PRODUCTION OF A POLYKETIDE NATURAL PRODUCT IN NONPOLYKETIDE-PRODUCINGPROKARYOTIC AND EUKARYOTIC HOSTS

The polyketides are a diverse group of natural products with great sig nificance as human and veterinary pharmaceuticals. A significant barri er to the production of novel genetically engineered polyketides has b een the lack of available heterologous expression systems for function al polyketide synthases (PKSs). Herein, we report the expression of an intact functional PKS in Escherichia coli and Saccharomyces cerevisia e. The fungal gene encoding 6-methylsalicylic acid synthase from Penic illium patulum was expressed in E. coli and S. cerevisiae and the poly ketide 6-methylsalicylic acid (6-MSA) was produced. In both bacterial and yeast hosts, polyketide production required coexpression of 6-meth ylsalicylic acid synthase and a heterologous phosphopantetheinyl trans ferase that was required to convert the expressed apo-PKS to its hole form, Production of 6-MSA in E. coli was both temperature-and glycerol -dependent and levels of production were lower than those of P. patulu m, the native host, In yeast, however, 6-MSA levels greater than 2-fol d higher than the native host were observed. The heterologous expressi on systems described will facilitate the manipulation of PKS genes and consequent production of novel engineered polyketides and polyketide libraries.