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)

Ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, is the most rapidly turned over mammalian enzyme. We have shown that its degradation is accelerated by ODC antizyme, an inhibitory protein induced by polyamines. This is a new type of enzyme regulation and may be a model for selective protein degradation. Here we report the identification of the protease responsible for ODC degradation. Using a cell-free degradation system, we demonstrate that immunodepletion of proteasomes from cell extracts causes almost complete loss of ATP- and antizyme-dependent degradation of ODC. In addition, purified 26S proteasome complex, but not the 20S proteasome, catalyses ODC degradation in the absence of ubiquitin. These results strongly suggest that the 26S proteasome, widely viewed as specific for ubiquitin-conjugated proteins, is the main enzyme responsible for ODC degradation. The 26S proteasome may therefore have a second role in ubiquitin-independent proteolysis.
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PMID:Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. 133 32

The multicatalytic proteinase complex (MPC), also referred to as proteasome, is a large molecular mass intracellular particle (approximately 700 kDa), which exhibits three distinct proteolytic activities designated as chymotrypsin-like, trypsin-like, and peptidylglutamyl-peptide hydrolyzing (PGPH), all sensitive to inhibition by 3,4-dichloroisocoumarin (DCI). The presence of a component resistant to inhibition by DCI with an apparent preference toward bonds on the carboxyl side of branched-chain amino acids has also been recently established. Peptide aldehydes and peptide alpha-keto esters containing a hydrophobic residue in the P1 position have been tested as potential inhibitors of the chymotrypsin-like activity. Three peptide aldehydes (benzyloxycarbonyl)-Leu-Leu-phenylalaninal (Z-LLF-CHO), N-acetyl-Leu-Leu-norleucinal (Ac-LLnL-CHO), and N-acetyl-Leu-Leu-methioninal (Ac-LLM-CHO) were found to be slow-binding reversible inhibitors with Ki values of 0.46, 5.7, and 33 microM, respectively. The simplest kinetic model for inhibition is consistent with a mechanism involving a slow and reversible association of the enzyme with the inhibitor to form a EI complex. The aldehyde inhibitors also inhibited the trypsin-like and PGPH activities of the complex albeit with much higher Ki values than those for chymotrypsin-like activity. Z-LLF-CHO, the most selective of the three aldehydes, did not inhibit the PGPH activity at concentrations of up to 200 microM and inhibited the trypsin-like activity with a Ki approximately 2 orders of magnitude higher than that for the chymotrypsin-like activity. The activity of the DCI-resistant component was not affected by Z-LLF-CHO.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of the chymotrypsin-like activity of the pituitary multicatalytic proteinase complex. 135 35

The proteasome or multicatalytic proteinase from the archaebacterium Thermoplasma acidophilum is a 700 kDa multisubunit protein complex. Unlike proteasomes from eukaryotic cells which are composed of 10-20 different subunits, the Thermoplasma proteasome is made of only two types of subunit, alpha and beta, which have molecular weights of 25.8 and 22.3 kDa, respectively. In this communication we present a three-dimensional stoichiometric model of the archaebacterial proteasome deduced from electron microscopic investigations. The techniques which we have used include image analysis of negatively stained single particles, image analysis of metal decorated small three-dimensional crystals after freeze-etching and STEM mass measurements of freeze-dried particles. The archaebacterial and eukaryotic proteasomes are almost identical in size and shape; the subunits are arranged in four rings which are stacked together such that they collectively form a barrel-shaped complex. According to a previous immunoelectron microscopic investigation, the alpha-subunits form the two outer rings of the stack, while the two rings composed of beta-subunits, which are supposed to carry the active sites, are sandwiched between them. Each of the alpha- and beta-rings contains seven subunits; hence the stoichiometry of the whole proteasome is alpha 14 beta 14 and the symmetry is 7-fold. Image simulation experiments indicate that the alpha- and beta-subunits are not in register along the cylinder axis; rather it appears that the beta-rings are rotated with respect to the alpha-rings by approximately 25 degrees. In contrast to some previous reports we have not been able to find stoichiometric amounts of RNA associated with highly purified proteolytically active proteasome preparations.
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PMID:Subunit stoichiometry and three-dimensional arrangement in proteasomes from Thermoplasma acidophilum. 137 80

The proteasome (multicatalytic proteinase) consists of a large number of non-identical protein subunits which are encoded by the evolutionarily conserved PROS gene family. Using the PROS-Dm35 and PROS-Dm28.1 cDNAs as probes, we have isolated the corresponding genomic DNA clones of Drosophila melanogaster. In situ hybridization shows that the members of the PROS gene family are not organized in a single gene cluster and that, in contrast to the PROS-Dm35 gene, the PROS-Dm28.1 gene is localized on the X chromosome. Analysis of the genomic organization of the PROS-Dm28.1 and PROS-Dm35 genes reveals that both genes are interrupted by two small introns whereby the relative positions of the introns within the two coding regions are not conserved. Neither gene possesses a distinct transcriptional start site as shown by nuclease S1 analysis. Since the promoter regions also do not contain a TATA box, PROS genes appear to be typical house-keeping genes. A putative heat-shock element in the promoter region of the PROS-Dm35 gene was shown to be inactive on stress induction when fused to a reporter gene and tested in transient transfections assays. In addition, promoter deletion analysis demonstrates that the promoter region between positions -605 and -330 contains sequence elements important for PROS-Dm35 gene activity and that deletions beyond position -150 result in an almost complete inhibition of transcription.
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PMID:Molecular characterization of the genomic regions of the Drosophila alpha-type subunit proteasome genes PROS-Dm28.1 and PROS-Dm35. 137 31

We have purified proteasomes to apparent homogeneity from the archaebacterium Thermoplasma acidophilum. This proteinase has a molecular mass of about 650 kDa and an isoelectric point of 5.6. The proteasome hydrolyses peptide substrates containing an aromatic residue adjacent to the reporter group, as well as [14C]methylated casein optimally at pH 8.5 and 90 degrees C. The enzyme activity is enhanced severalfold by Mg2+ and Ca2+ at 25-500 mM. This increase in activity results primarily from a change in Km. The serine-proteinase inhibitors diisopropylfluorophosphate and 3,4-dichloroisocoumarin irreversibly inhibit the enzyme, obviously by modification of both the alpha and beta subunits in the proteasome. The inhibition of proteasomal activity by the peptidylchloromethanes, Cbz-Leu-Leu-CH2Cl and Cbz-Ala-Ala-Phe-CH2Cl (Cbz, benzyloxycarbonyl), is reversible and predominantly of a competitive type. The enzyme is not activated by any of the compounds that typically stimulate the activities of the eukaryotic proteasome.
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PMID:Biochemical properties of the proteasome from Thermoplasma acidophilum. 139 84

The proteasome undergoes cell cycle-dependent changes in its subcellular distribution during ascidian embryonic development [(1992) Dev. Biol. 151, 27-33]. In this study, we demonstrate that the 26 S proteasome is markedly activated in both prophase and metaphase of the mitotic cell cycle in the ascidian embryos in comparison with the case of the 20 S proteasome. These results suggest that the 26 S proteasome is activated and participates in proteolysis at the restricted stages of the cell cycle.
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PMID:The 26 S proteasome is activated at two points in the ascidian cell cycle. 139 59

Screening of a lambda gt11 cDNA expression library of the HeLa cell genome with a monoclonal antibody that specifically recognizes prosomal 30-33-kDa proteins, allowed isolation of a 1264-nucleotide (nt) recombinant cDNA containing a 327-nt untranslated 5'-end. The amino acid (aa) sequence deduced from this cDNA revealed a protein of 269 aa (M(r) of 30,227) that includes a consensus box characteristic for Tyr phosphorylation, also observed in other prosomal proteins. Comparison with another prosomal 27-kDa protein, cloned in our laboratory, indicated the presence of three prosome-specific homology boxes observed in these proteins from archaebacteria to man. Interestingly, except for the untranslated 5'-end, as well as the sequence coding for the N-terminal six aa, this cDNA is identical to two recently published cDNAs encoding subunit C2 of human liver proteasome [Tamura et al., Biochim. Biophys. Acta 1089 (1991) 95-102] and subunit NU of human erythrocyte macropain [DeMartino et al., Biochim. Biophys. Acta 1079 (1991) 29-38]. Primer extension and Northern blot analysis using two specific 18-mer oligodeoxyribonucleotides indicated the presence of two mRNAs that have divergent 5'-ends. These results, as confirmed by the polymerase chain reaction, establish the existence of two distinct Hs PROS-30 mRNAs, differing in their 5'-noncoding regions and in the N-terminal six aa of their protein products.
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PMID:Two mRNAs exist for the Hs PROS-30 gene encoding a component of human prosomes. 139 36

The proteasome (multicatalytic protease complex), a high molecular weight protein complex, has been purified from spinach leaves by successive chromatography on DEAE-cellulose, Bio-Gel A-1.5m, DEAE-TOYOPEARL 650C, and DEAE-5PW. The molecular mass was estimated to be 850 kDa by gel filtration. Polyacrylamide gel electrophoresis of the proteasome gave a single protein band under nondenaturing conditions and at least 10 bands in the range of 21-32 kDa in the presence of sodium dodecyl sulfate. By electron microscopy after negative staining with uranyl acetate, the proteasome from spinach appeared as symmetrical ring-shaped particles. The substrate specificity of proteasomes indicates that they contain at least three types of activity, namely, chymotrypsin-like, Staphylococcus aureus V8 protease-like, and trypsin-like activities. The former two activities were enhanced by poly-L-lysine or sodium dodecyl sulfate. Moreover, we examined the immunological reactivities of proteasomes from various eukaryotes. As a result, cross-immunoreactivities of some subunits were observed. These properties of the proteasome are similar to those of proteasomes isolated from various other eukaryotic sources.
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PMID:Purification and initial characterization of the proteasome from the higher plant Spinacia oleracea. 140 Apr 79

Survival of cells in their natural environment is crucially dependent on their ability to adapt to constantly occurring changes. The ability of cells to respond to extremes of environmental influences is vital to survival. Proteolysis is a central cellular tool in stress response. Proteins of pathways necessary for normal growth, but harmful under stress conditions, as well as proteins damaged by stress have to be eliminated. The yeast Saccharomyces cerevisiae, a model eukaryote, has evolved two different proteolytic systems: (i) a membrane-enveloped, vacuolar (lysosomal) system, which contains a variety of non-specific peptidases and (ii) highly specific peptidases residing at different cellular locations. The best characterized peptidase of the specific system is proteinase yscE, the proteasome equivalent found in all eukaryotic cells. Both the vacuolar and the non-vacuolar systems are vital components of the stress response in yeast.
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PMID:Stress-induced proteolysis in yeast. 140 81

To investigate the role of calpains in myofibrillar protein degradation in skeletal muscle and the regulation of their activity in vivo, we studied the effects of fasting on gene expression of calpains and calpastatin in the skeletal muscle of rabbits. In response to fasting, myofibrillar protein degradation increased 2-fold and mRNA levels of calpain I, calpain II and calpastatin were also increased. However, calpain and calpastatin activities remained unchanged. To investigate this discrepancy, we analysed polysomal calpain mRNA. Results indicated that fasting caused a 2-fold increase in the loading of calpain I and II mRNAs on ribosomes. Thus transcription of genes encoding calpain may be increased during fasting to ensure adequate synthesis of the proteinases needed to mobilize muscle protein reserves. The effect of fasting on calpain and calpastatin mRNA expression is shared by cathepsin D and proteasome C2 but not by beta-actin, implying that fasting invokes control of several proteolytic systems in skeletal muscle and underscores the possibility that each proteolytic system plays a role in the adaptation of skeletal muscle to the fasted state.
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PMID:Gene expression of calpains and their specific endogenous inhibitor, calpastatin, in skeletal muscle of fed and fasted rabbits. 141 70


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