Disease relevance of GSH1

• In conformity with these results, the mutant lacking GSH1 showed a high sensitivity to dehydration [1].
• Glutathione synthesis in Streptococcus agalactiae. One protein accounts for gamma-glutamylcysteine synthetase and glutathione synthetase activities [2].
• A DNA fragment encoding gamma-glutamylcysteine synthetase [EC 6.3.2.2] of Schizosaccharomyces pombe was cloned by complementation of the cadmium hypersensitivity of a S. pombe mutant deficient in the enzyme [3].
• Yeast strains deficient in the antioxidant defense enzymes superoxide dismutase or gamma-glutamylcysteine synthetase were hypersensitive to cadmium toxicity [4].

High impact information on GSH1

• GSH is synthesized from its constituent amino acids by two ATP-dependent reactions catalyzed by gamma-glutamylcysteine synthetase and glutathione synthetase [5].
• Northern (RNA) blot analysis showed that GSH1 mRNA levels were responsive to YAP1 gene dosage [6].
• GSH1 encodes the rate-limiting step in yeast glutathione biosynthesis and contains within its promoter region a DNA element that matches the ARE in 11 of 12 positions [6].
• A mutant GSH1 gene lacking the YRE was unable to confer normal cadmium tolerance, although other yAP-1-mediated phenotypes remained normal [6].
• The GSH1 yAP-1 response element (YRE) was recognized by yAP-1 protein in vitro [6].

Biological context of GSH1

• In contrast to a strain deleted for GSH1, which lacks both GSH and gamma-Glu-Cys, the strain deleted for GSH2 was found to be unaffected in mitochondrial function as well as resistance to oxidative stress induced by hydrogen peroxide, tert-butyl hydroperoxide, and the superoxide anion [7].
• However, we show that Yap1 is not required for the superoxide anion-mediated induction of GSH1 gene expression [8].
• Thus, GSH1 is one of several genes that are transcriptionally controlled by yAP-1 and influence drug resistance [6].
• Northern blot analysis of stress-induced levels of TRX2 and GSH1 mRNAs indicated that the ability of the mutant Yap1 protein to induce transcriptional activation of target genes correlates well with its ability to confer stress resistance [9].
• Expression of the yeast GSH1 gene, encoding gamma-glutamylcysteine synthetase, is known to be regulated by hydrogen peroxide; in this study we show that expression of a GSH1-lacZ reporter gene is shown to be regulated by exposure to heavy metals, such as mercury and cadmium [10].

Associations of GSH1 with chemical compounds

• These results indicate that the Yap1-dependent activation of GSH1 expression in response to glutathione depletion is regulated by the sulfur status of the cell through a specific Met4-dependent mechanism [11].
• The addition of methionine, which promotes Met4 ubiquitination and inactivation, specifically represses GSH1 expression after 1-chloro-2,4-dintrobenzene exposure but does not affect Yap1 activation [11].
• This study shows that the regulation of the yeast GSH1 gene by oxidants and the heavy metal cadmium is at the level of transcription [12].
• The first contains GSH1, indicating that gamma-glutamylcysteine can functionally replace GSH if it is present in sufficiently high quantities [13].
• Our previous studies have shown that glutathione is an essential metabolite in the yeast Saccharomyces cerevisiae because a mutant deleted for GSH1, encoding the first enzyme in gamma-l-glutamyl-l-cysteinylglycine (GSH) biosynthesis, cannot grow in its absence [13].

Physical interactions of GSH1

• Genes GSH1/MET1 and GGT1 are involved in maturation and metabolism of cellular Cd-GSH complex, respectively [14].

Enzymatic interactions of GSH1

• GSH is synthesized by the action of two ATP-dependent enzymic steps, in which gamma-glutamylcysteine synthetase (gamma-GCS) catalyses the ligation of glutamate and cysteine and subsequently glutathione synthetase (GS) adds glycine to the dipeptide [15].

Regulatory relationships of GSH1

• The expression of GSH1 in Saccharomyces cerevisiae has been known to be up-regulated by Yap1p, a critical transcription factor for the oxidative stress response in yeast [16].

Other interactions of GSH1

• We show that expression of the yeast GSH1 gene (encoding gamma-glutamylcysteine synthetase) and the SSA1 gene (encoding an HSP70 isoform) are induced by oxidants [8].
• We propose that gsh1 cells are unable to form the Cd-GS(2) complex, while ycf1 cells would accumulate high levels of this complex in the cytoplasm [17].
• In summary, GSH biosynthesis is regulated in parallel with sulphate assimilation by activity of the Met4 protein, but GSH1-specific mechanisms exist that respond to GSH availability [13].
• A double mutant in GSH1 and ATM1 encoding a mitochondrial ATP binding cassette (ABC) transporter involved in cytosolic Fe/S protein maturation is nonviable even in the presence of dithiothreitol [18].
• In particular the transcription factors Met-4, Met-31, and Met-32 are essential for cadmium-mediated regulation of gene expression, whereas the DNA-binding protein Cbf1 appears to play a negative role in controlling GSH1 expression [19].

Analytical, diagnostic and therapeutic context of GSH1

• Molecular cloning of Drosophila gamma-glutamylcysteine synthetase by functional complementation of a yeast mutant [20].
• Sequence analysis identified this gene as the gamma-glutamylcysteine synthetase of yeast [21].

References