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)

Loss of lean body mass is common in patients with acute or chronic renal failure but the mechanisms causing this loss are only beginning to be understood. One mechanism involves an inability of uremic patients to activate the critical metabolic responses that maintain protein balance when dietary protein is limited. Metabolic responses to dietary protein restriction include a sharp reduction in the degradation of essential amino acids and protein; changes in protein synthesis are less reliable. If uremia prevents suppression of essential amino acid or protein degradation when dietary protein is reduced by anorexia, negative nitrogen balance and loss of lean body mass will ensue. One complication of uremia, metabolic acidosis, stimulates the degradation of branched-chain amino acids and proteins and therefore blocks the ability of the patient to respond to a low-protein diet. The mechanisms require glucocorticoids and involve increased activity of branched-chain keto acid dehydrogenase and the ubiquitin-proteasome proteolytic pathway; there also is increased transcription of genes encoding components of enzymes involved in the pathways. Besides acidosis, a low insulin concentration and cytokines activate the ubiquitin-proteasome proteolytic pathway. Understanding how proteolysis is activated, including how these genes are stimulated, is important because the same pathways are activated in diabetes, cancer, sepsis, burns, starvation, and muscle denervation. Activation of the ubiquitin-proteasome pathway leads to reduced lean body mass.
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PMID:Robert H Herman Memorial Award in Clinical Nutrition Lecture, 1997. Mechanisms causing loss of lean body mass in kidney disease. 949 77

Three-week-old maize (Zea mays L.) plants were submitted to light/dark cycles and to prolonged darkness to investigate the occurrence of sugar-limitation effects in different parts of the whole plant. Soluble sugars fluctuated with light/dark cycles and dropped sharply during extended darkness. Significant decreases in protein level were observed after prolonged darkness in mature roots, root tips, and young leaves. Glutamine and asparagine (Asn) changed in opposite ways, with Asn increasing in the dark. After prolonged darkness the increase in Asn accounted for most of the nitrogen released by protein breakdown. Using polyclonal antibodies against a vacuolar root protease previously described (F. James, R. Brouquisse, C. Suire, A. Pradet, P. Raymond [1996] Biochem J 320: 283-292) or the 20S proteasome, we showed that the increase in proteolytic activities was related to an enrichment of roots in the vacuolar protease, with no change in the amount of 20S proteasome in either roots or leaves. Our results show that no significant net proteolysis is induced in any part of the plant during normal light/dark cycles, although changes in metabolism and growth appear soon after the beginning of the dark period, and starvation-related proteolysis probably appears in prolonged darkness earlier in sink than in mature tissues.
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PMID:Induction of a carbon-starvation-related proteolysis in whole maize plants submitted to Light/Dark cycles and to extended darkness 970 83

Addition of ammonium ions to yeast cells growing on proline as the sole nitrogen source induces internalization of the general amino acid permease Gap1p and its subsequent degradation in the vacuole. An essential step in this down-regulation is Gap1p ubiquitination through a process requiring the Npi1p/Rsp5p ubiquitin ligase. We show in this report that NPI2, a second gene required for NH4+-induced down-regulation of Gap1p, codes for the ubiquitin hydrolase Doa4p/Ubp4p/Ssv7p and that NH4+-induced Gap1p ubiquitination is strongly reduced in npi2 cells. The npi2 mutation results in substitution of an aromatic amino acid located in a 33-residue sequence shared by some ubiquitin hydrolases of the Ubp family. In this mutant, as in doa4(delta) cells, the amount of free monomeric ubiquitin is at least four times lower than in wild-type cells. Both ubiquitination and down-regulation of the permease can be restored in npi2 cells by over-expression of ubiquitin. In proline-grown wild-type and npi2/doa4 cells overproducing ubiquitin, Gap1p appears to be mono-ubiquitinated at two lysine acceptor sites. Addition of NH4+ triggers rapid poly-ubiquitination of Gap1p, the poly-ubiquitin chains being specifically formed by linkage through the lysine 63 residue of ubiquitin. Gap1p is thus ubiquitinated differently from the proteins targeted by ubiquitination for proteolysis by the proteasome, but in the same manner as the uracil permease, also subject to ubiquitin-dependent endocytosis. When poly-ubiquitination through Lys63 is blocked, the Gap1p permease still undergoes NH4+-induced down-regulation, but to a lesser extent.
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PMID:NH4+-induced down-regulation of the Saccharomyces cerevisiae Gap1p permease involves its ubiquitination with lysine-63-linked chains. 1019 16

Acute inflammation induces changes in liver proteins with an increase in synthesis of positive acute-phase proteins such as alpha1-acid glycoprotein (alpha1-AGP) and a decrease in synthesis of negative acute-phase proteins such as albumin. This is associated with muscle wasting, mediated by increased proteolysis and impaired protein synthesis. As protein metabolism can be altered in other situations (malnutrition, growth) by the form of the dietary nitrogen, we studied the effects of the molecular form of nitrogen on liver and skeletal muscle adaptation, looking at gene expression for two acute-phase proteins (albumin and alpha1-AGP) and a number of muscle proteins (alpha1-actin, ubiquitin and C9 proteasome subunit). Two groups of 24 Wistar rats (250 g) were injected S/C with 0.125 ml turpentine/rat and were fed one of two liquid diets. These diets had caloric, nitrogen, carbohydrate and lipid content but differed in the molecular form of the nitrogen source (whole protein [WP] versus peptide hydrolysate [PH]). Liver and muscle adaptation were studied at 18, 42 or 66 h after turpentine injection. Weight, deoxyribonucleic acid and protein content of the liver were significantly higher with the WP diet than with the PH diet at 42 h and 66 h. There was more alpha1-AGP messenger ribonucleic acid (mRNA) at 18 h and less albumin mRNA at 42 h. Thus, the PH diet causes a more rapid increase in alpha1-AGP mRNA content and a smaller decrease in albumin mRNA content after turpentine injection than the WP diet. However, the changes in plasma acute-phase proteins (albumin and alpha1-AGP) were similar with the two diets. In skeletal muscle, there was no change in mRNA levels for the C9 proteasome subunit at any time point with both diets compared to the controls. However, there were greater ubiquitin mRNA levels at 18|h and less alpha-actin mRNA levels at 18 h, 42 h and 66 h following turpentine injection in the two dietary groups than in the controls. These results suggest that the molecular form of nitrogen ingested regulates hepatic gene transcription or mRNA stability of acute-phase proteins, during the early period of inflammation, but did not affect the expression of muscle proteins, which was altered by turpentine injection. Post-transcriptional control of acute-phase protein genes may contribute to the maintenance of similar plasma levels.
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PMID:Effects of alimentary whole proteins versus their small peptide hydrolysates on liver and skeletal muscle during the acute inflammation phase in the rat. 1020 35

Fusarium venenatum (formerly Fusarium graminearum) JeRS 325 produces heterologous glucoamylase (GAM) under the regulation of a Fusarium oxysporum alkaline (trypsin-like) protease promoter. The glucoamylase gene was used as a reporter gene to study the effects of ammonium and pH on GAM production under the control of the alkaline protease promoter. Between pH 4.0 and 5.8, GAM production in glucose-limited chemostat cultures of JeRS 325 grown at a dilution rate of 0.10 h-1 (doubling time, 6.9 h) on (NH4)2SO4 medium increased in a linear manner with increase in pH. However, at pH 4.0 and below GAM production was almost completely repressed in glucose-limited chemostat cultures grown on (NH4)2SO4 or NaNO3 medium. Thus GAM production in JeRS 325 is regulated by culture pH, not by the nature of the nitrogen source in the medium. The difficulty of using unbuffered medium when investigating putative ammonium repression is also shown. The study demonstrates the potential for use of the alkaline protease promoter in F. graminearum for the production of recombinant proteins in a pH dependent man ner.
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PMID:pH regulation of recombinant glucoamylase production in Fusarium venenatum JeRS 325, a transformant with a Fusarium oxysporum alkaline (trypsin-like) protease promoter. 1039 74

Acute renal failure was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow and urinary osmolality were measured to test the effectiveness of drugs. Renal function in untreated acute renal failure rats markedly decreased at 24 h after reperfusion. The administration of PSI, N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, a proteasome inhibitor, at a dose of 1 mg/kg before the occlusion abolished the decreases in the renal function of acute renal failure rats. Calpeptin (1 mg/kg), a calpain inhibitor, attenuated the deterioration of renal function to the same extent as 0.1 mg/kg PSI, but no significant difference was observed between the untreated and calpeptin-treated acute renal failure groups. Histopathological examination of the kidney of untreated acute renal failure rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were significantly suppressed by PSI (1 mg/kg) treatment. In contrast, calpeptin, at the same dose, was ineffective against the development of renal lesions. These results suggest that proteasome participates in the pathogenesis of ischemic acute renal failure. Thus, proteasome may be a potential target for the identification of agents that may be useful in the treatment of diseases whose etiology is dependent on ischemia/reperfusion.
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PMID:Proteasome participates in the pathogenesis of ischemic acute renal failure in rats. 1061 18

Uremia induces substantial changes in protein metabolism. The branched-chain amino acids serve as useful markers of these changes and their catabolism is increased in uremia, particularly in the presence of metabolic acidosis. Glucocorticoids also are involved in accelerating protein degradation, and the negative nitrogen balance which results in loss of lean body mass. Cellular mechanisms accounting for these changes include an up-regulation of the ubiquitin-proteasome pathway and branched-chain ketoacid dehydrogenase activity in muscle. A low insulin level also appears to play a permissive role in causing increased catabolism. These findings have important clinical implications because correction of the metabolic acidosis with alkali blunts these responses and improves nutritional status.
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PMID:Mechanisms of protein degradation: what do the rat studies tell us. 1085 69

Much has been learned from animal studies in chronic renal failure that is germane to clinical studies because animal models parallel human responses. Such studies have affirmed that correction of metabolic acidosis has a favorable effect on protein metabolism, nitrogen balance and growth. In the presence of metabolic acidosis, catabolism is increased in uremia. Glucocorticoids are involved in accelerating protein degradation in muscle, which results in loss of lean body mass, while a low insulin level appears to play a permissive role in accelerating increased catabolism. Cellular mechanisms mediating these changes include upregulation of the ubiquitin-proteasome pathway and branched-chain ketoacid dehydrogenase enzyme activity in muscle. Many of these findings from rat studies have been confirmed in human studies and have important clinical implications because correction of metabolic acidosis improves nutritional status and blunts the associated increase in protein catabolism.
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PMID:Twice-told tales of metabolic acidosis, glucocorticoids, and protein wasting: what do results from rats tell us about patients with kidney disease? 1092 49

Cancer is frequently associated with anorexia, weight loss, negative nitrogen balance, and skeletal-muscle wasting. Depletion of skeletal-muscle mass is critical to overall survival of the patient, can prolong rehabilitation to normal function after recovery, and decreases quality of life in a palliative-care setting. The biochemical and physiologic bases of cancer-associated muscle wasting have been most fully investigated in animal models. These studies provide evidence for suppressed protein synthesis and activated proteolysis in cancer-associated muscle wasting and indicate a need for both anabolic and anticatabolic therapies. Several humoral factors of host or tumor origin are implicated in altered muscle-protein metabolism, including cytokines, metabolites of arachidonic acid, and a proteolysis-inducing glycoprotein; their interrelationships are less well characterized. Several catabolic mediators may share common downstream mechanisms because they ultimately activate the ATP-, ubiquitin-, and proteasome-dependent intracellular proteolytic system. Although important gaps in our current understanding remain, data available from animal studies can be used as a basis to develop relevant studies in human subjects.
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PMID:Regulation of skeletal-muscle-protein turnover in cancer-associated cachexia. 1105 10

The objectives of this study were (1) to assess the role of a proteasome-dependent proteolytic pathway in the pathogenesis of acute renal failure (ARF) induced by ischemia-reperfusion, and (2) to determine the involvement of this proteolytic pathway in the enhanced production of renal endothelin-1 (ET-1) in this model of ARF. ARF was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow, urinary osmolality and fractional excretion of sodium were measured to test the effectiveness of drugs used. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion. In addition, a marked increase in renal ET-1 content was evident in the ARF rats, compared to the sham-operated rats. Intraperitoneal injection of a proteasome inhibitor (PSI), N-benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal, at a dose of 1 mg/kg, 1 h before the clamping, significantly attenuated the renal function impairment in the ischemic ARF rats, and the effect was accompanied by a decrease in renal ET-1 content. On the other hand, a calpain inhibitor, calpeptin, had little effect at the same dose. These results suggest that a proteasome-dependent proteolytic pathway is involved in the enhanced production of ET-1 in the kidney and the consequent renal functional damage in ischemic ARF.
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PMID:Proteasome inhibition attenuates renal endothelin-1 production and the development of ischemic acute renal failure in rats. 1107 83


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