ABSTRACT
This chapter addresses the relationship of glutathione (GSH) to Nrf2. It seems clear that there is both feedback and feed-forward signaling between Nrf2 activation and the use of GSH in protection of cells. Nrf2 activation leads to the transcription of enzymes that synthesize GSH, maintain it and NADPH in their reduced forms, and the use of GSH in protecting cells from hydroperoxides and other electrophiles. While glutathionylation of Keap1, which indicates an increase in hydroperoxide production, can signal for Nrf2 activation, GSH elimination of electrophiles and hydroperoxides decreases Nrf2 activation. These interactions contribute to redox homeostasis and, thereby, maintenance of the golden mean that defines a healthy life. Similarly, GSH is not the only nucleophile that is important in the maintenance of redox homeostasis. Other major contributing nucleophiles are NADPH, NADH, and the reduced form of thioredoxin (Trx). GSH also participates in protein folding. Protein disulfide isomerases (PDIs) and glutaredoxins (GRxs) are enzymes having a thioredoxin-like structure (thioredoxin fold).
