SMALL MOLECULE MODULATORS OF STATIN RESPONSE IN YEAST

$44,181P41FY2010RRNIH

University Of Washington, Seattle WA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We established a yeast-based screen to explore how endogenous metabolites interact with lovastatin, a cholesterol-lowering drug. Lovastatin and other statins inhibit HMG-CoA reductase, which carries out one of the first steps in the sterol biosynthesis pathway. In the yeast Saccharomyces cerevisiae, treatment with a statin results in reduced growth. By treating yeast with lovastatin in combination with a small library of diverse metabolites, we found that copper and zinc ions reduced the ability of the statin to inhibit growth. We analyzed both gene expression and levels of ergosterol and its precursor compounds after treatment with both lovastatin and either of these metals. Statin treatment alone induced sterol and cell wall biosynthesis genes and decreased the levels of ergosterol and its precursors. Metal treatment alone induced many metal homeostasis genes and upregulated a subset of sterol biosynthesis genes, resulting in significantly increased sterol levels. The combination of the drug plus metal synergistically upregulated some sterol biosynthesis genes, resulting in greater flux through the sterol biosynthesis pathway and a concomitant increase in ergosterol levels. The cell responds to the ergosterol deprivation induced by a statin with an increase in ergosterol biosynthesis, and copper and zinc can enhance this response. In cultured mammalian cells, these two metals also rescued statin growth inhibition. Thus, copper and zinc levels could have relevance to statin response in humans. Metabolite perturbation screens such as the one presented here can be performed against nearly any yeast phenotype, and therefore are applicable to a wide range of problems.

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