High-level semi-synthetic production of the potent antimalarial artemisinin
Open accessAbstract
In 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.
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When three copies of HMGR from A. annua were introduced into S. cerevisiae, significantly more artemisinic acid was produced than from single gene copies.
“When three copies of HMGR were introduced from A. annua into S. cerevisiae, significantly more artemisinic acid was produced than from single gene copies (Paddon et al. 2013).”
From Enhancing artemisinin content in and delivery from Artemisia annua: a review of alternative, classical, and transgenic approaches (2021) · cites this paper as Paddon et al. 2013
The pathway description (Figure 1 caption in the section labelled Abstract; page unavailable) identifies tHMG1 as encoding truncated HMG-CoA reductase. Our copy does not report introducing three copies of A. annua HMGR into yeast or comparing their artemisinic acid production with single-copy strains (searched: HMGR, HMG-CoA reductase, and three copies). (LLM, conf=0.76)
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- Authors
- Paddon, C. J., Westfall, P. J., Pitera, D. J., Benjamin, K., Fisher, K., McPhee, D., Leavell, M. D., Tai, A., Main, A., Eng, D., Polichuk, D. R., Teoh, K. H., Reed, D. W., Treynor, T., Lenihan, J., Jiang, H., Fleck, M., Bajad, S., Dang, G., Dengrove, D., Diola, D., Dorin, G., Ellens, K. W., Fickes, S., Galazzo, J., Gaucher, S. P., Geistlinger, T., Henry, R., Hepp, M., Horning, T., Iqbal, T., Kizer, L., Lieu, B., Melis, D., Moss, N., Regentin, R., Secrest, S., Tsuruta, H., Vazquez, R., Westblade, L. F., Xu, L., Yu, M., Zhang, Y., Zhao, L., Lievense, J., Covello, P. S., Keasling, J. D., Reiling, K. K., Renninger, N. S., & Newman, J. D.
- Affiliations
- Amyris (United States) (US)
- National Research Council Canada (CA)
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Paddon, C. J.
- Newman, J. D.
- ORCID
- Venue
- Nature
- Published
- 2013-04
- Volume
- 496
- Issue
- 7446
- Pages
- 528-532
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1990226486
- Cited by
- 2,060
- References
- 30
- Citations by year
- 2026: 115 · 2025: 139 · 2024: 164 · 2023: 147 · 2022: 176 · 2021: 176 · 2020: 160 · 2019: 163 · 2018: 176 · 2017: 150 · 2016: 163 · 2015: 144 · 2014: 144 · 2013: 40 · 2012: 2
- FWCI
- 73.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- NPARC (submittedVersion)
- Funders
- Bill and Melinda Gates Foundation
- Sanofi
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Keywords
- artemisinin, artemisinic acid, Saccharomyces cerevisiae, artemisinin biosynthesis, dehydrogenase, cytochromes, singlet oxygen, artemisinin-based combination therapy, malaria treatment, Plasmodium falciparum, industrial fermentation
- MeSH terms
- Antimalarials, Biotechnology, Fermentation, Genetic Engineering, Molecular Sequence Data, Saccharomyces cerevisiae, Malaria, Falciparum, Singlet Oxygen, Artemisinins, Biosynthetic Pathways
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