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)

Proteasomes are multisubunit proteases that exist universally among eukaryotes. They have multiple proteolytic activities, and are believed to have important roles in regulating cell cycle, selective intracellular proteolysis, and antigen presentation. To determine the possible role that proteasomes may play in controlling the life cycle of African trypanosomes, we have isolated proteasomes from the bloodstream and the insect (procyclic) forms of Trypanosoma brucei by DEAE-cellulose chromatography and glycerol gradient fractionation in the presence of ATP. No 26 S proteasome homologs was identified in T. brucei under these experimental conditions. The proteasomes isolated from these two forms of T. brucei are very similar to the rat blood cell 20 S proteasome in their general appearance under the electron microscope. The profile of trypanosome proteasome subunits in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) has eight visible protein bands with molecular weights ranging from 23 to 34 kDa, and cross-reacted very poorly with the anti-human 20 S proteasome antibodies on immunoblots. Two-dimensional gel electrophoresis of the parasite proteasomes shows a similar number of major subunits with pI's ranging from 4.5 to 7. Using a variety of fluorogenic peptides as substrates, the trypanosome proteasomes exhibited unusually high trypsin-like, but somewhat lower chymotrypsin-like activities, as compared to the rat 20 S proteasome. These proteolytic activities were, however, insensitive to phenylmethylsulfonyl fluoride (PMSF), tosyl-phenylalanine chloromethylketone (TPCK), tosyl-lysine chloromethylketone (TLCK) and trans-epoxy succinyl-L-leucylamido-(4 guanidino) butane (E-64), but the trypsin-like activity of trypanosome proteasomes was inhibited by leupeptin, an aldehyde known to inhibit the trypsin-like activity of mammalian proteasomes, thus ruling out possible contamination by other serine or cysteine proteases. Some quantitative differences in the substrate specificities between the proteasomes from bloodstream and procyclic forms were indicated, which may play a role in determining the differential protein turnovers at two different stages of development of T. brucei.
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PMID:Purification and characterization of proteasomes from Trypanosoma brucei. 881 75

To explore membrane-permeable synthetic inhibitors that discriminate between endogenous calpain and proteasome in cells, we examined the inhibition of profiles against calpain and proteasome in vitro and in vivo of peptidyl aldehydes possessing di-leucine and tri-leucine. The tripeptide aldehyde benzyloxycarbonyl-leucyl-leucinal (ZLLLal) strongly inhibited calpain and proteasome activities in vitro. The concentration required for 50% inhibition (IC50) of the casein-degrading activity of calpain was 1.25 microM, and the IC50s for the succinyl-leucyl-leucyl-valyl-tyrosine-4-methylcoumaryl-7-amide (Suc-LLVY-MCA)- and benzyloxycarbonyl-leucyl-leucyl-leucine-4-methylcoumaryl -7-amide (ZLLL-MCA)-degrading activities of proteasome were 850 and 100 nM, respectively. On the other hand, the synthetic dipeptide aldehyde benzyloxycarbonyl-leucyl-leucinal (ZLLal) strongly inhibited the casein degrading activity of calpain (IC50 1.20 microM), but the inhibition of proteasome was weak (IC50S for SucLLVY-MCA- and ZLLL-MCA-degrading activities were 120 and 110 microM, respectively). Thus, while calpain was inhibited by similar concentrations of ZLLal and ZLLLal, the inhibitory potencies of ZLLLal against the ZLLL-MCA- and Suc-LLVY-MCA-degrading activities in proteasome were 1,100 and 140 times stronger than those of ZLLal, respectively. To evaluate the effectiveness of these inhibitors on intracellular proteasome, the induction of neurite outgrowth in PC12 cells caused by proteasome inhibition was examined. ZLLLal and ZLLal initiated neurite outgrowth with optimal concentrations of 20 nM and 10 microM, respectively, again showing a big difference in the effective concentrations for the proteasome inhibition as in vitro. As for the effect on intracellular calpain, the concentration of ZLLLal and ZLLal required for the inhibition of the autolytic activation of calpain in rabbit erythrocytes were 100 and 100 microM or more, respectively. The almost equal inhibitory potencies of ZLLLal and ZLLal were in agreement with the inhibition of calpain in vitro. These differential effects of inhibitors against calpain and proteasome are potentially useful for identifying the functions of calpain and proteasome in cell physiology and pathology.
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PMID:Differential inhibition of calpain and proteasome activities by peptidyl aldehydes of di-leucine and tri-leucine. 883 56

Point mutations occurring within the Cu/Zn superoxide dismutase (SOD1) gene have been implicated in the etiology of some cases of familial amyotrophic lateral sclerosis (FALS). In order to better understand the functional consequences of these mutations, we have introduced FALS mutations into the mouse SOD1 gene and studied the expression of the mutant templates in stably transformed cell lines. Pulse-chase analyses of lysates derived from cell lines stably expressing the Cu/Zn SOD isoforms indicate that the FALS mutant Cu/Zn SOD proteins are turned over more rapidly than wild-type SOD. Protease inhibitors specific for the major intracellular proteolytic activities were used to characterize the degradative pathways involved in the turnover of mutant Cu/Zn SOD. Inhibition of the chymotrypsin-like activity of the proteasome (also known as multicatalytic proteinase or ubiquitin, ATP-dependent proteinase) by a synthetic dipeptide aldehyde led to a significant increase in levels of the mutant Cu/Zn SOD implicating this proteolytic pathway in the turnover of the FALS mutant SOD proteins.
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PMID:Proteasome inhibition enhances the stability of mouse Cu/Zn superoxide dismutase with mutations linked to familial amyotrophic lateral sclerosis. 883 67

The multicatalytic proteinase complex or 20S proteasome is involved in the extralysosomal degradation of both long- and short-lived proteins. The eukaryotic enzyme is composed of 14 nonidentical subunits arranged as a complex dimer of the composition (alpha7beta7)2. Recent studies identify N-terminal threonines present on some beta-subunits as the active-site residues. It has been proposed that the molecule contains three or four proteolytically active subunits [Seemuller et al., Science 268, 579-582 (1995)]. Studies with synthetic substrates, activators, and inhibitors, however, have identified at least five distinct catalytic activities. To further characterize the specificity of the previously defined "peptidyl glutamyl peptide bond hydrolyzing activity," N-benzyloxycarbonyl-Leucyl-Leucyl-Glutamal was synthesized as a potential inhibitor. Surprisingly, this aldehyde most potently inhibited the "branched chain amino acid preferring activity" (BrAAP). To further explore BrAAP specificity, novel substrates containing internal prolyl and glutamyl residues were synthesized. Their use established that the BrAAP activity catalyzed both a postproline and a postglutamate cleavage and therefore has a broader specificity than previously recognized. These results help explain earlier observations on treatment of the multicatalytic proteinase complex with 3,4-dichloroisocoumarin. This reagent activates both the BrAAP activity and the degradation of beta-casein and inhibits the other catalytic activities.
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PMID:Cleavage of Pro-X and Glu-X bonds catalyzed by the branched chain amino acid preferring activity of the bovine pituitary multicatalytic proteinase complex (20S proteasome). 883 46

Rb protein is a critical regulator of entry into the cell cycle, and loss of Rb function by deletions, mutations, or interaction with DNA viral oncoproteins leads to oncogenic transformation. We have shown that the human papilloma virus (HPV)-16 E7 gene is sufficient to induce the immortalization of mammary epithelial cells (MECs). Surprisingly, the steady-state level of Rb protein in these immortal cells was drastically decreased. Here, we used pulse-chase analysis to show that the in vivo loss of Rb protein in E7-immortalized MECs is a consequence of enhanced degradation. Expression of HPV16 E7 in a cell line with a temperature-sensitive mutation in the E1 enzyme of the ubiquitin pathway demonstrated that degradation of Rb was ubiquitin dependent. Treatment of E7-immortalized MECs with aldehyde inhibitors of proteasome-associated proteases led to a marked stabilization of Rb protein, particularly the hypophosphorylated form. Taken together, our results provide evidence for HPV-16 E7-induced enhanced degradation of Rb protein via a ubiquitin-proteasome pathway and suggest a second mechanism of oncogenic transformation by E7, in addition to its previously identified ability to sequester Rb from E2F. Our analyses also show that normal Rb levels are regulated by the ubiquitin-proteasome degradation pathway.
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PMID:E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. 884 Sep 74

Corn peptide (CP) was prepared from corn gluten meal by proteolysis with alkaline protease from alkalophilic Bacillus A-7. Free amino acids were not found in the CP product. Gel filtration on a Shodex OH-packed column revealed that the molecular weight distribution of the CP was less than about 2,000, characteristic of dipeptides to decapeptides, i.e. oligopeptides. The amino acid pattern of CP was similar to that of corn gluten meal, which was rich in alanine and branched-chain amino acids, but poor in basic amino acids. The effect of the CP administration on alcohol metabolism was examined with SHR-SP, which were given ethanol orally through a gastric tube at the rate of 1.0 g/kg. Prior administration of CP at 1.0 g/kg resulted in fast disappearance of ethanol and its oxidative product acetaldehyde from the blood relative to the control without administration. Hence, it is suggested that CP, rather than its constituent amino acids such as alanine and proline, effectively takes part in enhancing the metabolism of ethanol as well as acetaldehyde.
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PMID:Preparation of corn peptide from corn gluten meal and its administration effect on alcohol metabolism in stroke-prone spontaneously hypertensive rats. 886 58

Recent studies have suggested that activation of the ubiquitin-proteasome pathway is primarily responsible for the rapid loss of muscle proteins in various types of atrophy. The present studies were undertaken to test if different classes of muscle proteins are degraded by this pathway. In extracts of rabbit psoas muscle, the complete degradation of soluble proteins to amino acids was stimulated up to 6-fold by ATP. Peptide aldehyde inhibitors of the proteasome or the removal of proteasomes markedly inhibited only the ATP-dependent process. Addition of purified myosin, actin, troponin, or tropomyosin to these extracts showed that these proteins served as substrates for the ubiquitin-proteasome pathway. By contrast, degradation of myoglobin did not require ATP, proteasomes, or any known proteases in muscles. When myosin, actin, and troponin were added as actomyosin complexes or as intact myofibrils to these extracts, they were not hydrolyzed at a significant rate, probably because in these multicomponent complexes, these proteins are protected from degradation. Accordingly, actin (but not albumin or troponin) inhibited the degradation of 125I-myosin, and actin was found to selectively inhibit ubiquitin conjugation to 125I-myosin. Also, the presence of tropomyosin inhibited the degradation of 125I-troponin. However, neither actin nor tropomyosin inhibited the degradation of 125I-lysozyme or soluble muscle proteins. Thus, specific interactions between the myofibrillar proteins appear to protect them from ubiquitin-dependent degradation, and the rate-limiting step in their degradation is probably their dissociation from the myofibril.
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PMID:Importance of the ATP-ubiquitin-proteasome pathway in the degradation of soluble and myofibrillar proteins in rabbit muscle extracts. 890 Jan 46

We have studied whether various agents that inhibit purified yeast and mammalian 26 S proteasome can suppress the breakdown of different classes of proteins in Saccharomyces cerevisiae. The degradation of short-lived proteins was inhibited reversibly by peptide aldehyde inhibitors of proteasomes, carbobenzoxyl-leucinyl-leucinyl-leucinal (MG132) and carbobenzoxyl-leucinyl-leucinyl-norvalinal (MG115), in a yeast mutant with enhanced permeability, but not in wild-type strains. Lactacystin, an irreversible proteasome inhibitor, had no effect, but the beta-lactone derivative of lactacystin, which directly reacts with proteasomes, inhibited the degradation of short-lived proteins. These inhibitors also blocked the rapid ubiquitin-dependent breakdown of a beta-galactosidase fusion protein and caused accumulation of enzymatically active molecules in cells. The degradation of the bulk of cell proteins, which are long-lived molecules, was not blocked by proteasome inhibitors, but could be blocked by phenylmethylsulfonyl fluoride. This agent, which inhibits multiple vacuolar proteases, did not affect the proteasome or breakdown of short-lived proteins. These two classes of inhibitors can thus be used to distinguish the cytosolic and vacuolar proteolytic pathways and to increase the cellular content of short-lived proteins.
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PMID:Selective inhibitors of the proteasome-dependent and vacuolar pathways of protein degradation in Saccharomyces cerevisiae. 891 Mar 2

A prominent feature of the life cycle of intracellular parasites is the profound morphological changes they undergo during development in the vertebrate and invertebrate hosts. In eukaryotic cells, most cytoplasmic proteins are degraded in proteasomes. Here, we show that the transformation in axenic medium of trypomastigotes of Trypanosoma cruzi into amastigote-like organisms, and the intracellular development of the parasite from amastigotes into trypomastigotes, are prevented by lactacystin, or by a peptide aldehyde that inhibits proteasome function. Clasto-lactacystin, an inactive analogue of lactacystin, and cell-permeant peptide aldehyde inhibitors of T. cruzi cysteine proteinases have no effect. We have also identified the 20S proteasomes from T. cruzi as a target of lactacystin in vivo. Our results document the essential role of proteasomes in the stage-specific transformation of a protozoan.
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PMID:Proteasome activity is required for the stage-specific transformation of a protozoan parasite. 892 Aug 78

HeLa cells growing in vitro were treated with the peptidyl aldehyde inhibitor of the chymotrypsin-like activity of the proteasome N-benzyloxycarbonyl-Ile-Glu(O-t-butyl)-Ala-leucinal (PSI). Immunofluorescence studies of treated cells revealed the formation of massive perinuclear aggregates rich in ubiquitin and proteasomal antigens, which on the ultrastructural level appeared as perinuclear aggregates of electron-dense material, usually in the vicinity of Golgi cisternae. Histochemical studies disclosed that these cells contained protein-rich perinuclear aggregates detected by amido black staining, while unusual accumulations of lipids, carbohydrates, or nucleic acids were not present. Inhibition of protein synthesis by cycloheximide prevented the formation of aggregates, whereas microtubule disruption by nocodazole induced a dispersion of the aggregates. We hypothesize that aggregates induced by PSI treatment correspond to accumulations of proteasome-substrate complexes in a well-defined region, where the proteolytic processes of the ubiquitin-proteasome pathway seem to be somehow centered. We propose to call this region the proteolysis center.
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PMID:Ubiquitin-mediated proteolysis centers in HeLa cells: indication from studies of an inhibitor of the chymotrypsin-like activity of the proteasome. 892 70


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