High-level semi-synthetic production of the potent antimalarial artemisinin

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DOIResolve DOI: http://doi.org/10.1038/nature12051
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TypeArticle
Journal titleNature
ISSN0028-0836
Volume496
Issue7446
Pages528532; # of pages: 5
Subjectartemisinin; singlet oxygen; antimalarial agent; biological production; disease treatment; enzyme activity; malaria; yeast; article; chemical reaction; derivatization; drug potency; esterification; expressed sequence tag; extractive fermentation; fed batch fermentation; fermentation; open reading frame; oxidative stress; photochemistry; priority journal; protein expression; stereochemistry; Antimalarials; Artemisinins; Biosynthetic Pathways; Biotechnology; Fermentation; Genetic Engineering; Malaria, Falciparum; Molecular Sequence Data; Saccharomyces cerevisiae; Singlet Oxygen; Artemisia annua; Artesunate; Plasmodium falciparum; Saccharomyces cerevisiae
AbstractIn 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price. © 2013 Macmillan Publishers Limited. All rights reserved.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC)
Peer reviewedYes
NPARC number21270729
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Record identifier9aebe1d1-653b-49bb-9405-12dec558216f
Record created2014-02-17
Record modified2016-05-09
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