Production of the antimalarial drug precursor artemisinic acid in engineered yeast

Dae Kyun Ro, Eric M. Paradise, Mario Quellet, 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

Research output: Contribution to journalArticlepeer-review

2332 Scopus citations

Abstract

Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually1. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum2,3. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing4,5. 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 sufferers6. Although total synthesis of artemisinin is difficult and costly7, 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 artemisinin8,9. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mgl-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.

Original languageEnglish (US)
Pages (from-to)940-943
Number of pages4
JournalNature
Volume440
Issue number7086
DOIs
StatePublished - Apr 13 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Fingerprint

Dive into the research topics of 'Production of the antimalarial drug precursor artemisinic acid in engineered yeast'. Together they form a unique fingerprint.

Cite this