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

Literature Information ​

DOI10.1038/nature12051
PMID23575629
JournalNature
Impact Factor48.5
JCR QuartileQ1
Publication Year2013
Times Cited679
KeywordsArtemisinin, Semi-synthetic, Synthetic biology, Yeast, Antimalarial
Literature TypeJournal Article, Research Support, Non-U.S. Gov't
ISSN0028-0836
Pages528-32
Issue496(7446)
AuthorsC J Paddon, P J Westfall, D J Pitera, K Benjamin, K Fisher, D McPhee, M D Leavell, A Tai, A Main, D Eng, D R Polichuk, K H Teoh, D W Reed, T Treynor, J Lenihan, M Fleck, S Bajad, G Dang, D Dengrove, D Diola, G Dorin, K W Ellens, S Fickes, J Galazzo, S P Gaucher, T Geistlinger, R Henry, M Hepp, T Horning, T Iqbal, H Jiang, L Kizer, B Lieu, D Melis, N Moss, R Regentin, S Secrest, H Tsuruta, R Vazquez, L F Westblade, L Xu, M Yu, Y Zhang, L Zhao, J Lievense, P S Covello, J D Keasling, K K Reiling, N S Renninger, J D Newman

TL;DR ​

This study addresses the unstable supply of artemisinin, a critical antimalarial drug, by utilizing synthetic biology to develop high-yielding strains of Saccharomyces cerevisiae for the efficient production of artemisinic acid, achieving fermentation titres of 25 grams per liter. The research not only establishes a viable industrial process for converting artemisinic acid into artemisinin but also aims to lower costs and increase the availability of essential malaria treatments in the developing world.

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Artemisinin · Semi-synthetic · Synthetic biology · Yeast · Antimalarial

Abstract ​

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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Primary Questions Addressed ​

  1. What are the specific challenges faced in the large-scale production of artemisinin from plant sources compared to semi-synthetic methods?
  2. How does the introduction of synthetic biology in yeast strains improve the yield of artemisinic acid compared to previous production methods?
  3. What are the implications of using a chemical process for converting artemisinic acid to artemisinin on the overall production costs and efficiency?
  4. In what ways can the stable supply of semi-synthetic artemisinin impact the global malaria treatment landscape, especially in developing countries?
  5. What role does the discovery of new enzymes, such as the plant dehydrogenase and cytochrome, play in optimizing the biosynthetic pathway for artemisinin production?

Key Findings ​

1. Research Background and Objective ​

Malaria remains a critical global health challenge, with over 200 million cases and at least 655,000 deaths reported in 2010 alone. The World Health Organization endorses artemisinin-based combination therapies (ACTs) as the preferred treatment for uncomplicated malaria caused by the Plasmodium falciparum parasite. Artemisinin, a potent antimalarial compound derived from the plant Artemisia annua, faces significant supply instability due to fluctuations in plant availability. This inconsistency hampers the production planning of ACT manufacturers, necessitating a reliable and affordable source of artemisinin. The research aims to leverage synthetic biology to establish a high-yield production system for artemisinic acid, a precursor to artemisinin, utilizing engineered strains of Saccharomyces cerevisiae (baker's yeast).

2. Main Methods and Findings ​

The study employed synthetic biology to construct yeast strains capable of efficiently producing artemisinic acid. Previous attempts to achieve commercially relevant concentrations of artemisinic acid had limited success, yielding only 1.6 grams per liter. However, this research successfully elucidated the complete biosynthetic pathway for artemisinic acid production, identifying a plant dehydrogenase and an additional cytochrome that enhance the efficiency of the biosynthetic route. As a result, the engineered strains achieved fermentation titres of 25 grams per liter of artemisinic acid. Additionally, a scalable chemical process was developed to convert artemisinic acid into artemisinin using a chemical source of singlet oxygen, circumventing the need for specialized photochemical equipment.

3. Core Conclusions ​

The engineered yeast strains and the innovative chemical conversion process lay the groundwork for a viable industrial method for the semi-synthetic production of artemisinin. This approach addresses the instability in the supply of artemisinin derived from plants, providing a stable and potentially cost-effective alternative for the production of this essential antimalarial compound.

4. Research Significance and Impact ​

This research holds significant implications for global health, particularly in enhancing the availability of first-line antimalarial treatments in developing countries. By offering a reliable and affordable source of artemisinin, the technology can stabilize the supply chain for ACTs, potentially reducing costs and increasing accessibility for patients in need. Moreover, the open provision of intellectual property rights associated with this technology may foster further innovation and collaboration in the field, ultimately contributing to the global fight against malaria and improving public health outcomes in affected regions.

References ​

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Literatures Citing This Work ​

  1. Towards a molecular understanding of the biosynthesis of amaryllidaceae alkaloids in support of their expanding medical use. - Adam M Takos;Fred Rook - International journal of molecular sciences (2013)
  2. Small, synthetic, GC-rich mRNA stem-loop modules 5' proximal to the AUG start-codon predictably tune gene expression in yeast. - Erwin Lamping;Masakazu Niimi;Richard D Cannon - Microbial cell factories (2013)
  3. Metabolic analyses elucidate non-trivial gene targets for amplifying dihydroartemisinic acid production in yeast. - Ashish Misra;Matthew F Conway;Joseph Johnnie;Tabish M Qureshi;Bao Lige;Anne M Derrick;Eddy C Agbo;Ganesh Sriram - Frontiers in microbiology (2013)
  4. Bridging the gap between systems biology and synthetic biology. - Di Liu;Allison Hoynes-O'Connor;Fuzhong Zhang - Frontiers in microbiology (2013)
  5. Expression-level optimization of a multi-enzyme pathway in the absence of a high-throughput assay. - Michael E Lee;Anil Aswani;Audrey S Han;Claire J Tomlin;John E Dueber - Nucleic acids research (2013)
  6. Antiparasitic chemotherapy: from genomes to mechanisms. - David Horn;Manoj T Duraisingh - Annual review of pharmacology and toxicology (2014)
  7. Synthetic promoters functional in Francisella novicida and Escherichia coli. - Ralph L McWhinnie;Francis E Nano - Applied and environmental microbiology (2014)
  8. Statistical experimental design guided optimization of a one-pot biphasic multienzyme total synthesis of amorpha-4,11-diene. - Xixian Chen;Congqiang Zhang;Ruiyang Zou;Kang Zhou;Gregory Stephanopoulos;Heng Phon Too - PloS one (2013)
  9. Building synthetic cellular organization. - Jessica K Polka;Pamela A Silver - Molecular biology of the cell (2013)
  10. High-level diterpene production by transient expression in Nicotiana benthamiana. - Kathleen Brückner;Alain Tissier - Plant methods (2013)

... (669 more literatures)

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