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)

The objective of this study was to ascertain the mechanism by which serine and cysteine proteinase inhibitors interfere with production of NO by LPS-activated rat alveolar macrophages. Macrophages were incubated in the presence of LPS+ test agent for 24 hr. Culture media were analyzed for NOX- accumulation, harvested cells were assayed for iNOS activity, and cellular RNA was extracted for determination of iNOS mRNA by Northern blot analysis. TPCK, TLCK, calpain inhibitor 1 (CPI-1) and calpain inhibitor 2 (CPI-2) each inhibited NOX- production and inducible iNOS expression in a concentration-dependent manner at 1-100 microM. TPCK and CPI-1 were about 10-fold more potent than TLCK and CPI-2, respectively. These data suggest that a chymotrypsin-like serine or cysteine proteinase is required for the LPS-inducible expression of the iNOS gene, perhaps by mechanisms involving activation of transcription factor NF-kappa B. Accordingly, a potent inhibitor of NF-kappa B activation whose action is attributed to inhibition of the chymotrypsin-like activity of the multicatalytic proteinase complex (MPC) was tested. Z-IE(O-t-Bu)A-Leucinal abolished NOX- production and inducible iNOS expression at 1 microM and showed over 50% inhibition at 10 nM. These observations indicate that inhibitors of MPC interfere with iNOS induction and provide strong evidence that MPC functions importantly in iNOS induction in macrophages.
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PMID:Serine and cysteine proteinase inhibitors prevent nitric oxide production by activated macrophages by interfering with transcription of the inducible NO synthase gene. 748 14

A 645-kDa proteasome was purified from Methanosarcina thermophila which had chymotrypsin-like and peptidylglutamyl-peptide hydrolase activities and contained alpha (24-kDa) and beta (22-kDa) subunits. Processing of both subunits was suggested by comparison of N-terminal sequences with the sequences deduced from the alpha- and beta-encoding genes (psmA and psmB). Alignment of deduced sequences for the alpha and beta subunits revealed high similarity; however, the N-terminal sequence of the alpha subunit contained an additional 24 amino acids that were not present in the beta subunit. The alpha and beta subunits had high sequence identity with alpha- and beta-type subunits of proteasomes from eucaryotic organisms and the distantly related archaeon Thermoplasma acidophilum. The psmB gene was transcribed in vivo as a monocistronic message from a consensus archaeal promoter. The results suggest that proteasomes are more widespread in the Archaea than previously proposed. Southern blotting experiments suggested the presence of ubiquitin-like sequences in M. thermophila.
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PMID:A proteasome from the methanogenic archaeon Methanosarcina thermophila. 749 78

The proteasome (multicatalytic proteinase complex) is a large multimeric complex which is found in the nucleus and cytoplasm of eukaryotic cells. It plays a major role in both ubiquitin-dependent and ubiquitin-independent nonlysosomal pathways of protein degradation. Proteasome subunits are encoded by members of the same gene family and can be divided into two groups based on their similarity to the alpha and beta subunits of the simpler proteasome isolated from Thermoplasma acidophilum. Proteasomes have a cylindrical structure composed of four rings of seven subunits. The 26S form of the proteasome, which is responsible for ubiquitin-dependent proteolysis, contains additional regulatory complexes. Eukaryotic proteasomes have multiple catalytic activities which are catalysed at distinct sites. Since proteasomes are unrelated to other known proteases, there are no clues as to which are the catalytic components from sequence alignments. It has been assumed from studies with yeast mutants that beta-type subunits play a catalytic role. Using a radiolabelled peptidyl chloromethane inhibitor of rat liver proteasomes we have directly identified RC7 as a catalytic component. Interestingly, mutants in Pre1, the yeast homologue of RC7, have already been reported to have defective chymotrypsin-like activity. These results taken together confirm a direct catalytic role for these beta-type subunits. Proteasome activities are sensitive to conformational changes and there are several ways in which proteasome function may be modulated in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Catalytic components of proteasomes and the regulation of proteinase activity. 756 62

We have identified and purified an endogenous inhibitor of multicatalytic proteinase (MCP) from human erythrocyte membranes. The inhibitor showed a molecular mass of 90 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The inhibitor protein was purified from the erythrocyte membranes using Heparinagarose and hydroxylapatite chromatography and the size exclusion on a Biogel A 1.5 m column in the presence of high salt. The 90-kDa protein inhibited all three peptidase activities of MCP; trypsin-like, chymotrypsin-like and peptidyl glutamyl peptide hydrolyzing (PGPH). However, it failed to cause any significant inhibition of caseinolytic activity of MCP, suggesting that the regulation of proteinase and peptidase activities is distinct. The inhibition of the chymotrypsin-like activity was noncompetitive. The results suggest that the 90-kDa inhibitor protein may be an important regulator of membrane-bound MCP.
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PMID:Identification and purification of a 90-kDa membrane-bound endogenous inhibitor of multicatalytic proteinase from human erythrocytes. 757 69

Class I MHC (MHC-I) molecules present peptides derived from Ag that are processed in the cytosol. The proteasome is a multicatalytic protease complex that is present in the cytosol and has been implicated in cytosolic Ag processing. Novel dipeptide aldehydes were designed, synthesized, and demonstrated to specifically inhibit the chymotrypsin-like protease activity of isolated proteasomes, but produced relatively little inhibition of cathepsin B, a vacuolar cysteine protease. The inhibitors were membrane permeable and inhibited intracellular cleavage of a membrane-permeable fluorogenic substrate of the chymotrypsin-like proteasome activity. When a model Ag, OVA, was introduced into the cytoplasm of M12.B6 murine B cells by electroporation, the proteasome inhibitors blocked its processing for subsequent presentation by MHC-I molecules. The inhibitors had little effect on class II MHC processing of exogenous Ag. The potencies of different inhibitors for blockade of MHC-I Ag processing correlated directly with their potencies for inhibition of the chymotrypsin-like proteasome activity. In contrast, conventional inhibitors of vacuolar cysteine proteases (e.g., leupeptin and benzyloxycarbonyl-Phe-Ala-CHN2) had little effect on MHC-I processing or the chymotryspin-like activity of isolated proteasomes. These results directly demonstrate that inhibition of proteasome activity blocks MHC-I Ag processing, confirming a role for proteasomes in this pathway. Moreover, they suggest that the chymotrypsin-like activity of the proteasome may be of major importance to the cytosolic processing of at least some Ag.
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PMID:Novel dipeptide aldehydes are proteasome inhibitors and block the MHC-I antigen-processing pathway. 763 33

Intraneuronal accumulation of ubiquitin conjugates in inclusion bodies and neurofibrillary tangles is a pathological feature of neurodegenerative disorders such as Alzheimer's disease and Down's syndrome and of normal aging of the brain. Amyloid beta-protein (A beta) and its precursor are found in neurofibrillary tangle-containing neurons. A beta is the major component of extracellular plaques. We showed that A beta acts as an inhibitor of the ubiquitin-dependent protein degradation in vitro. We examined the effect of A beta on the steps of this proteolytic pathway that contribute to the level of ubiquitin conjugates in the cell. Neither conjugate formation nor conjugate deubiquitination was affected by the presence of A beta. However, A beta significantly reduced the rate of conjugate degradation. Our results indicate that A beta interacts with the proteolytic step of the ubiquitin degradative pathway. Since this step is performed by the 26 S proteasome, the effect of A beta on the catalytic core of this proteolytic complex, the 20 S proteasome, was determined. We found that A beta selectively inhibits the chymotrypsin-like activity of the 20 S proteasome. Under pathological conditions in the affected neuron, A beta could interfere with ubiquitin-dependent degradation by inhibiting the 26 S proteasome activity. This finding may explain the origin of the accumulation of ubiquitin conjugates.
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PMID:Amyloid beta-protein inhibits ubiquitin-dependent protein degradation in vitro. 764 80

Polyacrylamide gel electrophoresis and high performance liquid chromatography of multicatalytic proteinase complexes (MPC) isolated from bovine pituitary, lung, and liver showed marked differences in the pattern of subunits. The concentrations of LMP7 in the lung and liver were 10 and 5 times, respectively, greater than those in the pituitary, whereas the chymotrypsin-like activity and the amount of a subunit (BO2), necessary for its expression, were markedly decreased in the lung and moderately decreased in the liver. Lower trypsin-like, small neutral amino acid preferring, and peptidyl-glutamyl-peptide hydrolyzing activities were also found in the lung and liver. The activity of the branched chain amino acid preferring component (BrAAP), predominantly latent in the pituitary, was highly activated in the lung and liver, as evidenced by a greatly decreased Km and a 20-fold increase of the specificity constant Vmax/Km, indicating facilitated substrate access to its active site and increased affinity toward substrates with branched chain amino acids in the P1 position. It is suggested that overexpression of LMP7 in the lung is related to increased exposure of the airways to foreign antigens. The possible association between amounts of LMP7 and the activation of the BrAAP component needs further examination.
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PMID:Differences in catalytic activities and subunit pattern of multicatalytic proteinase complexes (proteasomes) isolated from bovine pituitary, lung, and liver. Changes in LMP7 and the component necessary for expression of the chymotrypsin-like activity. 767 55

The multicatalytic proteinase complex (MPC), also called the proteasome, is a ubiquitous particle (19S) that is required for life. It is found in the cytoplasm and nucleus of all eukaryotic cells where it degrades selected cytosolic and nuclear proteins. It forms the proteolytic core of the 26S complex that represents the final step in the ubiquitin-dependent pathway of proteolysis. The MPC expresses at least five distinct proteolytic activities. Three activities preferring cleavages on the carboxyl side of neutral amino acids were described: an activity cleaving after branched chain residues, termed branched chain amino acid preferring, that is a major factor in the degradation of proteins, an activity preferring cleavages after bulky hydrophobic residues designated chymotrypsin-like, and an activity cleaving between small neutral amino acids. Activities cleaving after basic (trypsin-like) and acidic residues (peptidylglutamyl peptide-hydrolyzing) have also been described. The expression of multiple proteolytic activities with diverse specificities may provide a functional advantage that allows efficient hydrolysis of target proteins.
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PMID:Catalytic components of the bovine pituitary multicatalytic proteinase complex (proteasome). 769 27

We have isolated and characterized a cDNA encoding the mouse proteasome subunit MC3 and identified four proteasome subtypes which differ in their peptide-hydrolyzing and polypeptide-cleavage properties. Immunoblotting data show that the 25-kD MC3 subunit is a constitutive proteasome subunit which exists in several isoforms. In addition, by immunoprecipitation of proteasomes with AbMC3, a subset of enzyme complexes could be recognized which differ in their relative subunit composition from the bulk of proteasomes. Using DEAE-column chromatography we identified three different proteasome subtypes in sol-80 mouse liver extracts and, by Trition X-100 extraction, a distinct membrane-bound subtype. The four proteasome subtypes are shown to differ in their trypsin- and chymotrypsin-like hydrolyzing activities as well as in their ability to cleave a 25mer polypeptide substrate derived from the MCMV IE pp89. Our data indicate that the enzymatic properties observed for the total proteasome population may be the summary of cleavage properties of different types of proteasome complexes.
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PMID:Characterization of mouse proteasome subunit MC3 and identification of proteasome subtypes with different cleavage characteristics. Proteasome subunits, proteasome subpopulations. 769 31

The proteasome plays a central role in ubiquitin-dependent and -independent proteolysis in eukaryotic cells. The hawkmoth proteasome was purified from larval body wall and characterized with respect to substrate specificity, sensitivity to protease inhibitors, and cross-reactivity with monoclonal antibodies (mAbs) raised against human placenta proteasome. Leupeptin selectively inhibited the trypsin-like activity (T-L) and N-ethylmaleimide inhibited both T-L and chymotrypsin-like activities, whereas 0.02% sodium dodecyl sulfate stimulated the peptidylglutamyl peptide hydrolase, branched-chain amino acid preferring, and caseinolytic activities 20-, 18-, and 3.8-fold, respectively. All four peptidase activities were inhibited by 3,4-dichloroisocoumarin. One-dimensional immunoblot analysis showed that the level and subunit composition of the proteasome varied between tissues. The relative levels of proteasome were high in intersegmental muscle and ovary, lower in Malpighian tubule, male accessory gland, and ventral nerve cord, and lowest in flight muscle and fat body. The tissues differed in the relative amount of a 41-kDa doublet; a 22-kDa subunit was present only in the male accessory gland. Two-dimensional polyacrylamide gel electrophoresis showed that the hawkmoth proteasome contained at least 26 subunits, compared with 28 subunits in lobster. Immunological analysis using four subunit-specific mAbs identified the putative homologs of the human zeta, C2, C3, and C8 alpha-type subunits in the hawkmoth and lobster enzymes. Two of the four mAbs reacted with three or more of the hawkmoth subunits and three of the mAbs reacted with two or more of the lobster subunits. In addition, two other mAbs that recognize epitopes shared by a number of alpha-type subunits indicated that at least 15 (lobster) or 16 (hawkmoth) subunits were alpha-type. These results suggest that much of the subunit complexity of the arthropod proteasomes is a consequence of extensive post-translational modifications.
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PMID:The multicatalytic proteinase (proteasome) of the hawkmoth, Manduca sexta: catalytic properties and immunological comparison with the lobster enzyme complex. 772 56


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