloprotease, since it is inhibited by o-phenanthroline and contains 0.77 moles of zinc per mole protein. The enzyme comprises 213 amino acids, including 9 methionine residues and one free sulphydryl group. It contains one polypeptide chain, which is terminated at the carboxyl end by serine. The amino terminal sequence of protease A is: Arg-Ser-Ser-Asp-Pro-Asn-Lys-Tyr-Phe-Asn-Val-Ile-Val-Val-Val-Asp-Asn-Arg- Met-Val-Asn-Tyr-Tyr-Lys-Gly-Glu-Leu-Asn-Lys-Ile-Thr-. Despite difficulties with 'insoluble peptide core' formation, a number of peptides were purified from peptic and tryptic digests of S-derivatized protease A.
 ...
PMID:Chemical studies on protease A of Bitis arietans (puff adder) venom. 352 Sep 56

Interleukin-1 beta (IL-1 beta)-converting enzyme (ICE) is a novel cysteine protease that cleaves the 31-kD inactive cytoplasmic IL-1 beta precursor into active extracellular 17-kD IL-1 beta. The ICE gene product is a 45-kD proenzyme that requires proteolytic processing to activate ICE. Active ICE is a heterodimer consisting of equal amounts of p20 and p10 subunits. Generation of active ICE is affected by the removal of an 11-kD NH2-terminal precursor domain (p11) and an internal 19-amino acid sequence that separates the 20- and 10-kD subunits. Immuno-electron microscopy was performed on human monocytes with immunoglobulins recognizing the active (p20) or precursor (p11) domains of ICE. Elutriated monocytes were stimulated with 50 pM lipopolysaccharide followed by heat-killed Staphylococcus aureus under conditions that induce maximal rates of IL-1 beta secretion. Ultrathin cryosections were cut from fixed frozen pellets of these monocytes and were immunogold labeled with either antibody. Active and precursor domain ICE epitopes were localized in the cytoplasmic ground substance, but they were not detected within the endoplasmic reticulum, the Golgi apparatus, and secretory granules of activated or inactive monocytes. Importantly, numerous ICE p20 epitopes were also observed on the extracellular surfaces of the cell membrane, and were concentrated on the microvilli. Very similar patterns of ICE localization were obtained with unstimulated blood monocytes. In contrast, ICE p11 epitopes were not detected on the surfaces of these monocytes. Likewise, labeling of fixed ultrathin cryosections of monocytes with a biotinylated irreversible ICE inhibitor [Ac-Tyr-Val-Lys(biotin)-Asp-(acyloxy)-methyl-ketone] showed that the compound localized on the outer cell surface as well, and to a lesser extent, within the cytoplasmic ground substance. Furthermore, antipeptide antibodies specific for either the mature or precursor domains of IL-1 beta were both localized upon the cell membrane after stimulation of IL-1 beta secretion. Lipopolysaccaride-primed monocytes that synthesized, but did not secrete IL-1 beta, exhibited only cytoplasmic staining. The data suggests that mature IL-1 beta is generated via cleavage of the 31-kD inactive cytoplasmic IL-1 beta precursor by ICE after association with the plasma membrane during secretion.
 ...
PMID:The interleukin-1 beta-converting enzyme (ICE) is localized on the external cell surface membranes and in the cytoplasmic ground substance of human monocytes by immuno-electron microscopy. 759 15

Moojeni protease A, a proteolytic enzyme isolated from Bothrops moojeni venom, hydrolyzes type I collagen, gelatin, fibrinogen, fibrin and the B-chain of oxidized insulin. The proteinase cleaves the A alpha-chain faster than the B beta-chain of human fibrinogen and shows no effect on the gamma-chain. Fibrin solubilization appears to occur from the hydrolysis of the alpha-polymer and unpolymerized alpha-chain. The enzyme cleaves the Ala(14)-Leu(15) bond of the oxidized insulin B-chain most rapidly, followed by splitting the Ser(9)-His(10) bond. The Tyr(16)-Leu(17) and Gly(20)-Glu(21) cleavage sites were hydrolyzed slightly more slowly, while the peptide bonds His(5)-Leu(6), His(10)-Leu(11), Glu(21)-Arg(22), Gly(23)-Phe(24) and Phe(24)-Phe(25) were more resistant to the enzyme attack. Small synthetic peptides were not hydrolyzed by moojeni protease A.
 ...
PMID:Proteolytic specificity of moojeni protease A isolated from the venom of Bothrops moojeni. 845 46

Cytotoxic T cells (CTL) represent the major defense mechanism against the spread of virus infection. It is believed that the pore-forming protein, perforin, facilitates the entry of a series of serine proteases (particularly granzyme B) into the target cell which ultimately leads to DNA fragmentation and apoptosis. We demonstrate here that during CTL-mediated cytolysis the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), an enzyme implicated in the repair of double strand breaks in DNA, is specifically cleaved by an interleukin (IL)-1 beta-converting enzyme (ICE)-like protease. A serine protease inhibitor, 3,4-dichloroisocoumarin (DCl), which is known to block granzyme B activity, inhibited CTL-induced apoptosis and prevented the degradation of DNA-PKcs in cells but failed to prevent the degradation of purified DNA-PKcs by CTL extracts. However, Tyr-Val-Ala-Asp-CH2Cl (YVAD-CMK) and other cysteine protease inhibitors prevented the degradation of purified DNA-PKcs by CTL extracts. Furthermore, incubation of DNA-PKcs with granzyme B did not produce the same cleavage pattern observed in cells undergoing apoptosis and when this substrate was incubated with either CTL extracts or the ICE-like protease, CPP32. Sequence analysis revealed that the cleavage site in DNA-PKcs during CTL killing was the same as that when this substrate was exposed to CPP32. This study demonstrates for the first time that the cleavage of DNA-PKcs in this intact cell system is exclusively due to an ICE-like protease.
 ...
PMID:Interleukin-1 beta-converting enzyme-like protease cleaves DNA-dependent protein kinase in cytotoxic T cell killing. 876 Aug 15

Recent work suggests that the proteolytic degradation of the nuclear lamins is a common event in apoptosis, although the nature of the proteases involved is still not clear. Our previous work showed that the degradation of lamin B1 in glucocorticoid-treated thymocytes occurs via a Ca2+-sensitive mechanism and that exogenous Ca2+ promotes lamin degradation in isolated thymocyte nuclei from untreated cells. Here we demonstrate that peptide-based inhibitors of the interleukin 1beta-converting enzyme family of cysteine proteases (Tyr-Val-Ala-Asp fluoromethyl ketone) and of the nuclear scaffold multicatalytic proteinase (Ala-Pro-Phe chloromethyl ketone) block the degradation of lamin B1 to a 21-kDa fragment in thymocytes treated with glucocorticoid, the Ca2+-mobilizing agent thapsigargin, or antibodies to the T cell receptor. However, among a panel of inhibitors specific for several different proteases implicated in apoptosis, only tosylphenylalanyl chloromethyl ketone and the nuclear scaffold protease inhibitor block lamin degradation, histone H1 cleavage, and DNA fragmentation in isolated thymocyte nuclei incubated with Ca2+. Overexpression of human BCL-2 in nuclei by stable transfection resulted in an inhibition of Ca2+-stimulated lamin degradation and DNA fragmentation, suggesting that endogenous nuclear BCL-2 regulates activation of the nuclear scaffold protease. The results demonstrate the existence of an alternative pathway of lamin degradation and DNA fragmentation mediated by a resident Ca2+-stimulated nuclear protease that is not directly dependent upon activation of the interleukin 1beta-converting enzyme family of cell death regulators.
 ...
PMID:Calcium-dependent, interleukin 1-converting enzyme inhibitor-insensitive degradation of lamin B1 and DNA fragmentation in isolated thymocyte nuclei. 879 2

Recent investigations indicate that proteolysis is an important event in generation of the apoptosis phenotype. Although various proteases have been suggested to be candidates for this proteolysis, the results from different laboratories are inconsistent. In the present studies, HL-60 cells were treated with cycloheximide to investigate proteases involved in apoptosis. The calpain inhibitors benzyloxycarbonyl-Leu-Leu-Tyr diazomethylketone and acetyl-Leu-Leu-Nle aldehyde were not capable of preventing apoptosis induced by cycloheximide. In the absence of cycloheximide, these two inhibitors could initiate apoptosis in HL-60 cells. The thiol protease inhibitor benzyloxycarbonyl-Leu-Val-Gly diazomethylketone neither prevented nor produced apoptosis. The serine protease inhibitors 3,4-dichloroisocoumarin (DCI) and tosyl-Phe chloromethylketone (TPCK) also induced apoptosis in the absence of cycloheximide. On the other hand, the latter two inhibitors decreased cycloheximide-induced apoptosis, assessed either by cell morphologic changes or DNA ladder generation. Benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone and iodoacetamide, inactivators of interleukin 1beta-converting enzyme (ICE)-like proteases, did not produce apoptosis and inhibited the induction of apoptosis by cycloheximide, calpain inhibitors, or serine protease inhibitors. These results are consistent with the ICE-like proteases having a central role in proteolysis during apoptosis, while calpain-like proteases and the serine proteases sensitive to DCI or TPCK are not required for generation of the apoptosis phenotype in HL-60 cells.
 ...
PMID:Calpain inhibitors and serine protease inhibitors can produce apoptosis in HL-60 cells. 883 53

The induction of apoptosis by the Fas/APO-1 receptor is important for T-cell-mediated cytotoxicity and down-regulation of immune responses. Binding of Fas ligand to the Fas/APO-1 receptor transduces an apoptotic signal that requires activation of interleukin 1beta-converting enzyme (ICE) and CPP32beta, members of a family of cysteine proteases that are evolutionarily conserved determinants of cell death. We report here that Fas/APO-1-triggered apoptosis involves ICE-mediated activation of p34cdc2 kinase. Ligation of the Fas receptor resulted in the rapid stimulation of ICE proteolytic activity and activation of p34cdc2 kinase. Specific tetrapeptide inhibitors of ICE (Acetyl-Tyr-Val-Ala-Asp-chloromethylketone) or CPP32beta (Acetyl-Asp-Glu-Val-Asp-aldehyde) prevented the anti-Fas antibody-mediated activation of p34cdc2 and inhibited apoptosis. Inhibition of p34cdc2 activity by transient overexpression of a dominant-negative cdc2 construct or human WEE1 kinase inhibited Fas-mediated apoptosis. These results suggest that activation of p34cdc2 kinase is a critical determinant of cell death mediated by Fas and ICE family proteases.
 ...
PMID:Requirement of p34cdc2 kinase for apoptosis mediated by the Fas/APO-1 receptor and interleukin 1beta-converting enzyme-related proteases. 884 Sep 58

Fas (Apo1/CD95) is a member of the tumour necrosis factor/nerve growth factor receptor superfamily and mediates apoptosis in various cell types (for review sec [1]). Although this apoptotic activity has been clearly related to homeostasis in the immune system and pathological situations in non-lymphoid organs, the Fas signaling pathway remains mostly elusive. We and others previously showed that Fas-induced apoptosis of primary culture hepatocytes requires either an inhibitor of translation or a protein kinase inhibitor, suggesting that two distinct pathways of Fas signaling exist in hepatocytes. We report here that activation of ICE-like and CPP32-like cysteine proteases are required for Fas-mediated apoptosis, but that these pathways involve different subclasses of serine proteases and are selectively modulated by inhibitors of protein tyrosine kinases. These results confirm that distinct pathways can lead to Fas-induced apoptosis in hepatocytes. Further understanding of these pathways could facilitate the rational design of anti-apoptotic drugs in liver diseases associated with massive Fas-mediated hepatocyte apoptosis, including fulminant hepatitis.
 ...
PMID:Multiple pathways of Fas-induced apoptosis in primary culture of hepatocytes. 895 79

We have begun to explore the mechanisms of apoptosis using a cell-free system based on extracts from Xenopus eggs. Nuclei assembled or placed in these extracts undergo the morphological changes typical of apoptosis and eventually disintegrate. We used this system to investigate the potential involvement in apoptosis of proteins containing Src homology 2 (SH2) domains, which are known to interact with specific tyrosine-phosphorylated ligands. SH2 domains from a number of signaling proteins, including Lck, Src, and Abl, inhibited apoptosis when present at concentrations of 10-100 nM. The inhibition was dependent on specific interaction with endogenous tyrosine-phosphorylated ligands. A synthetic peptide ligand for Src family SH2 domains also inhibited apoptosis in a phosphotyrosine-dependent manner. Kinetic analysis defined three phases in the apoptotic process occurring in this cell-free system. SH2 domains and ceramide act throughout the first 60-90 min of the process (the "initiation" phase). Next, Bcl-2, interleukin-1beta converting enzyme family(CPP32-like) proteases, and the heavy membrane fraction act in a period occurring approximately 90-120 min after the start of incubation (the "sentencing" phase). In the final phase ("execution"), the process of active nuclear destruction ensues.
 ...
PMID:Temporal phases in apoptosis defined by the actions of Src homology 2 domains, ceramide, Bcl-2, interleukin-1beta converting enzyme family proteases, and a dense membrane fraction. 916 11


1 2 3 4 5 6 7 8 9 Next >>