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)

Chlorophenols, mainly used as biocides, are compounds with a wide spectrum of toxic effects, including teratogenic and carcinogenic actions. The aim of this study was to examine possible 4-monochlorophenol (4-MCP) toxicity related to metabolic pathways, which may implicate semiquinones and reactive oxygen species (ROS), in human Hep G2 cells. The effects of 4-MCP were performed through cytotoxicity assays (viability, ATP level), metabolic activities (4-MCP intracellular concentration, NADPH cytochrome P-450 reductase (Cyt P-450 red.) and glutathione-S-transferase activities, CYP 3A7 mRNA expression) and oxidative stress (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities, glutathione status, malondialdehyde concentration, CYP 2E1 mRNA expression). According to the literature, in this work Hep G2 cells were incubated in the continuous presence of 4-MCP at 350 microM over 24 or 48 h. Results showed statistically significant decreases in ATP levels (24 or 48 h, P < 0.05) versus controls. The 4-MCP intracellular concentrations increased as early as 8-24 h and then decreased (P < 0.01). Decreases in Cyt. P-450 red. (24 h, P < 0.05), catalase (24 h, P < 0.05; 48 h, P < 0.01), glutathione peroxidase activities (48 h, P < 0.05) and reduced glutathione concentrations (48 h, P < 0.05) were observed. In addition, exposure to 4-MCP increased mRNA expressions of CYP 3A7 (24 h, P < 0.05; 48 h, P < 0.01) and CYP 2E1 (24 h, P < 0.01) versus controls. Taken together, these results suggest that 4-MCP metabolites could induce oxidative stress conditions in Hep G2 cells.
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PMID:Involvement of oxidative sress in the toxicity of 4-monochlorophenol in Hep G2 cells in culture. 1266 55

Proline is an important component of salt-stress responses of plants. In this study the role of proline as part of salt-stress signalling in the desert plant Pancratium maritimum L. was examined. The data showed that salt-stress brought about a reduction of the growth and protein content, particularly at 300 mM NaCl, that was significantly increased by exogenous proline. In the leaves, salt-stress up-regulated ubiquitin, a small protein targeting damaged proteins for degradation via the proteasome, up to 5-fold as detected by western blotting. This change was also affected by proline even in non-stressed leaves. However, salt-stress resulted in a decrease in the amount of ubiquitin-conjugates, particularly in the roots, and this effect was reversed by exogenous proline. Severe salt-stress resulted in an inhibition of the antioxidative enzymes catalase and peroxidase as revealed by spectrophotometric assays and activity gels, but the activity of these enzymes was also maintained significantly higher in the presence of proline. Salt-stress also up-regulated several dehydrin proteins, analysed by western blotting, even in non-stressed plants. It is concluded that proline improves the salt-tolerance of Pancratium maritimum L. by protecting the protein turnover machinery against stress-damage and up-regulating stress protective proteins.
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PMID:Proline induces the expression of salt-stress-responsive proteins and may improve the adaptation of Pancratium maritimum L. to salt-stress. 1451 86

Lifelong caloric restriction (CR) reduces the rate of mitochondrial oxidant production and the accumulation of oxidized proteins and prevents some of the age-associated decline in 20S proteasome activity. However, few studies have investigated how rapidly the beneficial effects of CR take place. We investigated whether 2 mo of CR in 6-mo-old rats would be of sufficient duration to elicit these beneficial changes. Mitochondrial oxidant production was significantly diminished in the CR rats compared with the ad libitum-fed animals. Short-term CR also caused a significant decrease in mitochondrial superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities, but there were no differences in cytosolic SOD and GPX activities, whereas mitochondrial and cytosolic catalase (CAT) activity was increased with CR. However, protein carbonyl content was significantly elevated in both the mitochondrial and cytosolic fractions from CR rats. Of the three major 20S proteasome activities (chymotrypsin-like, trypsin-like, and peptidylglutamyl-peptide hydrolase), the peptidylglutamyl-peptide hydrolase activity was significantly elevated in the CR animals, possibly because of the fact that there were more oxidized proteins to be degraded. Although fewer oxidants were produced in the CR animals, it is possible that the ability to scavenge oxidants was transiently suppressed because of the reduction in mitochondrial antioxidant enzyme activities, which may explain the observed increases in carbonyl content.
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PMID:Short-term CR decreases cardiac mitochondrial oxidant production but increases carbonyl content. 1459 35

It has been shown that large doses of acetaminophen can result in increased degradation of the hepatic cytochrome P450 (CYP) enzymes in vivo; however, the proteolytic pathways have not been identified. We found that incubating transfected HepG2 cells that express CYP3A4 or a reconstituted microsomal model containing human liver microsomes and cytosol, high concentrations of acetaminophen could induce a dose- and time-dependent degradation of CYP3A4. In the microsomal model the degradation could be blocked and augmented by the presence of catalase and superoxide dismutase, respectively. Tocopherol could also protect against the acetaminophen-induced degradation. However, lipid peroxidation assays showed no significant increases in lipid peroxidation products nor was there any protection by propyl gallate. Protease and proteasome inhibitors showed that the proteolytic process was mainly (85%) mediated by the lysosomal pathway, whereas a minor portion (15%) of the degradation was mediated by the proteasomal pathway. Both pepstatin A and anti-cathepsin D neutralizing antibody decreased acetaminophen-induced degradation of CYP3A4 in microsomal model systems. Pepstatin A also blocked the acetaminophen-induced degradation of the CYP3A4 in a transfected HepG2 cell line. Incubating the 3A4 cells in the presence of acetaminophen also increased cathepsin D content and activity. The lysosomal pathway, mainly mediated by cathepsin D, appears to be the major proteolytic pathway involved in the degradation of the P450 enzymes induced by toxic doses of acetaminophen.
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PMID:Characterization of the acetaminophen-induced degradation of cytochrome P450-3A4 and the proteolytic pathway. 1507 44

Bortezomib (1) is a potent first-in-class dipeptidyl boronic acid proteasome inhibitor employed in the treatment of patients with relapsed multiple myeloma where the disease is refractory to conventional lines of therapy. The potency of 1 is owed primarily to the presence of the boronic acid moiety, one which is suited to establish a tetrahedral intermediate with the active site N-terminal threonine residue of the proteasome. Hence, deboronation of 1 represents a deactivation pathway for this chemotherapeutic agent. Deboronation of 1 affords a near equal mixture of diastereomeric carbinolamide metabolites (M1/M2) and represents the principal metabolic pathway observed in humans. In vitro results from human liver microsomes and human cDNA-expressed cytochrome P450 enzymes (P450) indicate a role for P450 in the deboronation of 1. Use of 18O-labeled oxygen under controlled atmospheres confirmed an oxidative mechanism in the P450-mediated deboronation of 1, as 18O was found incorporated in both M1 and M2. Chemically generated reactive oxygen species (ROS), such as those generated as byproducts during P450 catalysis, were also found to deboronate 1 resulting in the formation of M1 and M2. Known to undergo efficient redox cycling, P450 2E1 was found to catalyze the deboronation of 1 predominantly to the carbinolamide metabolites M1 and M2, as well as to a pair of peroxycarbinolamides, 2 and 3. The presence of superoxide dismutase (SOD) and catalase prevented the deboronation of 1, thus, supporting the involvement of ROS in the P450 2E1-catalyzed deboronation reaction. The presence of SOD and catalase also protected 1 against P450 3A4-catalyzed deboronation, albeit to a lesser extent. The remaining deboronation activity observed in the P450 3A4 reaction may suggest the involvement of the more conventional activated enzyme-oxidants previously described for P450. Our present findings indicate that the oxidase activity of P450 (i.e., formation of ROS) represents a mechanism of deboronation.
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PMID:Oxidative deboronation of the peptide boronic acid proteasome inhibitor bortezomib: contributions from reactive oxygen species in this novel cytochrome P450 reaction. 1660 65

We set out to determine whether cellular hypoxia, via mitochondrial reactive oxygen species, promotes Na,K-ATPase degradation via the ubiquitin-conjugating system. Cells exposed to 1.5% O2 had a decrease in Na,K-ATPase activity and oxygen consumption. The total cell pool of alpha1 Na,K-ATPase protein decreased on exposure to 1.5% O2 for 30 hours, whereas the plasma membrane Na,K-ATPase was 50% degraded after 2 hours of hypoxia, which was prevented by lysosome and proteasome inhibitors. When Chinese hamster ovary cells that exhibit a temperature-sensitive defect in E1 ubiquitin conjugation enzyme were incubated at 40 degrees C and 1.5% O2, the degradation of the alpha1 Na,K-ATPase was prevented. Exogenous reactive oxygen species increased the plasma membrane Na,K-ATPase degradation, whereas, in mitochondrial DNA deficient rho(0) cells and in cells transfected with small interfering RNA against Rieske iron sulfur protein, the hypoxia-mediated Na,K-ATPase degradation was prevented. The catalase/superoxide dismutase (SOD) mimetic (EUK-134) and glutathione peroxidase overexpression prevented the hypoxia-mediated Na,K-ATPase degradation and overexpression of SOD1, but not SOD2, partially inhibited the Na+ pump degradation. Accordingly, we provide evidence that during hypoxia, mitochondrial reactive oxygen species are necessary to degrade the plasma membrane Na,K-ATPase via the ubiquitin-conjugating system.
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PMID:Hypoxia-mediated degradation of Na,K-ATPase via mitochondrial reactive oxygen species and the ubiquitin-conjugating system. 1661 3

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classical glycolytic enzyme that is involved in cellular energy production and has important housekeeping functions. We used the natural prooxidant and proatherogenic molecule oxidized low-density lipoprotein (OxLDL) to determine a potential link between OxLDL-promoted oxidative stress, GAPDH expression, and smooth muscle cell energy metabolism. OxLDL but not native LDL (nLDL) produced a 60% to 100% dose- and time-dependent reduction of GAPDH protein. OxLDL increased reactive oxygen species (ROS) formation, including rapid elevation of H2O2 levels. OxLDL decreased intracellular catalase expression, likely contributing to the increase in H2O2. Antioxidants, anti-CD36 receptor antibody, NADPH oxidase, or lipoxygenase blockers decreased OxLDL-specific ROS and prevented GAPDH downregulation. 12/15-Lipoxygenase or p47phox deficiency resulted in attenuation of GAPDH downregulation, but 5-lipoxygenase suppression had no effect. OxLDL or exogenous H2O2 oxidized GAPDH thiols, decreasing GAPDH protein half-life and increasing GAPDH sensitivity to proteasome-mediated protein degradation in vitro. OxLDL- or small interfering RNA-specific downregulation of GAPDH resulted in 65% reduction in glycolysis rate and 82% decrease in ATP levels. In conclusion, our data demonstrate that OxLDL downregulated GAPDH via a H2O2-dependent decrease in protein stability. GAPDH protein damage resulted in marked depletion of cellular ATP levels. Our data have important implications for understanding the metabolic effect of OxLDL on the vessel wall and mechanism of atherogenesis.
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PMID:Novel effect of oxidized low-density lipoprotein: cellular ATP depletion via downregulation of glyceraldehyde-3-phosphate dehydrogenase. 1677 34

We examined the ability of oxidation products of dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid (DOPAC) to inhibit proteasomal activity. Dopamine, DOPA, and DOPAC underwent tyrosinase-catalyzed oxidation to generate aminochrome, dopachrome, and furanoquinone, respectively. In these studies, the oxidation of dopamine by tyrosinase generated product(s) that inhibited the proteasome, and proteasomal inhibition correlated with the presence of the UV-visible spectrum of aminochrome. The addition of superoxide dismutase and catalase did not prevent proteasomal inhibition. The addition of NADH and the quinone reductase NAD(P)H:quinone oxidoreductase 1 (NQO1) protected against aminochrome-induced proteasome inhibition. Although NQO1 protected against dopamine-induced proteasomal inhibition, the metabolism of aminochrome by NQO1 led to oxygen uptake because of the generation of a redox-labile cyclized hydroquinone, further demonstrating the lack of involvement of oxygen radicals in proteasomal inhibition. DOPA underwent tyrosinase-catalyzed oxidation to form dopachrome, and similar to aminochrome, proteasomal inhibition correlated with the presence of a dopachrome UV-visible spectrum. The inclusion of NQO1 did not protect against proteasomal inhibition induced by dopachrome. Oxidation of DOPAC by tyrosinase generated furanoquinone, which was a poor proteasome inhibitor. These studies demonstrate that oxidation products, including cyclized quinones derived from dopamine and related compounds, rather than oxygen radicals have the ability to inhibit the proteasome. They also suggest an important protective role for NQO1 in protecting against dopamine-induced proteasomal inhibition. The ability of endogenous intermediates formed during dopaminergic metabolism to cause proteasomal inhibition provides a potential basis for the selectivity of dopaminergic neuron damage in Parkinson's disease.
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PMID:A potential role for cyclized quinones derived from dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid in proteasomal inhibition. 1679 May 33

Caulibugulones are novel but poorly characterized cytotoxic isoquinoline quinones and iminoquinones identified in extracts from the marine bryozoan Caulibugula intermis. We now report that the caulibugulones are selective in vitro inhibitors of the Cdc25 family of cell cycle-controlling protein phosphatases compared with either human vaccinia H1-related phosphatase (VHR) or tyrosine phosphatase 1B (PTP1B). The in vitro inhibition of Cdc25B by caulibugulone A was irreversible and attenuated by reducing agents or catalase, consistent with direct oxidation of the enzyme by reactive oxygen species. Mechanistically, caulibugulone A directly inhibited cellular Cdc25B activity, generated intracellular reactive oxygen species and arrested cells in both G1 and G2/M phases of the cell cycle. Caulibugulone A also caused the selective degradation of Cdc25A protein by a process that was independent of reactive oxygen species production, proteasome activity, and the Chk1 signaling pathway. Instead, caulibugulone A stimulated the phosphorylation and subsequent activation of p38 stress kinase, leading to Cdc25A degradation. Thus, caulibugulone inhibition of cellular Cdc25A and B phosphatases occurred through at least two different mechanisms, leading to pronounced cell cycle arrest.
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PMID:Independent mechanistic inhibition of cdc25 phosphatases by a natural product caulibugulone. 1701 77

Relationships among alpha-farnesene synthesis and oxidation, ethylene production and perception, antioxidative enzyme activities, and superficial scald development in fruit of three commercial apple cultivars were investigated at the biochemical and gene transcriptional levels. Scald-susceptible Cortland and Law Rome and scald-resistant Idared apples were untreated or treated with the ethylene action inhibitor 1-methylcyclopropene (1-MCP) and stored for up to 25 weeks at 0.5 degrees C. Separate blushed (red) and unblushed (green) peel tissue samples were taken at harvest and after 2, 4, 6, 10, 15, 20, and 25 weeks of storage. Large increases in peel tissue concentrations of alpha-farnesene and its conjugated trienol (CTol) oxidation products occurred in untreated Cortland and Law Rome and were about 4-9-fold greater than those in Idared. In both Cortland and Law Rome, accumulation of CTols in green peel was nearly twice that in red peel. 1-MCP treatment delayed and attenuated alpha-farnesene and CTol accumulation in each cultivar. Activities of peroxidase (POX) and catalase (CAT) were lower in red peel than in green peel, with the exception of CAT in Law Rome, whereas no effects of 1-MCP on enzyme activities were detected except for Cortland. In control fruit, internal ethylene concentrations (IECs) increased during the first 4-6 weeks to reach highest levels in Cortland, intermediate levels in Law Rome, and low levels in Idared. In 1-MCP-treated fruit, IECs increased gradually to modest levels by 25 weeks in Cortland and Law Rome but were almost nil in Idared. Expression patterns of the alpha-farnesene synthase gene MdAFS1, the ethylene receptor gene MdERS1, and the ethylene biosynthetic genes MdACS1 and MdACO1 were generally in accord with the patterns of alpha-farnesene and ethylene production. In particular, MdAFS1 and MdACS1 showed similar patterns of expression in each cultivar. Among the controls, transcript levels increased more rapidly in Cortland and Law Rome than in Idared during the first few weeks of storage. In 1-MCP-treated fruit, transcript abundance in Cortland and Law Rome rose to untreated control levels after 10-15 weeks but remained low in Idared. Scald symptoms were restricted to unblushed skin, and the incidence in controls after 25 weeks was nearly 100% in Cortland and Law Rome compared with 1% in Idared. 1-MCP treatment reduced scald incidence to 14, 3, and 0% in Cortland, Law Rome, and Idared, respectively. Overall, the results support the proposed role of CTols in scald induction and indicate that alpha-farnesene synthesis is tightly regulated by ethylene. However, gene transcription alone does not account for the big differences in ethylene and alpha-farnesene production in Cortland, Law Rome, and Idared apples.
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PMID:Ethylene and alpha-farnesene metabolism in green and red skin of three apple cultivars in response to 1-methylcyclopropene (1-MCP) treatment. 1753 20


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