The essential and ancillary role of glutathione in analysed using a grande disruptant strain

Lee, J; Straffon, Melissa; Jang, Taeyong; Higgins, Vincent J.; Grant, Chris M.; Dawes, Ian W.

doi:10.1016/s1567-1356(01)00004-6

Cited by 36 publications

(49 citation statements)

References 18 publications

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“…These findings were reinforced by the result that the gsh1Δ mutant, in which glutathione synthesis is blocked, is sensitive to 56MESS. As glutathione plays essential cellular functions including maintenance of mitochondrial genome, sporulation and detoxification of harmful compounds such as oxidants [27,48], glutathione deficiency can weaken cellular defence systems, thus exacerbating the cytotoxic action of 56MESS.…”

Section: Discussionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

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Section: Discussionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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“…Gsh1 enzyme activity is feedback inhibited by GSH (Meister 1988) and GSH1 expression is regulated by the cellular concentrations of GSH in parallel with sulfur amino acid biosynthesis (Wheeler et al , 2003. Mutants deleted for GSH1 are unable to grow in the absence of exogenous GSH, but can undergo a limited number of cell divisions in the absence of GSH during which they utilize preaccumulated stores of GSH (Lee et al 2001;Spector et al 2001). This has enabled the gsh1 mutant to be extensively used in studies aimed at determining the role of GSH during oxidative stress conditions, by examining the stress sensitivity of the gsh1 mutant in the absence of exogenous GSH.…”

Section: Antioxidant Defensesmentioning

confidence: 99%

The Response to Heat Shock and Oxidative Stress inSaccharomyces cerevisiae

2012

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A common need for microbial cells is the ability to respond to potentially toxic environmental insults. Here we review the progress in understanding the response of the yeast Saccharomyces cerevisiae to two important environmental stresses: heat shock and oxidative stress. Both of these stresses are fundamental challenges that microbes of all types will experience. The study of these environmental stress responses in S. cerevisiae has illuminated many of the features now viewed as central to our understanding of eukaryotic cell biology. Transcriptional activation plays an important role in driving the multifaceted reaction to elevated temperature and levels of reactive oxygen species. Advances provided by the development of whole genome analyses have led to an appreciation of the global reorganization of gene expression and its integration between different stress regimens. While the precise nature of the signal eliciting the heat shock response remains elusive, recent progress in the understanding of induction of the oxidative stress response is summarized here. Although these stress conditions represent ancient challenges to S. cerevisiae and other microbes, much remains to be learned about the mechanisms dedicated to dealing with these environmental parameters.

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“…Strains lacking GSH1 are viable but require a source of exogenous GSH for growth. For example, the gsh1 mutant grows normally on YEPD medium which contains approximately 0.5 mM GSH (24). The gsh1 mutant was therefore pregrown in YEPD medium, washed to remove exogenous GSH, and inoculated at different initial cell densities in minimal medium.…”

Section: Vol 29 2009 Mitochondrial 1-cys Peroxiredoxin 3231mentioning

confidence: 99%

“…Hence, redox regulation is critical for numerous mitochondrial functions. For example, GSH deficiency in mammalian cells leads to widespread mitochondrial damage (29), and yeast strains lacking GSH are unable to grow by respiration due to an accumulation of oxidative damage to mitochondrial DNA (24). GSH is synthesized in the cytosol and must be transported into mitochondria via an active energy-requiring process (7,17).…”

mentioning

confidence: 99%

Antioxidant Activity of the Yeast Mitochondrial One-Cys Peroxiredoxin Is Dependent on Thioredoxin Reductase and Glutathione In Vivo

Greetham

Grant

2009

Molecular and Cellular Biology

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Peroxiredoxins are ubiquitous enzymes which protect cells against oxidative stress. The first step of catalysis is common to all peroxiredoxins and results in oxidation of a conserved peroxidatic cysteine residue to sulfenic acid. This forms an intermolecular disulfide bridge in the case of 2-Cys peroxiredoxins, which is a substrate for the thioredoxin system. 1-Cys Prx's contain a peroxidatic cysteine but do not contain a second conserved cysteine residue, and hence the identity of the in vivo reduction system has been unclear. Here, we show that the yeast mitochondrial 1-Cys Prx1 is reactivated by glutathionylation of the catalytic cysteine residue and subsequent reduction by thioredoxin reductase (Trr2) coupled with glutathione (GSH). This novel mechanism does not require the usual thioredoxin (Trx3) redox partner of Trr2 for antioxidant activity, although in vitro assays show that the Trr2/Trx3 and Trr2/GSH systems exhibit similar capacities for supporting Prx1 catalysis. Our data also indicate that mitochondria are a main target of cadmium-induced oxidative stress and that Prx1 is particularly required to protect against mitochondrial oxidation. This study demonstrates a physiological reaction mechanism for 1-Cys peroxiredoxins and reveals a new role in protection against mitochondrial heavy metal toxicity.All aerobic organisms are exposed to reactive oxygen species (ROS) during the course of normal aerobic metabolism or following exposure to radical-generating compounds. ROS cause wide-ranging damage to macromolecules, which can result in genetic degeneration, physiological dysfunction, and eventual cell death (18,19). Sulfhydryls play a key role in the response to oxidative stress, regulated primarily by the glutathione (GSH)/glutaredoxin and thioredoxin systems (9,19,42,44). These redox systems were originally identified as hydrogen donors for ribonucleotide reductase, but they also act upon metabolic enzymes that form a disulfide as part of their catalytic cycle. They have proposed roles in diverse processes, including protein folding and regulation, reduction of dehydroascorbate, repair of oxidatively damaged proteins, and sulfur metabolism (20,42). Glutaredoxins and thioredoxins are structurally and functionally conserved. Despite this considerable functional overlap, they are differentially regulated. The oxidized disulfide form of thioredoxin is reduced directly by NADPH and thioredoxin reductase, whereas glutaredoxin is reduced by GSH using electrons donated by NADPH via GSH reductase. The two systems are therefore thermodynamically linked, as each uses NADPH as a source of reducing equivalents.During respiration, mitochondria are the primary source of ROS in the cell, and complex III of the respiratory chain is responsible for approximately 80% of ROS production (4, 5). Mitochondrial ROS cause wide-ranging damage to various cellular organelles and tissues and have been implicated in a number of disease processes. Not surprisingly, therefore, mitochondrial thiols are major ROS targets, a fact which...

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The essential and ancillary role of glutathione in analysed using a grande disruptant strain

Cited by 36 publications

References 18 publications

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

The Response to Heat Shock and Oxidative Stress inSaccharomyces cerevisiae

Antioxidant Activity of the Yeast Mitochondrial One-Cys Peroxiredoxin Is Dependent on Thioredoxin Reductase and Glutathione In Vivo

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