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)

Regulated proteolysis by the ubiquitin pathway has been implicated in control of the cell cycle, transcriptional activation, cell fate and growth, and synaptogenesis. The ubiquitin-proteasome system is involved in synaptic plasticity and is proposed to be part of a molecular switch that converts short-term synaptic potentiation to long-term changes in synaptic strength. In Aplysia, a component of the ubiquitin system termed ubiquitin C-terminal hydrolase (Ap-Uch) has been shown to be essential for long-term facilitation. To examine whether Uch plays a role in learning, memory, and synaptic plasticity in mammals, we have analyzed mice homozygous for a targeted mutation in ubiquitin C-terminal hydrolase L3 (Uchl3), an orthologue of Ap-Uch. Mice homozygous for the mutation in Uchl3 are viable, with no obvious developmental, histological, or fertility abnormalities. We demonstrate that Uchl3-/- mice have a significant learning deficit relative to wild type littermates in the spatial version of the Morris water maze and the 8-arm radial maze. Further, the impaired performance in the 8-arm radial maze of Uchl3-/- mice is due to significantly increased working memory errors. Examination of hippocampal long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory storage, revealed no significant differences in LTP in hippocampal slices from Uchl3-/- mice. Our results suggest a novel role for ubiquitin C-terminal hydrolase enzymes in mammals in spatial learning and working memory.
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PMID:Ubiquitin C-terminal hydrolase L3 (Uchl3) is involved in working memory. 1588 48

Aromatic hydrocarbons readily penetrate the skin on dermal exposure, leading to irritation, inflammation and cytotoxicity. The effects of short-term occlusive and long-term unocclusive dermal exposure to benzene and xylene on the skin irritation response (transepidermal water loss (TEWL), skin moisture content and erythema) and cytokine/chemokine expression (interleukin-1alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1)) were investigated in hairless rats. Occlusive dermal exposure was carried out with 230 microL of the chemicals for 1 h using Hill top chambers. In unocclusive dermal exposure, 15 microL of the chemicals were applied to the skin every 2 h, for 8 h a day, for 4 days. The occlusive dermal exposure revealed a clear difference in the TEWL and erythema response of these chemicals (xylene>benzene) whereas unocclusive exposure revealed similar TEWL and erythema scores for both benzene and xylene. The expression of IL-1alpha was elevated 2.5- and 3.8-fold in response to occlusive and unocclusive exposure, respectively, vs control (P<0.01) for both the chemicals (benzene and xylene). Similarly, TNF-alpha levels were elevated about 2.4- and 6.0-fold as a result of occlusive and unocclusive exposure, respectively, vs control (P<0.01). These results show that unocclusive exposure induced significantly higher TNF-alpha expression than occlusive exposure (P<0.05). The MCP-1 expression in blood was slightly elevated compared with the control group, but this increase was not statistically significant (P>0.05). Similarly, MCP levels in skin were increased approximately 1.7- and 1.8-fold by occlusive and unocclusive exposure, respectively, compared with the control group (P<0.05). Our study demonstrates that the skin irritation profiles of benzene and xylene are similar and unocclusive long-term exposure to small amounts of these chemicals can induce more skin irritation and cytokine response than occlusive exposure.
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PMID:The effect of occlusive and unocclusive exposure to xylene and benzene on skin irritation and molecular responses in hairless rats. 1590 27

This study investigated the testicular changes in the rat induced by the nonspecific phosphodiesterase inhibitor, theophylline using magnetic resonance microscopy (MRM) and ubiquitin immunostaining techniques. In vivo T1- and T2-weighted images were acquired at 2 T under anesthesia. Increased signal observed in the theophylline-treated rats suggests that leakage of MRM contrast was occurring. In vivo MRM results indicate that day 16 testis displayed an increased T1-weighted water signal in the area of the seminiferous tubule that decreased by day 32. These findings were validated by histopathology, suggesting that in vivo MRM has the sensitivity to predict changes in testis and epididymal tissues. The participation of the ubiquitin system was investigated, using probes for various markers of the ubiquitin-proteasome pathway. MRM can be used to detect subtle changes in the vascular perfusion of organ systems, and the up-regulation/mobilization of ubiquitin-proteasome pathway may be one of the mechanisms used in theophylline-treated epididymis to remove damaged cells before storage in the cauda epididymis. The combined use of in vivo MRM and subsequent tissue or seminal analysis for the presence of ubiquitin in longitudinal studies may become an important biomarker for assessing testis toxicities drug studies.
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PMID:Reproductive cytotoxicity is predicted by magnetic resonance microscopy and confirmed by ubiquitin-proteasome immunohistochemistry in a theophylline-induced model of rat testicular and epididymal toxicity. 1607 14

A new and effective proteasome inhibitor, beta-lactam 3, has been accessed enantioselectively by multistep synthesis from the readily prepared intermediates 7 and 8 which were joined by a [2 + 2]-cycloaddition reaction to form the spiro beta-lactam 9 stereoselectively. The intermediate 9 was converted to 3 in seven steps and 30% overall yield. The beta-lactam 3 is stable for many days in water at pH 7, in contrast to the natural beta-lactones salinosporamide A (1) and omuralide (2). In common with 1 and 2, the beta-lactam 3 effectively inhibits the mammalian proteasome.
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PMID:Proteasome inhibition by a totally synthetic beta-lactam related to salinosporamide A and omuralide. 1626 99

Toxic organic compounds detected generally in source water could combine with chlorine and contribute significantly to chlorination disinfection by-products (CDBPs). The effects of pH on species distribution of CDBPs and the kinetics of chlorination were investigated using phenol as a model of ionizable toxic organic compounds in the pH range of 6.0-9.0. It was found that five chlorination products including 2-monochlorophenol (2-MCP), 4-monochlorophenol (4-MCP), 2,6-dichlorophenol (2,6-DCP), 2,4-dichlorophenol (2,4-DCP) and 2,4,6-trichlorophenol (TCP) were produced by successive chlorination substitution. MCP (2-MCP and 4-MCP) were the dominant products and phenol partly remained in acid media, while TCP and DCP (2,6-DCP and 2,4-DCP) were the main components in neutral and alkaline media. A steady equilibrium of phenol and its chlorination products was reached in 20-30 min in acid-, neutral- and slightly alkaline media, and was delayed to 60-180 min in alkaline media. The difference in properties between phenols and phenolates, and those between HOCl and ClO(-) should be considered simultaneously in explaining the effects of pH on the chlorination process with the theory of electrophilic substitution. These results show that pH plays an important regulating role in the species distribution of CDBPs and the kinetics of chlorination for ionizable toxic organic compounds in chlorination.
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PMID:Effects of pH on the chlorination process of phenols in drinking water. 1633 40

The body complex of the soybean seed (BCSS) was isolated from the single cells (27.2%) by a sequential procedure of autoclaving with water, cellulase digestion for the primary cell wall, pectinase digestion for the secondary cell wall, and defatting with hexane washing. Its characteristics were then investigated. The defatted BCSS (DBCSS) consisted of protein (76.5%) and mannose-rich carbohydrates (3.2%). Screening of the food-processing protease for the digestion of DBCSS was carried out, and a kind of alkaline protease was selected. The inner protein of DBCSS was easily extracted with 0.1 M sodium carbonate buffer, pH 10, and the insoluble shell of the body complex (SDBCSS) was left. SDBCSS consisted of hydrophobic amino acid-rich protein. SDBCSS was easily digested by the selected alkaline protease. SDBCSS was dissolved by boiling with sodium dodecyl sulfate-mercaptoethanol, and it was found to consist of a protein of approximately 3 kDa. The high enzymatic digestion including the selected protease for soybean seed and defatted soybean meal was carried out; both were extracted and digested with a yield of >99.5%. The final indigestible residue was found as paired hexagonal and filamentous organs of the soybean cells.
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PMID:Isolation and enzymatic digestion of body complex of soybean seed. 1636 90

Synthesis of Bz-Arg-Gly-NH(2) (N-benzoylargininylglycinamide) [a precursor dipeptide of RGDS (Arg-Gly-Asp-Ser)] catalysed by protease in water/organic co-solvent systems was studied. Starting substrates were N-benzoyl-L-arginine ethyl ester hydrochloride (acyl donor) and glycinamide (nucleophile). Acetonitrile was selected as the organic solvent. Alcalase, an industrial alkaline protease, was applied to the synthesis of the target dipeptide. The conditions of the synthesis reaction were optimized by examining the effects of several factors, including water content, temperature, pH, molar ratio of the substrates and reaction time, on the yield of Bz-Arg-Gly-NH(2). The optimum conditions were established to be pH 10.0, 45 degrees C, in acetonitrile/0.1 M Na(2)CO(3)/NaHCO(3) buffer system (90:10, v/v) for 1 h with a dipeptide yield of 82.9%.
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PMID:Synthesis of a precursor dipeptide of RGDS (Arg-Gly-Asp-Ser) catalysed by the industrial protease alcalase. 1642 Jan 89

The protease-catalyzed, kinetically controlled synthesis of a precursor dipeptide of RGDS, Z-Asp-Ser-NH2 in organic solvents was studied. Alcalase, an industrial alkaline protease, was used to catalyze the synthesis of the target dipeptide in water-organic cosolvents systems with Z-Asp-OMe as the acyl donor and Ser-NH2 as the nucleophile. Acetonitrile was selected as the organic solvent from acetonitrile, ethanol, methanol, DMF, DMSO, ethyl acetate, 2-methyl-2-propanol, and chloroform tested under the experimental conditions. The conditions of the synthesis reaction were optimized by examining the effects of several factors, including water content, temperature, pH, and reaction time on the Z-Asp-Ser-NH2 yields. The optimum conditions are pH 10.0, 35 degrees C, in acetonitrile/Na2CO3-NaHCO3 buffer system (85:15, v/v), 6 h, with a dipeptide yield of 75.5%.
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PMID:Alcalase-catalyzed, kinetically controlled synthesis of a precursor dipeptide of RGDS in organic solvents. 1642 41

Hypercalcemia associated with malignancies is reported in up to 20 to 30% of patients with cancer during the course of the disease, and points to a poor prognosis. Symptoms related to the central nervous system, as progressive mental impairment, stupor and coma, predominate. Alterations in kidney function (water-concentrating defect leading to polyuria) and gastrointestinal tract (anorexia, nausea, vomiting) corroborate to dehydration and a further increase in serum calcium. Cancer-induced hypercalcemia may be classified as: 1) local osteolytic hypercalcemia (LOH), due to marked increase in osteoclastic bone resorption in areas surrounding the malignant cells within the marrow space; 2) humoral hypercalcemia of malignancy, caused by the secretion of parathyroid hormone-related protein (PTHrP) by the malignant tumor; 3) ectopic hyperparathyroidism; 4) 1,25(OH)2 D-secreting tumors. Adequate control of hypercalcemia is necessary to give the patient time to respond to anti-cancer therapy. Volume expansion with saline will correct dehydration, improve glomerular filtration and increase urinary calcium excretion, which may be further stimulated by loop diuretics. Intravenous bisphosphonates are the most effective agents to control hypercalcemia, as they block osteoclastic osteolysis and also have antitumoral effects, decreasing bone metastases. New approaches to control the skeletal manifestations of malignancies are anti-PTHrP and anti-RANKL antibodies, osteoprotegerin, and also proteasome inhibitors in the case of multiple myeloma.
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PMID:[Hypercalcemia of malignancy: clinical features, diagnosis and treatment]. 1644 66

The crystal structures of the yeast 20S proteasome core particle (CP) in complex with Salinosporamides A (NPI-0052; 1) and B (4) were solved at <3 angstroms resolution. Each ligand is covalently bound to Thr1O(gamma) via an ester linkage to the carbonyl derived from the beta-lactone ring of the inhibitor. In the case of 1, nucleophilic addition to the beta-lactone ring is followed by addition of C-3O to the chloroethyl group, giving rise to a cyclic ether. The crystal structures were compared to that of the omuralide/CP structure solved previously, and the collective data provide new insights into the mechanism of inhibition and irreversible binding of 1. Upon opening of the beta-lactone ring, C-3O assumes the position occupied by a water molecule in the unligated enzyme and hinders deacylation of the enzyme-ligand complex. Furthermore, the resulting protonation state of Thr1NH2 deactivates the catalytic N-terminus.
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PMID:Crystal structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in complex with the 20S proteasome reveal important consequences of beta-lactone ring opening and a mechanism for irreversible binding. 1660 49


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