Cadmium-inducible Expression of the Yeast GSH1 Gene Requires a Functional Sulfur-Amino Acid Regulatory Network

Ulla H Dormer,John Westwater,Niall F Mclaren,Nicholas A Kent,Jane Mellor,Derek J Jamieson

doi:10.1074/jbc.m004167200

Ulla H Dormer, John Westwater + Show 4 more

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https://doi.org/10.1074/jbc.m004167200

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Abstract

Glutathione (gamma-l-glutamyl-l-cysteinylglycine) is an important antioxidant molecule, helping to buffer the cell against free radicals and toxic electrophiles. Expression of the yeast GSH1 gene, encoding the first enzyme involved in glutathione biosynthesis, gamma-glutamylcysteine synthetase, is regulated by oxidants and the heavy metal cadmium at the level of transcription. We present evidence that the transcription factors involved in controlling the network of sulfur amino acid metabolism genes are also responsible for regulating GSH1 expression in response to cadmium. 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.

Highlights

Glutathione (␥-L-glutamyl-L-cysteinylglycine) is an important antioxidant molecule, helping to buffer the cell against free radicals and toxic electrophiles
In view of the central importance of glutathione in countering environmental stress caused by reactive oxidants and heavy metals, we have studied the regulation of glutathione biosynthesis in S. cerevisiae
We have found that expression of the GSH1 gene, encoding the first and rate-limiting step in the GSH biosynthetic pathway, ␥-glutamylcysteine synthetase, is regulated by reactive oxygen species, such as H2O2, superoxide anion generators, and the heavy metal cadmium [13, 20]

Summary

Introduction

Glutathione (␥-L-glutamyl-L-cysteinylglycine) is an important antioxidant molecule, helping to buffer the cell against free radicals and toxic electrophiles. Expression of the yeast GSH1 gene, encoding the first enzyme involved in glutathione biosynthesis, ␥-glutamylcysteine synthetase, is regulated by oxidants and the heavy metal cadmium at the level of transcription. We present evidence that the transcription factors involved in controlling the network of sulfur amino acid metabolism genes are responsible for regulating GSH1 expression in response to cadmium. Glutathione (␥-L-glutamyl-L-cysteinylglycine) is an important molecule that plays a major role in protecting cells against damage caused by oxidants, heavy metals, and pesticides [1]. Mutations in a number of genes give rise to either resistance or hypersensitivity toward toxic levels of both metal ions and oxidants, reviewed by Santoro and Thiel [6], exposure of yeast cells to cadmium has been demonstrated to lead to the production of reactive oxidants [24]. We show that the genes involved in regulating sulfur amino acid biosynthesis regulate GSH1 expression

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