Engineering of the pyruvate dehydrogenase bypass in Saccharomyces cerevisiae for high-level production of isoprenoids

Amorphadiene, a sesquiterpene precursor to the anti-malarial drug artemisinin, is synthesized by the cyclization of farnesyl pyrophosphate (FPP). Saccharomyces cerevisiae produces FPP through the mevalonate pathway using acetyl-CoA as a starting compound. In order to enhance the supply of acetyl-CoA to the mevalonate pathway and achieve high-level production of amorphadiene, we engineered the pyruvate dehydrogenase bypass in S. cerevisiae. Overproduction of acetaldehyde dehydrogenase and introduction of a Salmonella enterica acetyl-CoA synthetase variant increased the carbon flux into the mevalonate pathway resulting in increased amorphadiene production. This work will be generally applicable to the production of a broad range of isoprenoids in yeast.