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)

Adherence of P. aeruginosa to the lining of the respiratory tract is probably mediated by interaction of pili or alginate with lactosyl and sialosyl residues on the respiratory cells. The toxins produced by P. aeruginosa (for example, elastase and alkaline protease) may play a key role during the initial persistent colonization as they interfere with important defense mechanisms. Neutralizing antibodies are eventually produced, and a poor prognosis is correlated to a pronounced antibody response. The bacteria are protected against the host's defense mechanisms by production of alginate which encapsulates microcolonies of P. aeruginosa in the lungs. During the chronic infection, toxins of P. aeruginosa probably play little if any direct pathogenic role, however, immune complexes seem to be a major trigger of chronic inflammation in the lungs. Proteolytic enzymes and oxygen radicals released from the abundance of neutrophils in the lungs are probably responsible for most of the tissue damage. The individual course of the chronic infection may be explained by regulatory mechanisms, such as cleavage of immune complexes by neutrophil elastase, and by the balance between the different IgG subclass-specific antibody responses.
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PMID:Immunology of Pseudomonas aeruginosa infection in cystic fibrosis. 213 Jun 83

In the presence of O2, Fe(III) or Cu(II), and an appropriate electron donor, a number of enzymic and nonenzymic oxygen free radical-generating systems are able to catalyze the oxidative modification of proteins. Whereas random, global modification of many different amino acid residues and extensive fragmentation occurs when proteins are exposed to oxygen radicals produced by high energy radiation, only one or a few amino acid residues are modified and relatively little peptide bond cleavage occurs when proteins are exposed to metal-catalyzed oxidation (MCO) systems. The available evidence indicates that the MCO systems catalyze the reduction of Fe(III) to Fe(II) and of O2 to H2O2 and that these products react at metal-binding sites on the protein to produce active oxygen (free radical?) species (viz; OH, ferryl ion) which attack the side chains of amino acid residues at the metal-binding site. Among other modifications, carbonyl derivatives of some amino acid residues are formed; prolyl and arginyl residues are converted to glutamylsemialdehyde residues, lysyl residues are likely converted to 2-amino-adipylsemialdehyde residues; histidyl residues are converted to asparagine and/or aspartyl residues; prolyl residues are converted to glutamyl or pyroglutamyl residues; methionyl residues are converted to methionylsulfoxide residues; and cysteinyl residues to mixed-disulfide derivatives. The biological significance of these metal ion-catalyzed reactions is highlighted by the demonstration: (i) that oxidative modification of proteins "marks" them for degradation by most common proteases and especially by the cytosolic multicatalytic proteinase from mammalian cells; (ii) protein oxidation contributes substantially to the intracellular pool of catalytically inactive and less active, thermolabile forms of enzymes which accumulate in cells during aging, oxidative stress, and in various pathological states, including premature aging diseases (progeria, Werner's syndrome), muscular dystrophy, rheumatoid arthritis, cataractogenesis, chronic alcohol toxicity, pulmonary emphysema, and during tissue injury provoked by ischemia-reperfusion. Furthermore, the metal ion-catalyzed protein oxidation is the basis of biological mechanisms for regulating changes in enzyme levels in response to shifts from anaerobic to aerobic metabolism, and probably from one nutritional state to another. It is also involved in the killing of bacteria by neutrophils and in the loss of neutrophil function following repeated cycles of respiratory burst activity.
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PMID:Metal ion-catalyzed oxidation of proteins: biochemical mechanism and biological consequences. 228 87

Previous studies in this laboratory have shown that glutamine synthetase (GS) and other key metabolic enzymes are inactivated by metal-catalyzed oxidation reactions in vitro. Oxidative inactivation renders these proteins highly susceptible to proteolysis, especially to a class of newly identified alkaline proteases which exhibit little or no activity against the native enzymes. These studies have suggested that oxidative inactivation may be an important marking step for intracellular protein degradation. Because many of the enzymes which have been shown to accumulate as inactive or less active forms during aging are readily inactivated by metal-catalyzed oxidation reactions in vitro, we have investigated the possible relationship between protein oxidation and proteolysis during aging and oxidative stress in vivo. Oxidized proteins accumulate in hepatocytes of rats exposed to 100% oxygen during the first 48 h of oxygen treatment. In the interval between 48 and 54 h the levels of oxidized proteins decline sharply. The specific activities of at least two liver enzymes, glutamine synthetase and glucose-6-phosphate dehydrogenase (G-6-PDH), decrease during the 54-h experiment. GS and G-6-PDH specific immunological cross-reactivity remains high during the first 48 h of oxygen treatment and then declines in the interval between 48 and 54 h. During this same interval the levels of alkaline proteases which degrade oxidized proteins increase, indicating that these activities are induced or activated in response to oxidative stress and subsequently degrade the proteins which have become oxidized during the initial phase of oxygen treatment. Oxidized proteins accumulate progressively during aging in hepatocytes from rats 3 to 26 months old, with the largest incremental increase between 20 and 26 months. The increase in protein oxidation is correlated with a loss of specific activity of GS and G-6-PDH without a concomitant loss of immunological cross-reactivity. The levels of alkaline proteases which degrade oxidized proteins in hepatocytes from 26-month-old rats is only 20% that of 3-month-old rats, suggesting that oxidized proteins accumulate in hepatocytes from old rats, in part, because the proteases which degrade them are deficient or defective. moreover, when old rats are subjected to treatment with 100% oxygen, the levels of oxidized proteins continue to increase and the alkaline protease activity remains low, indicating that these protease activities are not increased in response to oxidative stress in old rats.
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PMID:Protein oxidation and proteolysis during aging and oxidative stress. 257 64

An intensive parasexual genetics program in which industrial strains of Penicillium chrysogenum were used culminated in the isolation of a number of heterozygous diploid strains. The diploid clones were selected from heterokaryons formed from matings between mutant strains having complementary biochemical and conidial color markers. Several diploid cultures were compared with their haploid wild-type parents and other distantly related production strains on the basis of a variety of cultural and physiological criteria. The diploid strains characteristically produced conidia of larger volume and higher deoxyribonucleic acid content. Some were vigorous with respect to growth rate and onset and degree of conidiation. One diploid strain (WC-9) had a 46% greater oxygen uptake rate and oxidized glucose at a 57% greater rate than its haploid parent (M-2). It also produced 33% higher concentrations of beta-galactosidase, 66% more alkaline protease, and 53% more glucose oxidase than the M-2 haploid parent. The selection of rare stable diploid mold cultures through the use of parasexual genetics offers a unique approach to the direct selection of mutants with potential for increased enzyme formation.
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PMID:Biochemical properties of haploid and diploid strains of Penicillium chrysogenum. 511 5

The production of an extracellular collagenase and alkaline protease by Vibrio alginolyticus during stationary phase was inhibited by a temperature shift from 30 to 37 degrees C and by a lack of oxygen. The stability of the exoproteases was unaffected by incubation at 37 degrees C and aeration. The optimum growth temperature for the V. alginolyticus strain was 33.5 degrees C and there was no difference in the growth rate at 30 and 37 degrees C. Aeration enhanced the rate of growth of exponential phase cells. Temperature and oxygen did not affect the growth of stationary phase cells when the exoproteases were being produced. Macromolecular synthesis in stationary phase cells was not affected by temperature. There was no rapid release of the exoproteases after temperature shift down and chloramphenicol inhibited the production of the enzymes when added at time of temperature shift down from 37 to 30 degrees C. The regulation of exoprotease production by temperature and oxygen was specific and has implications regarding the ecology of V. alginolyticus. Cerulenin, quinacrine and O-phenanthroline inhibited the production of the exoproteases.
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PMID:Regulation of exoprotease production by temperature and oxygen in Vibrio alginolyticus. 627 66

Little is known about the interaction of Pseudomonas aeruginosa extracellular products and human polymorphonuclear leukocytes. The present study was designed to examine the effect of alkaline protease and elastase purified from P. aeruginosa on human neutrophil function. Neutrophil chemotaxis, oxygen consumption, glucose oxidation, superoxide production, and nitro blue tetrazolium reduction were studied. It was found that alkaline protease and elastase at fairly low concentrations (0.05 and 0.0025 micrograms/ml, respectively) inhibited chemotaxis. The inhibitory effect of both enzymes was increased at higher concentrations. The chemotaxis of preincubated and washed cells was also inhibited. Alkaline protease but not elastase inhibited opsonized zymosan-stimulated neutrophil oxygen consumption, whereas neither of the enzymes had any effect on glucose oxidation and nitro blue tetrazolium-reducing activity of stimulated neutrophils. The data on superoxide production ability of the cells indicated that the cells preincubated with enzyme and washed were capable of producing superoxide equal to the amount produced by untreated cells when they were stimulated with phorbol myristate acetate or zymosan. However, when elastase was present in the reaction mixture, the reduction of cytochrome c as a measure of superoxide production was inhibited. Inhibition of neutrophil function, particularly chemotaxis, will have important bearing on the escape of the microorganism from the phagocytic defense system of the host. The role of these products in localized infections and avascular areas such as skin burns, cornea, and, at least initially, in chronic lung colonization in cystic fibrosis patients becomes important.
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PMID:Interaction of Pseudomonas aeruginosa alkaline protease and elastase with human polymorphonuclear leukocytes in vitro. 631 65

Red blood cells (RBC) and many other cell types exhibit increased rates of proteolysis during exposure to oxygen radicals and other activated oxygen species (oxidative stress). One of the major RBC proteins modified and proteolytically degraded during oxidative stress is hemoglobin (Hb). We now show that Hb undergoes a partial unfolding (or denaturation) during exposure to hydroxyl radicals (.OH), with an increase in hydrophobicity (hydrophobic interaction chromatography). At low .OH/Hb molar ratios, oxidatively modified Hb exhibits increased proteolytic susceptibility during incubation with RBC lysates, cell-free extracts, Fraction II, a 40-80% (NH4)2SO4 fraction, and purified proteasome (the 670-kDa RBC multicatalytic proteinase complex that we have previously called macroxyproteinase. At higher .OH/Hb molar ratios covalent cross-linking between Hb tetramers, and decreased proteolytic susceptibility are observed. The selective degradation of .OH-modified Hb is an ATP- and ubiquitin-independent process (in fact ATP is slightly inhibitory), and antibody precipitation studies, as well as inhibitor studies, indicate that proteasome is responsible for at least 60-70% of the activity in RBC. We propose that the mechanism of oxidation-induced proteolysis involves exposure of hydrophobic amino acid R groups during the partial Hb unfolding (or partial denaturation) that occurs at relatively low .OH/Hb molar ratios. Peptide bonds flanked by hydrophobic residues are preferred substrates for the proteasome complex, which degrades .OH-modified Hb in a processive process involving apparent serine-protease, sulfhydryl-protease, and metallo-peptidase activities. Highly denatured and covalently cross-linked Hb molecules, produced at high .OH/Hb molar ratios, are poorly degraded in RBC lysates and at all stages of proteasome purification. These cross-linked Hb tetramers have molecular sizes of 120-180 kDa and are presumably too large to fit in the proteasome active site(s). Recognition of exposed hydrophobic amino acid R groups provides a simple, energy-independent, and universal explanation for the proteasome-dependent proteolysis that accompanies oxidative stress.
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PMID:Hydrophobicity as the signal for selective degradation of hydroxyl radical-modified hemoglobin by the multicatalytic proteinase complex, proteasome. 839 40

It is well established that the functional properties of proteins can be compromised by oxidative damage and, in vivo, proteins modified by oxidants are rapidly degraded. It was hypothesized that oxidants may also affect the ability of proteases to hydrolyze peptides and proteins. We therefore examined the effect of oxidants on the endopeptidase activities of the 650 kDa 20S proteasome or multicatalytic endopeptidase (MCP), which is thought to play a central role in nonlysosomal protein breakdown. Treatment of the MCP with the oxidant system, FeSO4-EDTA-ascorbate, stimulated the peptidase activities of the MCP while H2O2 treatment showed little or no stimulation. However, treatment of the MCP with FeSO4-EDTA-ascorbate or H2O2 stimulated proteinase activity by 480% and 730%, respectively. An endogenous activator of the MCP, PA28, stimulated the acidic, basic, and hydrophobic peptidase activities of the MCP, but had no effect on proteolytic activity. Treatment of PA28 with oxidants in the presence of MCP or alone did not greatly affect PA28's ability to activate the peptidase activities of the MCP. Using nondenaturing polyacrylamide gel electrophoresis, structural alterations in the enzyme which may be responsible for the activation of peptidase and protease activities following exposure to oxidants were investigated. Treatment of the MCP with reagents that activate proteolysis, including H2O2, as well as the serine protease inhibitor 3,4-dichloroisocoumarin and the cysteine protease inhibitor p-(chloromercuri) benzenesulfonic acid, all caused dissociation of the 650 kDa MCP. However, exposure to FeSO4-EDTA-ascorbate resulted in little or no dissociation of the complex. The MCP complex dissociated by p-(chloromercuri) benzenesulfonic acid could be reassociated upon treatment with the reducing agent dithiothreitol, but dithiothreitol failed to completely reassociate 3,4-dichloroisocoumarin- or H2O2 treated MCP. Therefore, chemical modification of the MCP can cause activation with varying degrees of complex dissociation. These results suggest that metabolites, such as reactive oxygen species, in addition to endogenous proteins, such as PA28, are capable of modulating MCP activity.
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PMID:Activation of the multicatalytic endopeptidase by oxidants. Effects on enzyme structure. 867 41

The crystal structure of the unliganded alkaline protease from Pseudomonas aeruginosa IFO3080 has been determined at 2.0 A resolution by the X-ray method. The enzyme consists of N-terminal catalytic and C-terminal beta-helix domains. On structural comparison between the present unliganded enzyme and structurally- known liganded enzyme, some structural changes were observed around the active site. In the unliganded enzyme, Y216 serves as the fifth ligand for the active site zinc ion. On ligand binding, Y216 may move to form a hydrogen-bond with the carbonyl oxygen of the P1 residue of a ligand peptide. D191 in the flexible loop, Y190 to D196, over the active site cleft forms hydrogen-bonds with the backbone atoms of the P1 and P2 residues of the ligand to close the entrance to the cleft. The water molecule which is the fourth ligand for the zinc ion is replaced by the carbonyl oxygen of the P1 residue. These structural changes around the active site may reflect the substrate-binding mode during the enzymatic reaction.
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PMID:Crystal structure of the unliganded alkaline protease from Pseudomonas aeruginosa IFO3080 and its conformational changes on ligand binding. 869 Jul 4

Activities of the multicatalytic proteinase complex (MPC) were detected in turtle (Trachemys scripta elegans) liver. The ratio of peptidylglutamyl-peptide bond hydrolyzing, trypsin-like, and chymotrypsin-like activities was 6:2.7:1 for the MPC partially purified by Sepharose CL-6B gel filtration. Molecular mass of the turtle liver enzyme was 940 +/- 46 kD. Nondenaturing PAGE revealed a single band containing MPC activity reacting with peptide substrate. In vivo anoxia exposure (20 h submergence in N2-bubbled water) and subsequent 24 h aerobic recovery stimulated changes in liver protease activity. Peptidylglutamyl-peptide bond hydrolyzing activity of the partially purified MPC increased by 29% during aerobic recovery. Elevated MPC activity during recovery may serve to catabolize specific stress-related proteins or to remove proteins damaged by oxygen free radicals generated upon the reintroduction of oxygen.
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PMID:Multicatalytic proteinase activity in turtle liver: responses to anoxia stress and recovery. 882 3


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