S165: Semi-synthetic antimalarial from yeast: Crucial roles for improved enzymes and fermentation processes in the high-level production of artemisinic acid

There are estimated to be 350-500 million episodes of malaria annually, resulting in 1 million deaths.  The World Health Organization recommends treatment with Artemisinin Combination Therapies (ACTs), but the supply and price of artemisinin (extracted from the plant Artemisia annua) have fluctuated greatly.  An additional source of artemisinin might stabilize the price and increase availability of ACTs.  To this end, we have used metabolic engineering to produce artemisinic acid in Saccharomyces cerevisiae for subsequent chemical conversion to artemisinin. We altered the expression level of nine ergosterol-pathway genes to increase flux to farnesyl pyrophosphate or FPP. To convert FPP to artemisinic acid, we introduced five A. annua genes to our yeast.  In addition to extensive genetic engineering using synthetic biology methods, high-level production of artemisinic acid required fermentation process improvements to enable accurate measurement of fermentation progress, to decrease media costs, and to increase productivity.