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)

Copper is found in all living organisms and is a crucial trace element in redox chemistry, growth and development. It is important for the function of several enzymes and proteins involved in energy metabolism, respiration, and DNA synthesis, notably cytochrome oxidase, superoxide dismutase, ascorbate oxidase, and tyrosinase. The major functions of copper-biological molecules involve oxidation-reduction reactions in which they react directly with molecular oxygen to produce free radicals. Therefore, copper requires tightly regulated homeostatic mechanisms to ensure adequate supplies without any toxic effects. Overload or deficiency of copper is associated, respectively, with Wilson disease (WD) and Menkes disease (MD), which are of genetic origin. Researches on Menkes and Wilson disorders have provided useful insights in the field of copper homeostasis and in particular into the understanding of intracellular trafficking and distribution of copper at molecular levels. Therapies based on metal supplementation with copper histidine or removal of copper excess by means of specific copper chelators are currently effective in treating MD and WD, respectively. Copper chelation therapy is now attracting much attention for the investigation and treatment of various neurodegenerative disorders such as Alzheimer, Parkinson and CreutzfeldtJakob. An excess of copper appears to be an essential co-factor for angiogenesis. Moreover, elevated levels of copper have been found in many types of human cancers, including prostate, breast, colon, lung, and brain. On these basis, the employment of copper chelators has been reported to be of therapeutic value in the treatment of several types of cancers as anti-angiogenic molecules. More recently, mixtures of copper chelators with copper salts have been found to act as efficient proteasome inhibitors and apoptosis inducers, specifically in cancer cells. Moreover, following the worldwide success of platinum(II) compounds in cancer chemotherapy, several families of individual copper complexes have been studied as potential antitumor agents. These investigations, revealing the occurrence of mechanisms of action quite different from platinum drugs, head toward the development of new anticancer metallodrugs with improved specificity and decreased toxic side effects.
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PMID:Copper in diseases and treatments, and copper-based anticancer strategies. 1962 97

Neurodegenerative disorders share common features comprising aggregation of misfolded proteins, failure of the ubiquitin-proteasome system, and increased levels of metal ions in the brain. Protein aggregates within affected cells often contain ubiquitin, however no report has focused on the aggregation propensity of this protein. Recently it was shown that copper, differently from zinc, nickel, aluminum, or cadmium, compromises ubiquitin stability and binds to the N-terminus with 0.1 micromolar affinity. This paper addresses the role of copper upon ubiquitin aggregation. In water, incubation with Cu(II) leads to formation of spherical particles that can progress from dimers to larger conglomerates. These spherical oligomers are SDS-resistant and are destroyed upon Cu(II) chelation or reduction to Cu(I). In water/trifluoroethanol (80:20, v/v), a mimic of the local decrease in dielectric constant experienced in proximity to a membrane surface, ubiquitin incubation with Cu(II) causes time-dependent changes in circular dichroism and Fourier-transform infrared spectra, indicative of increasing beta-sheet content. Analysis by atomic force and transmission electron microscopy reveals, in the given order, formation of spherical particles consistent with the size of early oligomers detected by gel electrophoresis, clustering of these particles in straight and curved chains, formation of ring structures, growth of trigonal branches from the rings, coalescence of the trigonal branched structures in a network. Notably, none of these ubiquitin aggregates was positive to tests for amyloid and Cu(II) chelation or reduction produced aggregate disassembly. The early formed Cu(II)-stabilized spherical oligomers, when reconstituted in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomes and in POPC planar bilayers, form annular and pore-like structures, respectively, which are common to several neurodegenerative disorders including Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, and prion diseases, and have been proposed to be the primary toxic species. Susceptibility to aggregation of ubiquitin, as it emerges from the present study, may represent a potential risk factor for disease onset or progression while cells attempt to tag and process toxic substrates.
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PMID:Copper-triggered aggregation of ubiquitin. 1975 45

We have previously reported that when mixed with copper, 8-hydroxyquinoline (8-OHQ) and its analog clioquinol (CQ) inhibited the proteasomal activity and proliferation in cultured human cancer cells. CQ treatment of high-copper-containing human tumor xenografts also caused cancer suppression, associated with proteasome inhibition in vivo. However, the nature of the copper dependence of these events has not been elucidated experimentally. In the current study, using chemical probe molecules that mimic the structures of 8-OHQ and CQ, but have no copper-binding capability, we dissected the complex cellular processes elicited by 8-OHQ-Cu and CQ-Cu mixtures and revealed that copper binding to 8-OHQ or CQ is required for transportation of the copper complex into human breast cancer cells and the consequent proteasome-inhibitory, growth-suppressive, and apoptosis-inducing activities. In contrast, the non-copper-binding analogs of 8-OHQ or CQ blocked the very first step-copper binding-in this chain of events mediated by 8-OHQ-Cu or CQ-Cu.
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PMID:Tumor cellular proteasome inhibition and growth suppression by 8-hydroxyquinoline and clioquinol requires their capabilities to bind copper and transport copper into cells. 1980 36

Compounds that bind metals such as copper and zinc have many biological activities, including the ability to induce apoptosis in cancer cells. Although some of these compounds have been considered to act as chelators of metals, decreasing their bioavailability, others increase intracellular metal concentrations. We review recent work regarding the recognition of the biological effects of metal ionophores with different structures, particularly with regard to their actions upon cancer cells focusing on dithiocarbamates, pyrithione, and the 8-hydroxyquinoline derivative, clioquinol. We provide a biologically based classification of metal-binding compounds that allows an experimental distinction between chelators and ionophores that can be readily used by biologists, which may lead to further study and classification of metal-binding drugs. Metal ionophores may kill cancer cells by a number of mechanisms, including lysosomal disruption and proteasome inhibition, and likely others. Because some of these compounds have been safely administered to animals and humans, they have the potential to become clinically useful anticancer agents.
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PMID:Metal ionophores - an emerging class of anticancer drugs. 1985 83

An elevated level of copper (Cu), which is necessary for the growth and metastasis of tumor cells, has been found in many types of cancer, including breast, prostate, lung and brain. Although its molecular basis is unclear, this tumor-specific Cu elevation has been proposed to be a novel target for developing selective anti-cancer therapies. We previously reported that 8-hydroxylquinoline (8-OHQ) is able to form a Cu complex that inhibits the proteasome and induces apoptosis in cultured cancer cells. Toward the goal of discovering novel 8-OHQ analogs as potential anti-copper and anti-cancer drugs, in the current study we synthesized several 8-OHQ analogs and their copper complexes and evaluated their biological activities in human breast cancer cells. We report that when substitutions are made on the hydroxyl group of 8-OHQ, their copper mixtures have profound effects on the proteasome-inhibitory and apoptosis-inducing abilities in breast cancer MDA-MB-231 cells. In addition, the proteasome-inhibitory and apoptosis-inducing activities of 8-OHQ analog-copper mixtures are determined by both the polarity and position of the substituents. Finally, a synthetic complex of 8-OHQ analog-copper was able to inhibit the proteasome activity, induce cell death and suppress the growth selectively in breast cancer MDA-MB-231 cells, but not in normal immortalized human breast MCF-10A cells. Our results support the concept that human cancer cells and tissues, which contain an elevated copper level and are highly dependent on proteasome activity for their survival, should be sensitive to treatment with anti-copper drugs such as the novel 8-OHQ analogs described here.
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PMID:Novel 8-hydroxylquinoline analogs induce copper-dependent proteasome inhibition and cell death in human breast cancer cells. 1988 72

A proteomic analysis combining peptide de novo sequencing and BLAST analysis was used to identify novel proteins involved in copper tolerance in the marine alga Scytosiphon gracilis (Phaeophyceae). Algal material was cultivated in seawater without copper (control) or supplemented with 100 microg L(-1) for 4 days, and protein extracts were separated by two-dimensional gel electrophoresis (2-DE). From the proteins obtained in the copper treatment, 25 over-expressed, 5 under-expressed and 5 proteins with no changes as compared with the control, were selected for sequencing. Tryptic-peptides obtained from 35 spots were analyzed by capillary liquid chromatography and tandem mass spectroscopy (capLC/MS/MS), and protein identity was determined by BLASTP. We identified 19 over-expressed proteins, including a chloroplast peroxiredoxin, a cytosolic phosphomannomutase, a cytosolic glyceraldehyde-3-phosphate dehydrogenase, 3 ABC transporters, a chaperonine, a subunit of the proteasome and a tRNA synthase, among others. The possible involvement of these over-expressed proteins in buffering oxidative stress and avoiding metal uptake in S. gracilis exposed to copper excess is discussed taking into consideration the information available for other plant models.
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PMID:Proteomic analysis and identification of copper stress-regulated proteins in the marine alga Scytosiphon gracilis (Phaeophyceae). 1989 29

Copper plays a central role in conserved processes such as respiration, and in highly specialized processes, such as protein modification. The metalloprotease neprilysin (NEP) degrades a variety of bioactive peptides and is involved in many physiological processes. However, very little is known about the regulation of NEP activity. In the current study, we focused on the effect of Cu2+ on the enzymatic activity and protein stability of NEP. Using mouse neuroblastoma N2a cells, we found that the enzymatic activity of NEP was decreased by treatment with Cu2+ in a dose- and time-dependent manner. In our investigation of the mechanism by which Cu2+ downregulates NEP enzyme activity, we found that treatment with Cu2+ caused a decrease in the level of NEP as determined by Western blot analysis. Quantitative analysis of NEP mRNA with RT-PCR excluded the possibility that Cu2+ downregulates NEP protein at the gene transcription level. Moreover, specific proteasome inhibitors, MG132 and lactacystin, blocked the turnover of NEP, whereas inhibitors of lysosome had no significant effect, suggesting that Cu2+-induced degradation of NEP is via a proteasome pathway. Taken together, our data suggest that copper downregulates NEP activity through modulation of NEP protein degradation.
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PMID:Copper downregulates neprilysin activity through modulation of neprilysin degradation. 2006 35

Aging is accompanied by an intracellular accumulation of lipofuscin, a hydrophobic yellow-brownish material that accumulates especially in the lysosomal compartment, where it can be neither degraded nor exocytosed from the cell. The intracellular effects of accumulating lipofuscin are still a subject of speculation. In addition to the demonstrated inhibition of the proteasome, it was proposed that lipofuscin is cytotoxic because of its ability to incorporate transition metals such as copper and iron, resulting in a redox-active surface, able to catalyze the Fenton reaction. This characteristic of lipofuscin may contribute to an increased level of radical formation and oxidatively modified cellular components such as proteins, lipids, and RNA/DNA, which has been shown to be extensive in aging cells. In this study for the first time the lipofuscin-mediated formation of oxidants and the role of iron in this process are directly shown in a model of senescent fibroblasts, as well as in vitro with artificial lipofuscin. We demonstrate that this oxidant production is independent of mitochondria and has cytotoxic effects. The ability of lipofuscin to produce oxidants is dependent on the amount of transition metals incorporated. Although the amount of oxidants formed by cellular lipofuscin turned out to be moderate, it is chronic and thus lipofuscin is able to catalyze its own formation.
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PMID:Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. 2011 26

The metal ion copper is a cofactor essential for maintaining normal biological and physical functions in human beings. High copper levels have been found in variety of tumor tissues and are involved in tumor angiogenesis processes. The ubiquitin-proteasome system plays an important role in cell growth and apoptosis and has been shown as a novel target for cancer therapy. We previously reported that some organic copper complexes can inhibit the proteasomal chymotrypsin-like activity and induce apoptosis in human cancer cells and xenograft models. In the current study, we investigated the effect of oxidation status of copper, Cu(I) or Cu(II), on inhibition of proteasome activity, induction of apoptosis, and induction of reactive oxygen species (ROS) in human cancer cells. We report four major findings here: i) both Cu(I) and Cu(II) could inhibit the chymotrypsin-like activity of purified 20S proteasome, but Cu(I) was more potent than Cu(II), ii) purified 20S proteasome protein was able to reduce Cu(II) to Cu(I), suggesting that Cu(I) is the oxidation status of copper that directly reacts with the proteasome, iii) when complexed with the copper ligand neocuproine, Cu(I) showed higher ability to induce ROS production in cancer cells, compared with Cu(II), iv) addition of a ROS scavenger in the cancer cell culture-blocked copper-induced ROS generation, but did not overcome copper-mediated proteasome-inhibitory and cell death-inducing events, demonstrating the ROS-independent proteasome-inhibitory property of copper complexes.
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PMID:Molecular study on copper-mediated tumor proteasome inhibition and cell death. 2051 99

Copper is an essential element for multiple biological processes. Its concentration is elevated to a very high level in cancer tissues for promoting cancer development through processes such as angiogenesis. Organic chelators of copper can passively reduce cellular copper and serve the role as inhibitors of angiogenesis. However, they can also actively attack cellular targets such as proteasome, which plays a critical role in cancer development and survival. The discovery of such molecules initially relied on a step by step synthesis followed by biological assays. Today high-throughput chemistry and high-throughput screening have significantly expedited the copper-binding molecules discovery to turn "cancer-promoting" copper into anti-cancer agents.
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PMID:Turning tumor-promoting copper into an anti-cancer weapon via high-throughput chemistry. 2058 23


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