Engineering Production of Cholesterol Drugs Simvastatin and Lovastatin in Saccharomyces Cerevisiae

Polyketide-derived natural products are a rich source of bioactive molecules, and fungal polyketides have been an important source of pharmaceuticals. These molecules are challenging to directly synthesize due to their complexity, so they are usually produced industrially through fermentation. This can be limiting due to hosts that are difficult to engineer for production of more potent analogs or increased titers. As there is great interest in producing natural product analogs, a more tractable host is desired. The yeast Saccharomyces cerevisiae is a well-studied organism that has long been in use industrially. An engineered drop-in yeast host for the high production of fungal polyketides and their analogs would shift the industrial paradigm of native host polyketide production and enable greater ease in the characterization of new polyketide clusters.
The lovastatin pathway from filamentous fungi Aspergillus terreus was used for the initial development of such a yeast host because of the importance lovastatin and its analogs play as cholesterol medications. Episomal and genomic expression of the seven genes of the lovastatin pathway from Aspergillus terreus, or engineered versions of enzymes, has led to the production of lovastatin and blockbuster cholesterol-lowering drug simvastatin in S. cerevisiae. Over 35 mg/L of the first major precursor, DMLA, has been produced de novo in yeast using the promiscuity of enzymes from the lovastatin pathway and the analogous compactin pathway from Penicillium citrinum. The strains and strategies developed in the process of optimizing lovastatin and simvastatin production in yeast will introduce a cheaper method of synthesizing the blockbuster drug simvastatin and provide tools for improved production and engineering of other fungal polyketide pathways, smoothing the pipeline from the characterization of new natural product clusters to the industrial-scale production of the polyketides they encode.