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)

Glutamatergic hyperactivity, associated with Ca2+ influx and consequent production of nitric oxide (NO), is potentially involved in both normal brain aging and age-related neurodegenerative disorders. Many neurodegenerative diseases are characterized by conformational changes in proteins that result in their misfolding and aggregation. Normal protein degradation by the ubiquitin-proteasome system can prevent accumulation of aberrantly folded proteins. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. In particular, molecular chaperones - such as protein disulfide isomerase, glucose regulated protein 78, and heat shock proteins - can provide neuroprotection from misfolded proteins by facilitating proper folding and thus preventing aggregation. Here, we present evidence for the hypothesis that NO contributes to normal brain aging and degenerative conditions by S-nitrosylating specific chaperones that would otherwise prevent accumulation of misfolded proteins.
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PMID:Contribution of glutamatergic signaling to nitrosative stress-induced protein misfolding in normal brain aging and neurodegenerative diseases. 1738 98

Sensing and responding to changes in oxygen partial pressure assures that the cellular oxygen supply is tightly controlled in order to balance the risks of oxidative damage vs. oxygen deficiency. The hypoxia inducible factor (HIF) regulatory system is controlled by prolyl hydroxylases (PHDs), the von Hippel Lindau protein (pVHL), and the 26S proteasome and transduces changes in oxygenation to adequate intracellular adaptive responses. A functional HIF response requires stabilization of the alpha-subunit, e.g. HIF-1alpha, during hypoxia and dimerization with HIF-1beta, to drive target gene activation. Intriguingly, high concentrations of nitric oxide (NO) stabilize HIF-1alpha and thus mimic a hypoxic response under normoxia. Mechanistically, NO blocks PHD activity and attenuates proline hydroxylation of HIF-1alpha. This causes dissociation of pVHL from HIF-1alpha and, consequently, HIF-1alpha accumulates because proteasomal destruction is impaired. However, during hypoxia low concentrations of NO facilitate destruction of HIF-1alpha and thus reverse HIF signaling. Under these conditions, NO impairs respiration and avoids oxygen gradients that limit PHD activity. An additional layer of complexity comprises the interaction of NO with O(2)(-). Signaling qualities attributed to NO are antagonized by compensatory flux rates of O(2)(-) and vice versa to adjust levels of HIF-1alpha under normoxia and hypoxia. The liaison of NO and hypoxia is versatile and ranges from courting to matrimony and divorce.
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PMID:Nitric oxide and superoxide: interference with hypoxic signaling. 1741 15

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 mitochondria have several important functions in the cell. A mitochondrial dysfunction causes an abatement in ATP production, oxidative damage and the induction of apoptosis, all of which are involved in the pathogenesis of numerous disorders. This review focuses on mitochondrial dysfunctions and discusses their consequences and potential roles in the pathomechanism of neurodegenerative disorders. Other pathogenetic factors are also briefly surveyed. The second part of the review deals with the kynurenine metabolic pathway, its alterations and their potential association with cellular energy impairment in certain neurodegenerative diseases. During energy production, most of the O(2) consumed by the mitochondria is reduced fully to water, but 1-2% of the O(2) is reduced incompletely to give the superoxide anion (O(2)(-)). If the function of one or more respiratory chain complexes is impaired for any reason, the enhanced production of free radicals further worsens the mitochondrial function by causing oxidative damage to macromolecules, and by opening the mitochondrial permeability transition pores thereby inducing apoptosis. These high-conductance pores offer a pathway which can open in response to certain stimuli, leading to the induction of the cells' own suicide program. This program plays an essential role in regulating growth and development, in the differentiation of immune cells, and in the elimination of abnormal cells from the organism. Both failure and exaggeration of apoptosis in a human body can lead to disease. The increasing amount of superoxide anions can react with nitric oxide to yield the highly toxic peroxynitrite anion, which can destroy cellular macromolecules. The roles of oxidative, nitrative and nitrosative damage are discussed. Senescence is accompanied by a higher degree of reactive oxygen species production, and by diminished functions of the endoplasmic reticulum and the proteasome system, which are responsible for maintenance of the normal protein homeostasis of the cell. In the event of a dysfunction of the endoplasmic reticulum, unfolded proteins aggregate in it, forming potentially toxic deposits which tend to be resistant to degradation. Cells possess adaptive mechanisms with which to avoid the accumulation of incorrectly folded proteins. These involve molecular chaperones that fold proteins correctly, and the ubiquitin proteasome system which degrades misfolded, unwanted proteins. Both the endoplasmic reticulum and the ubiquitin proteasome system fulfill cellular protein quality control functions. The kynurenine system: Tryptophan is metabolized via several pathways, the main one being the kynurenine pathway. A central compound of the pathway is kynurenine (KYN), which can be metabolized in two separate ways: one branch furnishing kynurenic acid, and the other 3-hydroxykynurenine and quinolinic acid, the precursors of NAD. An important feature of kynurenic acid is the fact that it is one of the few known endogenous excitatory amino acid receptor blockers with a broad spectrum of antagonistic properties in supraphysiological concentrations. One of its recently confirmed sites of action is the alpha7-nicotinic acetylcholine receptor and interestingly, a more recently identified one is a higher affinity positive modulatory binding site at the AMPA receptor. Kynurenic acid has proven to be neuroprotective in several experimental settings. On the other hand, quinolinic acid is a specific agonist at the N-methyl-d-aspartate receptors, and a potent neurotoxin with an additional and marked free radical-producing property. There are a number of neurodegenerative disorders whose pathogenesis has been demonstrated to involve multiple imbalances of the kynurenine pathway metabolism. These changes may disturb normal brain function and can add to the pathomechanisms of the diseases. In certain disorders, there is a quinolinic acid overproduction, while in others the alterations in brain kynurenic acid levels are more pronounced. A more precise knowledge of these alterations yields a basis for getting better therapeutic possibilities. The last part of the review discusses metabolic disturbances and changes in the kynurenine metabolic pathway in Parkinson's, Alzheimer's and Huntington's diseases.
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PMID:Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. 1746 70

Protein quality control is a critical feature of intracellular homeostasis. In particular, unfolded or misfolded proteins resulting from environmental stresses or free radicals are rapidly degraded via the ubiquitin-proteasome pathway. Nitric oxide (NO), a free radical gas, has been reported to be involved in such processes as vasorelaxation and neurotransmission. Conversely, NO also is implicated in neuronal cell death or neurodegeneration. Recent reports suggest that S-nitrosylation of proteins is a significant cause of neural dysfunction leading to neurodegenerative disorders. Specifically, S-nitrosylation of parkin eventually leads to the accumulation of unfolded proteins and subsequent neuronal death. The focus of this review is the identity of the target of NO. Nitrosative stress prevents normal functioning of the endoplasmic reticulum (ER) via S-nitrosylation of protein-disulfide isomerase (PDI), which is located in the ER lumen. This may contribute to the accumulation of misfolded proteins, as well as sustained activation of the unfolded protein response (UPR) pathway. These phenomena may be linked to the development of sporadic neurodegenerative diseases.
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PMID:Accumulation of misfolded protein through nitrosative stress linked to neurodegenerative disorders. 1746 82

The endothelium releases multiple mediators, not only regulators of vasomotor function but also important physiological and pathophysiological inflammatory mediators. Endothelial dysfunction is caused by chronic exposure to various stressors such as oxidative stress and modified low-density lipoprotein (LDL) cholesterol, resulting in impaired nitric oxide (NO) production and chronic inflammation. Biomechanical forces on the endothelium, including low shear stress from disturbed blood flow and hypertension, are also important causes of endothelial dysfunction. These processes seem to be augmented in patients with diabetes. In states of insulin resistance and in type 2 diabetes insulin signalling is impaired. Increased vascular inflammation, including enhanced expression of interleukin- 6 (IL-6), vascular cellular adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein (MCP- 1) are observed, as is a marked decrease in NO bioavailability. Furthermore, hyperglycaemia leads to increased formation of advanced glycation end products (AGE), which quench NO and impair endothelial function. In summary, during the development of diabetes a number of biochemical and mechanical factors converge on the endothelium, resulting in endothelial dysfunction and vascular inflammation. In the presence of insulin resistance, these processes are potentiated and they provide a basis for the macrovascular disease seen in diabetes.
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PMID:The endothelium and vascular inflammation in diabetes. 1765 40

Overactivation of N-methyl-D-aspartate (NMDA)-type glutamate receptors accounts, at least in part, for excitotoxic neuronal damage, potentially contributing to a wide range of acute and chronic neurologic disorders. Recent studies have suggested that generation of excessive nitric oxide (NO) and reactive oxygen species (ROS) can mediate excitotoxicity, in part by triggering protein misfolding. S-Nitrosylation, which is a covalent reaction of a NO group with a cysteine thiol, represents one such mechanism that can contribute to NO-induced neurotoxicity. The ubiquitin-proteasome system (UPS), in conjunction with molecular chaperones, can prevent accumulation of aberrantly-folded proteins. For example, protein disulfide isomerase (PDI) can provide neuroprotection from misfolded proteins or endoplasmic reticulum stress through its molecular chaperone and thiol-disulfide oxidoreductase activities. Here, the authors present recent evidence suggesting that NO contributes to degenerative conditions by S-nitrosylating PDI (forming SNO-PDI) and the ubiquitin protein ligase, parkin (forming SNO-parkin). Moreover, it is demonstrated for the first time that inhibition of excessive NMDA receptor activity by memantine, via a mechanism of uncompetitive open-channel block with a relatively rapid off-rate, can ameliorate excessive production of NO, protein misfolding, and neurodegeneration.
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PMID:Emerging roles of S-nitrosylation in protein misfolding and neurodegenerative diseases. 1796 Oct 71

Creating conditions similar to those occurring during exposure of cells to microgravity modulates endothelial functions. We have previously demonstrated that human macrovascular endothelial cells in simulated hypogravity proliferate faster than controls, partly because they downregulate interleukin 1alpha. On the contrary, murine microvascular endothelial cells are growth inhibited in simulated hypogravity, and this is due, at least in part, to the decrease of interleukin 6. Since endothelial cells are very heterogeneous and differences between various species have been reported, we exposed human microvascular cells to gravitational unloading and found that it retards cell growth without affecting cell migration. Interestingly, we detected the induction of Tissue Inhibitor of Metalloprotease-2, which inhibits endothelial growth in vitro and angiogenesis in vivo. Together with the finding that hypogravity stimulates the synthesis of nitric oxide, involved also in neovascularization, our results underscore a modulation of the angiogenic properties of microvascular human endothelial cells. We also show that hypogravity inhibits proteasome activity, thus suggesting that post-translational mechanisms are involved in the adaptations of these cells to hypogravity. These results underscore that hypogravity differently impacts on micro- and macro-vascular human endothelial cells. In particular, these results may shed some light on the molecular mechanisms contributing to the impairment of angiogenesis observed in different models in space. Our data might also explain why bioengineered tissues to be used for regenerative medicine fail to neovascularize when assembled in simulated hypogravity.
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PMID:Gravitational unloading induces an anti-angiogenic phenotype in human microvascular endothelial cells. 1797 29

In renal carcinoma cells (RCC4) hypoxia inducible factor-1 (HIF-1) is constitutively expressed due to a von Hippel Lindau protein deficiency, but can be degraded by calpain, independently of the 26S proteasome, when exposed to hypoxia/nitric oxide (NO). In this study we examined molecular mechanisms to explain calpain activation. The inability of hypoxia/NO to degrade HIF-1alpha in respiratory-deficient RCC4-rho0 cells pointed to the requirement for mitochondria-derived reactive oxygen species. A prerequisite for O(2)(-) in combination with NO to destabilize HIF-1alpha was corroborated in RCC4-rho0 cells, when the redox cycler 2,3-dimethoxy-1,4-naphthoquinone was used as a source of superoxide. Degradation of HIF-1alpha required intracellular calcium transients and calpain activation. Using uric acid to interfere with signal transmission elicited by NO/O(2)(-) blocked HIF-1alpha degradation and attenuated a calcium increase. We conclude that an oxidative signal as a result of NO/O(2)(-) coformation triggers a calcium increase that activates calpain to degrade HIF-1alpha, independently of the proteasome.
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PMID:The interaction of superoxide with nitric oxide destabilizes hypoxia-inducible factor-1alpha. 1798 22

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


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