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)

1. Parkinson's disease (PD) is considered to be an aging-related neurodegeneration of catecholamine (CA) systems [typically A9 dopamine (DA) neurons in the substantia nigra and A6 noradrenaline (NA) neurons in the locus coeruleus]. The main symptom is movement disorder caused by a DA deficiency at the nerve terminals of fibers that project from the substantia nigra to the striatum. Most PD is sporadic (sPD) without any hereditary history. sPD is speculated to be caused by some exogenous or endogenous substances that are neurotoxic toward CA neurons, which toxicity leads to mitochondrial dysfunction and subsequent oxidative stress resulting in the programmed cell death (apoptosis or autophagy) of DA neurons. 2. Recent studies on the causative genes of rare familial PD (fPD) cases, such as alpha-synuclein and parkin, suggest that dysfunction of the ubiquitin-proteasome system (UPS) and the resultant accumulation of misfolded proteins and endoplasmic reticulum stress may cause the death of DA neurons. 3. Activated microglia, which accompany an inflammatory process, are present in the nigro-striatum of the PD brain; and they produce protective or toxic substances, such as cytokines, neurotrophins, and reactive oxygen or nitrogen species. These activated microglia may be neuroprotective at first in the initial stage, and later may become neurotoxic owing to toxic change to promote the progression toward the death of CA neurons.4. All of these accumulating evidences on sPD and fPD points to a hypothesis that multiple primary causes of PD may be ultimately linked to a final common signal-transduction pathway leading to programmed cell death, i.e., apoptosis or autophagy, of the CA neurons.
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PMID:Cellular and molecular mechanisms of Parkinson's disease: neurotoxins, causative genes, and inflammatory cytokines. 1682 25

In Parkinson's disease (PD), the selective depletion of dopamine neurons in the substantia nigra, particular those containing neuromelanin (NM), is the characteristic pathological feature. The role of NM in the cell death of dopamine neurons has been considered either to be neurotoxic or neuroprotective, but the precise mechanism has never been elucidated. In human brain, NM is synthesized by polymerization of dopamine and relating quinones, to which bind heavy metals including iron. The effects of NM prepared from human brain were examined using human dopaminergic SH-SY5Y cells. It was found that NM inhibits 26S proteasome activity through generation of reactive oxygen and nitrogen species from mitochondria. The mitochondrial dysfunction was also induced by oxidative stress mediated by iron released from NM. NM accumulated in dopamine neurons in ageing may determine the selective vulnerability of dopamine neurons in PD.
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PMID:The effect of neuromelanin on the proteasome activity in human dopaminergic SH-SY5Y cells. 1701 19

Nitric oxide (NO) has been demonstrated to be the principal effector molecule mediating intracellular killing of Leishmania, both in vitro and in vivo. We investigated the type of cell death process induced by NO for the intracellular amastigote stage of the protozoa Leishmania. Specific detection methods revealed a rapid and extensive cell death with morphological features of apoptosis in axenic amastigotes exposed to NO donors, in intracellular amastigotes inside in vitro - activated mouse macrophages and also in activated macrophages of regressive lesions in a leishmaniasis-resistant mouse model. We extended our investigations to the dog, a natural host-reservoir of Leishmania parasites, by demonstrating that co-incubation of infected macrophages with autologous lymphocytes derived from dogs immunised with purified excreted-secreted antigens of Leishmania resulted in a significant NO-mediated apoptotic cell death of intracellular amastigotes. From the biochemical point of view, NO-mediated Leishmania amastigotes apoptosis did not seem to be controlled by caspase activity as indicated by the lack of effect of cell permeable inhibitors of caspases and cysteine proteases, in contrast to specific proteasome inhibitors, such as lactacystin or calpain inhibitor I. Moreover, addition of the products of two NO molecular targets, cis-aconitase and glyceraldehyde-3-phosphate dehydrogenase, also had an inhibitory effect on the cell death induced by NO. Interestingly, activities of these two enzymes plus 6-phosphogluconate dehydrogenase, parasitic enzymes involved in both glycolysis and respiration processes, are overexpressed in amastigotes selected for their NO resistance. This review focuses on cell death of the intracellular stage of the pathogen Leishmania induced by nitrogen oxides and gives particular attention to the biochemical pathways and the molecular targets potentially involved. Questions about the role of Leishmania amastigotes NO-mediated apoptosis in the overall infection process are raised and discussed.
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PMID:Phenotypical characteristics, biochemical pathways, molecular targets and putative role of nitric oxide-mediated programmed cell death in Leishmania. 1701 62

The molecular bases of organic nitrogen (N) metabolism in arbuscular mycorrhizal (AM) fungi remain so far largely unexplored. To isolate genes responsive to low versus high organic N concentrations, the techniques of suppressive subtractive hybridization (SSH) and reverse Northern dot blot were performed on extraradical structures of the AM fungus Glomus intraradices grown on carrot hairy roots. This approach allowed the identification of 32 up-regulated and 2 down-regulated genes following a 48-h treatment with 2 microM of an amino acid pool (leucine, alanine, asparagine, lysine, tyrosine). The expression profile of eight genes was further confirmed by semi-quantitative and real-time RT-PCR. The majority of the sequences showed no significant similarity to proteins in databases. The other responsive genes code for putative glyoxal oxidases, transcription factors, a subunit of the 20S proteasome, a protein kinase and a Ras protein. This novel set of data indicates that G. intraradices extraradical structures perceive organic N limitation in the surrounding environment leading to a response at transcriptional level and supports the role of N as signalling molecule in AM fungi.
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PMID:A limiting source of organic nitrogen induces specific transcriptional responses in the extraradical structures of the endomycorrhizal fungus Glomus intraradices. 1706 Oct 94

In a previous screen for Mycobacterium tuberculosis mutants that are hypersusceptible to reactive nitrogen intermediates (RNI), two genes associated with the M. tuberculosis proteasome were identified. One of these genes, pafA (proteasome accessory factor A), encodes a protein of unknown function. In this work, we determined that pafA is in an operon with two additional genes, pafB and pafC. In order to assess the contribution of these genes to RNI resistance, we isolated mutants with transposon insertions in pafB and pafC. In contrast to the pafA mutant, the pafB and pafC mutants were not severely sensitized to RNI, but pafB and pafC were nonetheless required for full RNI resistance. We also found that PafB and PafC interact with each other and that each is likely required for the stability of the other protein in M. tuberculosis. Finally, we show that the presence of PafA, but not PafB or PafC, regulates the steady-state levels of three proteasome substrates. Taken together, these data demonstrate that PafA, but not PafB or PafC, is critical for maintaining the steady-state levels of known proteasome substrates, whereas all three proteins appear to play a role in RNI resistance.
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PMID:Characterization of the proteasome accessory factor (paf) operon in Mycobacterium tuberculosis. 1727 63

Nitrosative and oxidative stress, associated with the generation of excessive reactive oxygen or nitrogen species, are thought to contribute to neurodegenerative disorders. Many such diseases are characterized by conformational changes in proteins that result in their misfolding and aggregation. Accumulating evidence implies that at least two pathways affect protein folding: the ubiquitin-proteasome system (UPS) and molecular chaperones. Normal protein degradation by the UPS can prevent accumulation of aberrantly folded proteins. Molecular chaperones - such as protein-disulfide isomerase, glucose-regulated protein 78, and heat shock proteins - can provide neuroprotection from aberrant proteins by facilitating proper folding and thus preventing their aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Here, we present evidence for the hypothesis that nitric oxide contributes to degenerative conditions by S-nitrosylating specific chaperones or UPS proteins that would otherwise prevent accumulation of misfolded proteins.
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PMID:Molecular mechanisms of nitrosative stress-mediated protein misfolding in neurodegenerative diseases. 1745 43

The kidney undergoes hypertrophy under conditions that paradoxically cause a loss of lean body mass, such as diabetes, acidosis, and chronic kidney disease. What unique mechanisms account for kidney growth during negative nitrogen balance? One adaptation is that renal tubular cells substantially decrease protein breakdown during kidney cell growth. In this review, we discuss how acidosis and diabetes reduce protein breakdown within the kidney and the intracellular signaling pathways that may regulate protein metabolism. Our results suggest that in cell culture models and in acute diabetes, kidney cells specifically reduce protein breakdown by the lysosomal pathway of chaperone-mediated autophagy. This differs from the activation of proteolysis by the ubiquitin-proteasome system in muscle in acute diabetes and uremia. A shared signaling pathway regulates protein breakdown in both kidney and skeletal muscle, namely, phosphatidylinositol-3 kinase signaling. Diabetes mellitus activates signaling through this pathway in the kidney while down-regulating it in skeletal muscle. We conclude that similar signaling pathways may regulate distinct proteolytic pathways in different tissues.
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PMID:Kidney growth during catabolic illness: what it does not destroy makes it grow stronger. 1746 48

Calcium-alginate immobilization method for the production of alkaline protease by Bacillus licheniformis NCIM-2042 was optimized statistically. Four variables, such as sodium-alginate concentration, calcium chloride concentration, inoculum size and agitation speed were optimized by 2(4) full factorial central composite design and subsequent analysis and model validation by a second-order regression equation. Eleven carbon, 11 organic nitrogen and seven inorganic nitrogen sources were screened by two-level Plackett-Burman design for maximum alkaline protease production by using optimized immobilized conditions. The levels of four variables, such as Na-alginate 2.78%; CaCl(2), 2.15%; inoculum size, 8.10% and agitation, 139 rpm were found to be optimum for maximal production of protease. Glucose, soybean meal and ammonium sulfate were resulted in maximum protease production at 644 U/ml, 720 U/ml, and 806 U/ml when screened for carbon, organic nitrogen and inorganic nitrogen sources, respectively, using optimized immobilization conditions. Repeated fed batch mode of operation, using optimized immobilized conditions, resulted in continuous operation for 12 cycles without disintegration of beads. Cross-sectional scanning electron microscope images have shown the growth pattern of B. licheniformis in Ca-alginate immobilized beads.
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PMID:Evaluation of various parameters of calcium-alginate immobilization method for enhanced alkaline protease production by Bacillus licheniformis NCIM-2042 using statistical methods. 1764 99

Exposure to inflammatory agents or cytokines causes the suppression of cytochrome P450 (CYP) enzyme activities and expression in liver and primary hepatocyte cultures. We showed previously that phenobarbital-induced CYP2B protein is down-regulated in primary cultures of rat hepatocytes after exposure to bacterial endotoxin (lipopolysaccharide) in a nitric oxide (NO) -dependent manner. In this study, we found that CYP2B proteins in primary rat hepatocyte cultures were suppressed >60% after 6 h of treatment with interleukin-1beta (IL-1). This effect was NO-dependent, and treatment of cells with the NO donors (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl) aminodiazen-1-ium-1,2-diolate (NOC-18), S-nitrosoglutathione, and S-nitroso-N-acetylpenicillamine also suppressed CYP2B proteins. However, the down-regulation by IL-1 was insensitive to inhibition of cGMP-dependent protein kinases. The down-regulation by IL-1 or NO donors was abolished by treatments with the proteasome inhibitors MG132 and lactacystin that did not affect NO production. The calpain inhibitor E64-d or the lysosomal protease inhibitors NH(4)Cl and chloroquine did not attenuate the down-regulation of CYP2B by IL-1. Treatment of HeLa cells expressing c-Myc-tagged CYP2B1 with NOC-18 down-regulated its expression and enhanced its ubiquitination. Treatment of rat liver microsomes with S-nitrosoglutathione caused S-nitrosylation of CYP2B protein and enhanced the ubiquitination pattern of CYP2B compared with unmodified CYP2B in an in vitro ubiquitination assay. These data are consistent with the hypothesis that NO-dependent CYP2B ubiquitination and proteasomal degradation are dependent on protein modification by reactive nitrogen species.
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PMID:Nitric oxide-dependent proteasomal degradation of cytochrome P450 2B proteins. 1799 47

Mitochondria are a major intracellular source of free radicals and related oxidants. It is generally agreed that the mitochondrial production of such reactive oxygen and nitrogen species increases with age. Antioxidant systems in the mitochondria play an important role in limiting the amount of oxidative damage to tolerable levels. The Lon protease degrades oxidatively modified proteins in the mitochondrial matrix, a function similar to that of the 20S proteasome in the cytoplasm. Recently it was shown that inactive aconitase, a preferential substrate for the Lon protease, might be involved in the maintenance of the mitochondrial genome. Lon protease expression and activity declines with age, which may contribute to the accumulation of the oxidatively modified protein aggregates typically observed in aging and diseased cells. In addition, Lon has multiple functions, such as DNA binding and chaperone activity, for the assembly of respiratory complexes in the Electron Transport Chain. Taken together, Lon and aconitase may be key players in the maintenance of mitochondrial homeostasis under conditions of stress, and (partial) compromise of their function may contribute to both aging and degenerative diseases.
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PMID:Importance of the lon protease in mitochondrial maintenance and the significance of declining lon in aging. 1805 57


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