Yeast as a model system to study metabolic impact of selenium compounds

Abstract

Inorganic Se forms such as selenate or selenite (the two more abundant forms in nature) can be toxic in Saccharomyces cerevisiae cells, which constitute an adequate model to study such toxicity at the molecular level and the functions participating in protection against Se compounds. Those Se forms enter the yeast cell through other oxyanion transporters. Once inside the cell, inorganic Se forms may be converted into selenide through a reductive pathway that in physiological conditions involves reduced glutathione with its consequent oxidation into diglutathione and alteration of the cellular redox buffering capacity. Selenide can subsequently be converted by molecular oxygen into elemental Se, with production of superoxide anions and other reactive oxygen species. Overall, these events result in DNA damage and dose-dependent reversible or irreversible protein oxidation, although additional oxidation of other cellular macromolecules cannot be discarded. Stress-adaptation pathways are essential for efficient Se detoxification, while activation of DNA damage checkpoint and repair pathways protects against Se-mediated genotoxicity. We propose that yeast may be used to improve our knowledge on the impact of Se on metal homeostasis, the identification of Se-targets at the DNA and protein levels, and to gain more insights into the mechanism of Se-mediated apoptosis.

Keywords: DNA damage; mitochondrial function; oxidative stress; selenium; signal transduction; yeast.

Figure 1. FIGURE 1: Scheme for the metabolic reduction of inorganic selenium forms, and their conversion into organic forms.

Reductive reactions are indicated with red arrows. Arrow 1 corresponds to the reactions involving ATP sulfurylase and other enzymes that take part in the initial steps of the sulfate assimilation pathway. Reactions 2 to 5 are non-enzymatic and result in the net conversion of reduced glutathione (GSH) into oxidized glutathione (GSSG). Reaction 6 is also non-enzymatic and results in the formation of diverse reactive oxygen species. Adapted from , , and .

Figure 2. FIGURE 2: Description of factors and pathways involved in the uptake, intracellular selenium tolerance and detoxification in S. cerevisiae.

See the text for details. Toxic consequences (blue) and protective mechanisms (red) are indicated.