Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A genetic locus implicated in the synthesis and secretion of alkaline protease (APR) in Pseudomonas aeruginosa has been previously described [Guzzo et al., J. Bacteriol. 172 (1990) 942-948]. The nucleotide sequence of the DNA fragment encoding these functions was determined and revealed the existence of five open reading frames: aprA, the structural gene encoding APR; aprI, which encodes a protease inhibitor; and aprD, aprE, aprF whose products are involved in protease secretion. The AprD, AprE and AprF proteins share significant homology with proteins implicated in secretion of Erwinia chrysanthemi proteases and Escherichia coli alpha-haemolysin. These results provide further evidence for the existence of a specialized secretory system widespread among Gram- bacteria.
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PMID:Sequence of a cluster of genes controlling synthesis and secretion of alkaline protease in Pseudomonas aeruginosa: relationships to other secretory pathways. 142 98

1. A chymotrypsin-like proteolytic activity was found both in unfertilized eggs and in embryos of Bufo bufo. 2. A dramatical change of activity can be observed in the course of embryonic development. The activity rapidly increases after fertilization up to the stage 9 followed by a fall to a level close to unfertilized eggs. 3. Gel chromatography analysis reveals, in all stages of development, the presence of a single peak of proteinase activity characterized by a very high molecular mass. 4. Proteinase activity, found change during the development of Bufo bufo, was characterized by substrate specificity, protease inhibitor and pH effect. All results obtained suggest that the chymotrypsin-like activity can be assigned to the multicatalytic proteinase.
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PMID:Changes of a high molecular mass proteinase activity during Bufo bufo development. 212 27

Pseudomonas aeruginosa alkaline protease (AP) has recently been shown to produce limited proteolysis of human gamma interferon (IFN-gamma) and thereby destroy the antiviral and macrophage-activating activities of the lymphokine. In the present study we describe some of the characteristics of Pseudomonas elastase (E) with regard to inactivation of human IFN-gamma. The inhibitory effect of E on IFN-gamma bioactivity differed from that of AP in that the direct effects of E were reduced in the presence of human serum. That this property of human serum was in large part attributable to the protease inhibitor alpha 2-macroglobulin (alpha 2-M) was suggested by the following observations: (i) methylamine treatment of serum reduced its effect on E, (ii) E interacted directly with alpha 2-M to induce a characteristic conformational change in the protease inhibitor, and (iii) preformed E-alpha 2-M complexes lacked IFN-gamma-degrading activity. Despite these findings, anti-E antiserum partially neutralized the effect that a Pseudomonas filtrate showed on IFN-gamma, suggesting that E contributes to the activity of bacterial filtrates. Treatment of IFN-gamma with E in the presence of a suboptimal concentration of AP resulted in an E dose-dependent inactivation of the lymphokine. Preformed E-alpha 2-M complexes, although ineffective by themselves at cleaving IFN-gamma, degraded the lymphokine, providing AP was also present in the reaction mixture. These data demonstrate that the destruction of small, biologically significant peptides by Pseudomonas proteases can involve protease-protease synergy that acts even in the presence of the serum protease inhibitor alpha 2-M.
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PMID:Inactivation of human gamma interferon by Pseudomonas aeruginosa proteases: elastase augments the effects of alkaline protease despite the presence of alpha 2-macroglobulin. 247 Jun 75

Data are presented showing that treatment of burned, Pseudomonas aeruginosa-infected mice with the protease inhibitor alpha 2-macroglobulin but not treatment with phosphoramidon enhanced survival. Treatment with alpha 2-macroglobulin caused reductions in bacterial counts in the skin and livers of infected mice and also protected liver elongation factor 2. Similar results were observed when human IgG was used for treatment. The protective effect of the IgG treatment was probably due to the presence of opsonizing antibodies in the preparation. The protective capacity of the IgG could be removed by its adsorption with heat-killed cells of the strain used for infecting the mice. The protection afforded by alpha 2-macroglobulin was not due to the presence of opsonizing antibodies in the preparation used. It appeared to be due to inhibition of the proteolytic, not the elastolytic, activities of alkaline protease and elastase elaborated by the organisms growing in the burned skin tissue. Proteolytic activities of these enzymes appeared to serve as virulence factors in P. aeruginosa by decreasing the generation time in vivo of the microorganisms growing in the burned skin tissue and by allowing the organisms to spread from this local site into the systemic circulation. Treatment of pseudomonas infections of burn wounds with protease inhibitors may serve as an alternative to antibiotic treatment and/or immunotherapy.
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PMID:Experimental studies of the pathogenesis of infections due to Pseudomonas aeruginosa: effect of treatment with protease inhibitors. 619 36

Leupeptin, a nontoxic thiol protease inhibitor, has been proposed to have therapeutic use in hereditary muscular dystrophies. The purpose of this study was to characterize the in vivo changes in proteolytic activity of skeletal muscles induced by the repeated administration of leupeptin. Further, whether the modulation of proteolytic capacity by leupeptin affects the repair process of muscle injuries caused by heavy exercise was studied. Leupeptin was administered in mice intraperitoneally at a dose level of 15.5 mg/kg twice a day for 9 days. Leupeptin, known to be an inhibitor of cathepsin B both in vitro and after a single injection in vivo, paradoxically induced an increase of cathepsin B activity in mouse skeletal muscles after repeated administration. In addition, leupeptin administration for 9 days increased the activities of cathepsins C and D, as well as the rate of acid autolysis. The activity of beta-glucuronidase also increased, while those of arylsulfatase, ribonuclease, and alkaline protease were unaffected. No histopathologic changes were observed. At the low dosage used, leupeptin had no effect on the repair process of skeletal muscle after exercise injuries, although several proteolytic processes occur during the regeneration. It is suggested that the increase of acid protease activities in skeletal muscles is an adaptive response to the administration of the proteolytic inhibitor leupeptin and that leupeptin can be administered without prevention or delay of regenerative processes after the onset of myopathic changes.
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PMID:Effects of the protease inhibitor leupeptin on proteolytic activities and regeneration of mouse skeletal muscles after exercise injuries. 638 26

Pseudomonas aeruginosa elastase, but not alkaline protease, degraded pooled, normal, human IgG in vitro and this degraded IgG lost its protective effect when used to treat burned, P. aeruginosa infected mice. Plasma IgG levels in burned, uninfected mice declined immediately postburning, but remained relatively constant thereafter; the levels in burned, P. aeruginosa infected mice continued to decline until death ensued. Infection of burned mice with an elastase+ strain caused the IgG decline, while infection with an elastase- strain did not, suggesting that elastase production caused the in vivo decline in plasma IgG. Local treatment with the protease inhibitor alpha 2-macroglobulin, of burned mice infected with an elastase+ organism, reduced the IgG decline observed in control mice. These data support the hypothesis that P. aeruginosa elastase acts as an IgG protease both in vitro and in vivo and gives insight into how this enzyme may act as a virulence factor in P. aeruginosa.
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PMID:Experimental studies of the pathogenesis of infections owing to Pseudomonas aeruginosa: elastase, an IgG protease. 643 5

A tripeptide aldehyde protease inhibitor, benzyloxycarbonyl(Z)-Leu-Leu-leucinal (ZLLLa1), initiates neurite outgrowth in PC12 cells at an optimal concentration of 30nM. This result suggests the existence of a protease which regulates neurite formation in PC12 cells. We report here an attempt to identify this target protease in bovine brain using Z-Leu-Leu-Leu-4-methylcoumaryl-7-amide (ZLLL-MCA), in which the aldehyde moiety of ZLLLa1 was changed to 4-methylcoumaryl-7-amide to serve as a substrate for the protease. As a result, we have purified a proteasome with a molecular weight of about 660 kDa as a ZLLL-MCA degrading protease. The activity of the proteasome was inhibited efficiently by ZLLLa1, and was different from known catalytic activities of proteasome in some aspects, suggesting it to be a novel one. Thus, the proteasome may be involved in the regulation of neurite formation in PC12 cells.
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PMID:Purification and characterization of a Z-Leu-Leu-Leu-MCA degrading protease expected to regulate neurite formation: a novel catalytic activity in proteasome. 825 Aug 77

N-acetyl-L-leucyl-L-leucyl-L-norleucinal, (LLnL), which inhibits proteasomes in addition to other proteases, was found to prolong the association of major histocompatibility complex class I molecules with the transporters associated with antigen processing (TAP), and to slow their transport out of the endoplasmic reticulum (ER). LLnL induced a reversible accumulation of ubiquitinated proteins and changed the spectrum of peptides bound by class I molecules. These effects can probably be attributed to proteasome inhibition. Unexpectedly, in the TAP-deficient cell line .174, the rate of intracellular transport of human histocompatibility leukocyte antigen (HLA) A2 was also reduced by LLnL, and the generation of most HLA-A2-associated signal sequence peptides was inhibited. The inhibition of HLA-A2 transport in .174 cells was found to be less sensitive to LLnL than in wild-type cells, and a similar difference was found for a second protease inhibitor, benzyloxycarbonyl-L-leucyl-L-leucyl-L-phenylalanilal. These data suggest that under some conditions such inhibitors can block trimming of peptides by an ER peptidase in addition to inhibiting cytosolic peptide generation.
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PMID:The protease inhibitor, N-acetyl-L-leucyl-L-leucyl-leucyl-L-norleucinal, decreases the pool of major histocompatibility complex class I-binding peptides and inhibits peptide trimming in the endoplasmic reticulum. 866 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.
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PMID:Calcium-dependent, interleukin 1-converting enzyme inhibitor-insensitive degradation of lamin B1 and DNA fragmentation in isolated thymocyte nuclei. 879 2

Proteases are known to play important roles in cell growth control, although the underlying mechanisms are still poorly understood. Here we show that the protease inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal induced cell cycle arrest in platelet-derived growth factor-stimulated human fibroblasts at the G1/S boundary of the cell cycle by inhibiting the proteasome. Inhibition of the proteasome resulted in accumulation of the tumor suppressor p53, which was followed by an increase in the amount of the cyclin-dependent kinase-inhibitor p21. As a consequence, both phosphorylation and activity of the cyclin-dependent kinase 2/cyclin E complex were inhibited. We further observed that the retinoblastoma gene product, pRb, remained in the hypophosphorylated state, thus preventing cells from progression into the S-phase. These studies strongly support the hypothesis that the proteasome is a key regulator in the G1-phase of cell cycle progression.
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PMID:p53-dependent cell cycle arrest induced by N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal in platelet-derived growth factor-stimulated human fibroblasts. 885 63


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