SUMMARY PARAGRAPH for GSH1
GSH1 encodes gamma glutamylcysteine synthetase, which catalyzes the first, and rate-limiting, step in the glutathione (GSH) biosynthetic pathway, the conjugation of glutamate and cysteine (2, 7, 3).
Glutathione is an essential antioxidant that protects cells against damage induced by oxidative stress, which is caused by the production of reactive oxygen species (ROS) produced during aerobic metabolism or upon exposure to radical-generating compounds. Glutathione contains a redox-active free sulfhydryl moiety, which can be oxidized to the disulfide form (GSSG) by reaction with free radicals or in reactions mediated by glutathione peroxidases (such as Gpx1p, Gpx2p, and Hyr1p). GSH is regenerated by the action of glutathione reductase Glr1p (reviewed in 8).
Null gsh1 mutants are unable to grow on minimal medium lacking glutathione, and exhibit instability of the mitochondrial genome and increased sensitivity to hydrogen peroxide (9). Mutant cells, like wild type, do show an adaptive response to sublethal doses of hydrogen peroxide (9). Because null mutations in GSH1 prevent synthesis of glutathione, studies with these mutants have been, and continue to be, important in defining the roles of glutathione in the cell (see, for example, 10).
Regulation of GSH1 expression is multifaceted. In the presence of glutathione, expression is repressed (10). In the absense of glutathione, GSH1 expression is induced by Met4p, a transcription activator that also induces expression of genes involved in sulfur assimilation (11, 10). In addition, GSH1 expression is induced by oxidants, such as hydrogen peroxide, and by heat shock, both types of regulation involving the Yap1p transcription factor (4, 12). The GSH1 promoter contains a Yap1p binding site that is required for transcriptional regulation by Yap1p (13). Moreover, the promoter contains two hydrogen peroxide responsive elements that are separate from the Yap1p binding site, suggesting that additional factors may be involved in regulation (14).
GSH1 homologs have been reported in S. pombe, Drosophila, and mammals (15, 16, 17). Mutations in the human homolog GCLC cause the disorder gamma-glutamylcysteine synthetase deficiency which is associated with hemolytic anemia (18).
Last updated: 2007-01-02