Dual Effects of Plant Steroidal Alkaloids on <i>Saccharomycescerevisiae</i>

<jats:title>ABSTRACT</jats:title> <jats:p> Many plant species accumulate sterols and triterpenes as antimicrobial glycosides. These secondary metabolites (saponins) provide built-in chemical protection against pest and pathogen attack and can also influence induced defense responses. In addition, they have a variety of important pharmacological properties, including anticancer activity. The biological mechanisms underpinning the varied and diverse effects of saponins on microbes, plants, and animals are only poorly understood despite the ecological and pharmaceutical importance of this major class of plant secondary metabolites. Here we have exploited budding yeast ( <jats:italic>Saccharomyces cerevisiae</jats:italic> ) to investigate the effects of saponins on eukaryotic cells. The tomato steroidal glycoalkaloidα -tomatine has antifungal activity towards yeast, and this activity is associated with membrane permeabilization. Removal of a single sugar from the tetrasaccharide chain of α-tomatine results in a substantial reduction in antimicrobial activity. Surprisingly, the complete loss of sugars leads to enhanced antifungal activity. Experiments with α-tomatine and its aglycone tomatidine indicate that the mode of action of tomatidine towards yeast is distinct from that of α-tomatine and does not involve membrane permeabilization. Investigation of the effects of tomatidine on yeast by gene expression and sterol analysis indicate that tomatidine inhibits ergosterol biosynthesis. Tomatidine-treated cells accumulate zymosterol rather than ergosterol, which is consistent with inhibition of the sterol C <jats:sub>24</jats:sub> methyltransferase Erg6p. However, <jats:italic>erg6</jats:italic> and <jats:italic>erg3</jats:italic> mutants (but not <jats:italic>erg2</jats:italic> mutants) have enhanced resistance to tomatidine, suggesting a complex interaction of <jats:italic>erg</jats:italic> mutations, sterol content, and tomatidine resistance. </jats:p>