The Experts below are selected from a list of 231 Experts worldwide ranked by ideXlab platform
Hideyo Sato - One of the best experts on this subject based on the ideXlab platform.
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the oxidative stress inducible Cystine glutamate antiporter system x c Cystine supplier and beyond
Amino Acids, 2012Co-Authors: Marcus Conrad, Hideyo SatoAbstract:The oxidative stress-inducible Cystine/glutamate exchange system, system xc−, transports one molecule of Cystine, the oxidized form of cysteine, into cells and thereby releases one molecule of glutamate into the extracellular space. It consists of two protein components, the 4F2 heavy chain, necessary for membrane location of the heterodimer, and the xCT protein, responsible for transport activity. Previously, system xc− has been regarded to be a mere supplier of cysteine to cells for the synthesis of proteins and the antioxidant glutathione (GSH). In that sense, oxygen, electrophilic agents, and bacterial lipopolysaccharide trigger xCT expression to accommodate with increased oxidative stress by stimulating GSH biosynthesis. However, emerging evidence established that system xc− may act on its own as a GSH-independent redox system by sustaining a redox cycle over the plasma membrane. Hallmarks of this cycle are Cystine uptake, intracellular reduction to cysteine and secretion of the surplus of cysteine into the extracellular space. Consequently, increased levels of extracellular cysteine provide a reducing microenvironment required for proper cell signaling and communication, e.g. as already shown for the mechanism of T cell activation. By contrast, the enhanced release of glutamate in exchange with Cystine may trigger neurodegeneration due to glutamate-induced cytotoxic processes. This review aims to provide a comprehensive picture from the early days of system xc− research up to now.
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the Cystine cysteine cycle a redox cycle regulating susceptibility versus resistance to cell death
Oncogene, 2008Co-Authors: Ana Banjac, Shiro Bannai, Hideyo Sato, Tamara Perisic, Alexander Seiler, N Weiss, Pirkko Kolle, K Tschoep, Rolf D IsselsAbstract:The Cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death
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redox imbalance in Cystine glutamate transporter deficient mice
Journal of Biological Chemistry, 2005Co-Authors: Hideyo Sato, Michiko Tamba, Ayako Shiiya, Mayumi Kimata, Kanako Maebara, Yuki Sakakura, Nobuo Makino, Fumihiro Sugiyama, Kenichi YagamiAbstract:Abstract Cystine/glutamate transporter, designated as system x–c, mediates Cystine entry in exchange for intracellular glutamate in mammalian cells. This transporter consists of two protein components, xCT and 4F2 heavy chain, and the former is predicted to mediate the transport activity. This transporter plays a pivotal role for maintaining the intracellular GSH levels and extracellular Cystine/cysteine redox balance in cultured cells. To clarify the physiological roles of this transporter in vivo, we generated and characterized mice lacking xCT. The xCT–/– mice were healthy in appearance and fertile. However, Cystine concentration in plasma was significantly higher in these mice, compared with that in the littermate xCT–/– mice, while there was no significant difference in plasma cysteine concentration. Plasma GSH level in xCT–/– mice was lower than that in the xCT–/– mice. The embryonic fibroblasts derived from xCT–/– mice failed to survive in routine culture medium, and 2-mercaptoethanol was required for survival and growth. When 2-mercaptoethanol was removed from the culture medium, cysteine and GSH in these cells dramatically decreased, and cells started to die within 24 h. N-Acetyl cysteine also rescued xCT–/–-derived cells and permitted growth. These results demonstrate that system x–c contributes to maintaining the plasma redox balance in vivo but is dispensable in mammalian development, although it is vitally important to cells in vitro.
Michael T. Ashby - One of the best experts on this subject based on the ideXlab platform.
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Reactive sulfur species: kinetics and mechanisms of the reaction of cysteine thiosulfinate ester with cysteine to give cysteine sulfenic acid.
Journal of Organic Chemistry, 2007Co-Authors: Péter Nagy, Kelemu Lemma, Michael T. AshbyAbstract:The kinetics and mechanisms of the reaction of cysteine with cysteine thiosulfinate ester in aqueous solution have been studied by stopped-flow spectrophotometry between pH 6 and 14. Two reaction pathways were observed for pH > 12: (1) an essentially pH-independent nucleophilic attack of cysteinate on cysteine thiosulfinate ester, and (2) a pH-dependent fast equilibrium protonation of cysteine sulfenate that is followed by rate-limiting comproportionation of cysteine sulfenic acid with cysteinate to give Cystine. For 6 < pH < 12, the rate-determining reaction between cysteinate and cysteine thiosulfinate ester becomes pH-dependent due to the protonation of their amine groups. Hydrolysis of cysteine thiosulfinate ester does not play a role in the aforementioned mechanisms because the rate-determining nucleophilic attack by hydroxide is relatively slow.
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Reactive sulfur species: kinetics and mechanisms of the oxidation of cysteine by hypohalous acid to give cysteine sulfenic acid.
Journal of the American Chemical Society, 2007Co-Authors: Péter Nagy, Michael T. AshbyAbstract:Cysteine sulfenic acid has been generated in alkaline aqueous solution by oxidation of cysteine with hypohalous acid (HOX, X = Cl or Br). The kinetics and mechanisms of the oxidation reaction and the subsequent reactions of cysteine sulfenic acid have been studied by stopped-flow spectrophotometry between pH 10 and 14. Two reaction pathways were observed: (1) below pH 12, the condensation of two sulfenic acids to give cysteine thiosulfinate ester followed by the nucleophilic attack of cysteinate on cysteine thiosulfinate ester and (2) above pH 10, a pH-dependent fast equilibrium protonation of cysteine sulfenate that is followed by rate-limiting comproportionation of cysteine sulfenic acid with cysteinate to give Cystine. The observation of the first reaction suggests that the condensation of cysteine sulfenic acid to give cysteine thiosulfinate ester can be competitive with the reaction of cysteine sulfenic acid with cysteine.
Dean P Jones - One of the best experts on this subject based on the ideXlab platform.
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cysteine Cystine redox signaling in cardiovascular disease
Free Radical Biology and Medicine, 2011Co-Authors: Dean P JonesAbstract:Abstract Extracellular thiol/disulfide redox environments are highly regulated in healthy individuals. The major thiol/disulfide redox couple in human plasma is cysteine (Cys) and its disulfide form, Cystine (CySS). Oxidation of this redox couple, measured as a more positive steady-state redox potential ( E h ), is associated with risk factors for cardiovascular disease (CVD), including aging, smoking, obesity, and alcohol abuse. Rodent and vascular cell studies show that the extracellular redox state of Cys/CySS ( E h CySS) can play a vital role in controlling CVD through proinflammatory signaling. This inflammatory signaling is regulated by cell-surface protein redox state and involves mitochondrial oxidation, nuclear factor-κB activation, and elevated expression of genes for monocyte recruitment to endothelial cells. Gene array and proteomics studies reveal the global nature of redox effects, and different cell types, e.g., endothelial cells, monocytes, fibroblasts, and epithelial cells, show cell-specific redox responses with different phenotypic traits, e.g., proliferation and apoptosis, which can contribute to CVD. The critical nature of the proinflammatory redox signaling and cell biology associated with E h CySS supports the use of plasma levels of Cys, CySS, and E h CySS as key indicators of vascular health. Plasma redox-state-based pharmacologic interventions to control or improve E h CySS may be effective in preventing CVD onset or progression.
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cysteine Cystine couple is a newly recognized node in the circuitry for biologic redox signaling and control
The FASEB Journal, 2004Co-Authors: Dean P Jones, Corinna L Anderson, Thomas R Ziegler, Joseph M Kinkade, W G KirlinAbstract:SPECIFIC AIMSReversible oxidation of sulfur-containing side chains of cysteine and methionine in proteins functions in signaling and control of gene expression, cell proliferation, and apoptosis. Glutathione (GSH) and thioredoxin (Trx) systems maintain signaling components in a reduced state and are counterbalanced in signaling by oxidative mechanisms, typically thought to directly depend upon reactive oxygen species (ROS). However, in cisternae of the endoplasmic reticulum, an oxidase is used to generate an intermediate disulfide to oxidize target protein thiols by a thiol/disulfide exchange mechanism. In principle, similar systems could function elsewhere in redox signaling. Cystine is a ubiquitous disulfide generated from cysteine by an oxidase on extracellular surfaces, and cysteine/Cystine redox state in human plasma is considerably oxidized relative to GSH/GSSG. If cysteine/Cystine redox were similarly oxidized in cells, this system could function in redox signaling and control with Cystine being an...
Isabelle Martin-verstraete - One of the best experts on this subject based on the ideXlab platform.
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Global regulation of the response to sulfur availability in the cheese-related bacterium Brevibacterium aurantiacum
Applied and Environmental Microbiology, 2011Co-Authors: Marie-pierre Forquin, Agnes Hebert, Aurélie Roux, Julie Aubert, Caroline Proux, Jean-françois Heilier, Sophie Landaud, Christophe Junot, Pascal Bonnarme, Isabelle Martin-verstraeteAbstract:In this study, we combined metabolic reconstruction, growth assays, and metabolome and transcriptome analyses to obtain a global view of the sulfur metabolic network and of the response to sulfur availability in Brevibacterium aurantiacum. In agreement with the growth of B. aurantiacum in the presence of sulfate and Cystine, the metabolic reconstruction showed the presence of a sulfate assimilation pathway, thiolation pathways that produce cysteine (cysE and cysK) or homocysteine (metX and metY) from sulfide, at least one gene of the transsulfuration pathway (aecD), and genes encoding three MetE-type methionine synthases. We also compared the expression profiles of B. aurantiacum ATCC 9175 during sulfur starvation or in the presence of sulfate. Under sulfur starvation, 690 genes, including 21 genes involved in sulfur metabolism and 29 genes encoding amino acids and peptide transporters, were differentially expressed. We also investigated changes in pools of sulfur-containing metabolites and in expression profiles after growth in the presence of sulfate, Cystine, or methionine plus Cystine. The expression of genes involved in sulfate assimilation and cysteine synthesis was repressed in the presence of Cystine, whereas the expression of metX, metY, metE1, metE2, and BL613, encoding a probable cystathionine-gamma-synthase, decreased in the presence of methionine. We identified three ABC transporters: two operons encoding transporters were transcribed more strongly during cysteine limitation, and one was transcribed more strongly during methionine depletion. Finally, the expression of genes encoding a methionine gamma-lyase (BL929) and a methionine transporter (metPS) was induced in the presence of methionine in conjunction with a significant increase in volatile sulfur compound production.
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Three different systems participate in l-Cystine uptake in Bacillus subtilis
Journal of Bacteriology, 2004Co-Authors: Pierre Burguière, Sandrine Auger, Marie-françoise Hullo, Antoine Danchin, Isabelle Martin-verstraeteAbstract:The symporter YhcL and two ATP binding cassette transporters, YtmJKLMN and YckKJI, were shown to mediate L-Cystine uptake in Bacillus subtilis. A triple yhcL ytmJKLMN yckK mutant was unable to grow in the presence of L-Cystine and to take up L-Cystine. We propose that yhcL, ytmJKLMN, and yckKJI should be renamed tcyP, tcyJKLMN, and tcyABC, respectively. The L-Cystine uptake by YhcL (Km 0.6 M) was strongly inhibited by seleno-DL-Cystine, while the transport due to the YtmJKLMN system (Km 2.5 M) also drastically decreased in the presence of DL-cystathionine, L-djenkolic acid, or S-methyl-L-cysteine. Accordingly, a ytmJKLMN mutant did not grow in the presence of 100 M DL-cystathionine, 100 M L-djenkolic acid, or 100 M S-methyl-L-cysteine. The expression of the ytmI operon and the yhcL gene was regulated in response to sulfur availability, while the level of expression of the yckK gene remained low under all the conditions tested.
Giovanni E Mann - One of the best experts on this subject based on the ideXlab platform.
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redox status in mammalian cells and stem cells during culture in vitro critical roles of nrf2 and Cystine transporter activity in the maintenance of redox balance
Redox biology, 2014Co-Authors: Tetsuro Ishii, Giovanni E MannAbstract:Culturing cells and tissues in vitro has provided valuable insights into the molecular mechanisms regulating redox signaling in cells with implications for medicine. However, standard culture techniques maintain mammalian cells in vitro under an artificial physicochemical environment such as ambient air and 5% CO2. Oxidative stress is caused by the rapid oxidation of cysteine to Cystine in culture media catalyzed by transition metals, leading to diminished intracellular cysteine and glutathione (GSH) pools. Some cells, such as fibroblasts and macrophages, express Cystine transport activity, designated as system [Formula: see text], which enables cells to maintain these pools to counteract oxidative stress. Additionally, many cells have the ability to activate the redox sensitive transcription factor Nrf2, a master regulator of cellular defenses against oxidative stress, and to upregulate xCT, the subunit of the [Formula: see text] transport system leading to increases in cellular GSH. In contrast, some cells, including lymphoid cells, embryonic stem cells and iPS cells, express relatively low levels of xCT and cannot maintain cellular cysteine and GSH pools. Thus, fibroblasts have been used as feeder cells for the latter cell types based on their ability to supply cysteine. Other key Nrf2 regulated gene products include heme oxygenase 1, peroxiredoxin 1 and sequestosome1. In macrophages, oxidized LDL activates Nrf2 and upregulates the scavenger receptor CD36 forming a positive feedback loop to facilitate removal of the oxidant from the vascular microenvironment. This review describes cell type specific responses to oxygen derived stress, and the key roles that activation of Nrf2 and membrane transport of Cystine and cysteine play in the maintenance and proliferation of mammalian cells in culture.
