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. 2006 Apr 13;440(7086):940-3.
doi: 10.1038/nature04640.

Production of the antimalarial drug precursor artemisinic acid in engineered yeast

Dae-Kyun Ro  1 , Eric M Paradise, Mario Ouellet, Karl J Fisher, Karyn L Newman, John M Ndungu, Kimberly A Ho, Rachel A Eachus, Timothy S Ham, James Kirby, Michelle C Y Chang, Sydnor T Withers, Yoichiro Shiba, Richmond Sarpong, Jay D Keasling
Affiliations

Production of the antimalarial drug precursor artemisinic acid in engineered yeast

Dae-Kyun Ro et al. Nature. .

Abstract

Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers. Although total synthesis of artemisinin is difficult and costly, the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l(-1)) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid. The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.

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