Evolution of Glutathione Metabolism

Fahey, Robert C.; Sundquist, Alfred R.

doi:10.1002/9780470123102.ch1

Cited by 103 publications

(67 citation statements)

References 263 publications

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“…Glutathione, c-Glu-Cys-Gly, is an essential metabolite in almost all eukaryotic organisms (Fahey & Sundquist, 1991;Meister & Anderson, 1983), and plays a key role in redox homeostasis and in the cellular response to oxidative stress (Meister & Anderson, 1983;Penninckx, 2002;Sipos et al, 2002). The importance of oxidative stress responses in the virulence and survival of pathogens in their natural environment has been suggested by many studies, but the relative importance of the glutathione-dependent redox pathway, as opposed to other pathways for redox homeostasis and oxidative stress, has not been rigorously evaluated.…”

Section: Introductionmentioning

confidence: 99%

Glutathione biosynthesis in the yeast pathogens Candida glabrata and Candida albicans: essential in C. glabrata, and essential for virulence in C. albicans

et al. 2011

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Redox pathways play a key role in pathogenesis. Glutathione, a central molecule in redox homeostasis in yeasts, is an essential metabolite, but its requirements can be met either from endogenous biosynthesis or from the extracellular milieu. In this report we have examined the importance of glutathione biosynthesis in two major human opportunistic fungal pathogens, Candida albicans and Candida glabrata. As the genome sequence of C. glabrata had suggested the absence of glutathione transporters, we initially investigated exogenous glutathione utilization in C. glabrata by disruption of the MET15 gene, involved in methionine biosynthesis. We observed an organic sulphur auxotrophy in a C. glabrata met15Δ strain; however, unlike its Saccharomyces cerevisiae counterpart, the C. glabrata met15Δ strain was unable to grow on exogenous glutathione. This inability to grow on exogenous glutathione was demonstrated to be due to the lack of a functional glutathione transporter, despite the presence of a functional glutathione degradation machinery (the Dug pathway). In the absence of the ability to obtain glutathione from the extracellular medium, we examined and could demonstrate that γ-glutamyl cysteine synthase, the first enzyme of glutathione biosynthesis, was essential in C. glabrata. Further, although γ-glutamyl cysteine synthase has been reported to be non-essential in C. albicans, we report here for what is believed to be the first time that the enzyme is required for survival in human macrophages in vitro, as well as for virulence in a murine model of disseminated candidiasis. The essentiality of γ-glutamyl cysteine synthase in C. glabrata, and its essentiality for virulence in C. albicans, make the enzyme a strong candidate for antifungal development.

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Section: Introductionmentioning

confidence: 99%

Glutathione biosynthesis in the yeast pathogens Candida glabrata and Candida albicans: essential in C. glabrata, and essential for virulence in C. albicans

et al. 2011

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“…glycine, is the major low-molecular-weight thiol compound present in almost all eukaryotic cells (Meister and Anderson 1983;Fahey and Sundquist 1991) at intracellular concentrations ranging from 0.1 to 10 mm (Hwang et al 1992). This is in contrast to other redox couples that are in micromolar concentrations in the cell (Holmgren et al 1978).…”

Section: G Lutathione (Gsh) L-g-glutamyl-l-cysteinyl-mentioning

confidence: 99%

The Alternative Pathway of Glutathione Degradation Is Mediated by a Novel Protein Complex Involving Three New Genes in Saccharomyces cerevisiae

Ganguli¹,

Kumar²,

Bachhawat

2007

Genetics

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Glutathione (GSH), l-g-glutamyl-l-cysteinyl-glycine, is the major low-molecular-weight thiol compound present in almost all eukaryotic cells. GSH degradation proceeds through the g-glutamyl cycle that is initiated, in all organisms, by the action of g-glutamyl transpeptidase. A novel pathway for the degradation of GSH that requires the participation of three previously uncharacterized genes is described in the yeast Saccharomyces cerevisiae. These genes have been named DUG1 (YFR044c), DUG2 (YBR281c), and DUG3 (YNL191w) (defective in utilization of glutathione). Although dipeptides and tripeptides with a normal peptide bond such as cys-gly or glu-cys-gly required the presence of only a functional DUG1 gene that encoded a protein belonging to the M20A metallohydrolase family, the presence of an unusual peptide bond such as in the dipeptide, g-glu-cys, or in GSH, required the participation of the DUG2 and DUG3 gene products as well. The DUG2 gene encodes a protein with a peptidase domain and a large WD40 repeat region, while the DUG3 gene encoded a protein with a glutamine amidotransferase domain. The Dug1p, Dug2p, and Dug3p proteins were found to form a degradosomal complex through Dug1p-Dug2p and Dug2p-Dug3p interactions. A model is proposed for the functioning of the Dug1p/Dug2p/Dug3p proteins as a specific GSH degradosomal complex.

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“…3 Based on sequence similarity and exon structure, plant GSTs have been subdivided in class Phi, Zeta, Tau, Theta and Lambda. [4][5][6] Individual GST isozymes can selectively detoxify specific xenobiotics with species differences in GST specificity and capacity determining herbicide selectivity.…”

Section: Introductionmentioning

confidence: 99%

Site-directed Mutagenesis of the Evolutionarily Conserved Tyr8 Residue in Rice Phi-class Glutathione S-transferase F3

Jo¹,

Pack²,

Seo³

et al. 2013

Bulletin of the Korean Chemical Society

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To elucidate the role of the evolutionarily conserved Tyr8 residue in rice Phi-class GSTF3, this amino acid was replaced with alanine and phenylalanine by site-directed mutagenesis, respectively. The replacement of Tyr8 with Ala significantly affected the catalytic activity and the kinetic parameters, whereas the substitutions of Tyr8 with Phe had almost no effect. The Y8A mutant resulted in approximately 90-100% decrease of the specific activity. Moreover, the Y8A mutant resulted approximately in 2-fold increase of K m , approximately 60-80% decrease of k cat , and approximately 6.5-fold decrease in k cat /K m . From the pH/log k cat /K m plot, pK a values of the GSH in the wild-type enzyme-GSH complex, Y8A-GSH complex and Y8F-GSH complex were estimated to be approximately 6.8, 8.5 and 6.9, respectively. From these results, we suggest that the evolutionarily conserved Tyr8 residue in OsGSTF3 seems to influence the structural stability of the active site of OsGSTF3 rather than directly its catalytic activity.

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Evolution of Glutathione Metabolism

Cited by 103 publications

References 263 publications

Glutathione biosynthesis in the yeast pathogens Candida glabrata and Candida albicans: essential in C. glabrata, and essential for virulence in C. albicans

Glutathione biosynthesis in the yeast pathogens Candida glabrata and Candida albicans: essential in C. glabrata, and essential for virulence in C. albicans

The Alternative Pathway of Glutathione Degradation Is Mediated by a Novel Protein Complex Involving Three New Genes in Saccharomyces cerevisiae

Site-directed Mutagenesis of the Evolutionarily Conserved Tyr8 Residue in Rice Phi-class Glutathione S-transferase F3

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