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Abstract

In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths(1). 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(2). 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(3). 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.

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.;  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.;  Jiang, H.;  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.

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  • Abstract, title and references ● Is the aim clear? Yes ● Is it clear what the study found and how they did it? Yes ● Is the title informative and relevant? Yes ● Are the references: ● Relevant? Yes ● Recent? Yes ● Referenced correctly? Yes ● Are appropriate key studies included? Yes Introduction/ background ● Is it clear what is already known about this topic? Yes ● Is the research question clearly outlined? Yes ● Is the research question justified given what is already known about the topic? Yes Methods ● Is the process of subject selection clear? Yes ● Are the variables defined and measured appropriately? Yes ● Are the study methods valid and reliable? To some Extent ● Is there enough detail in order to replicate the study? Yes Results ● Is the data presented in an appropriate way? Yes ● Tables and figures relevant and clearly presented? Yes ● Appropriate units, rounding, and number of decimals? Yes ● Titles, columns, and rows labelled correctly and clearly? Yes ● Categories grouped appropriately? Yes ● Does the text in the results add to the data or is it repetitive? repetitive ● Are you clear about what is a statistically significant result? Yes ● Are you clear about what is a practically meaningful result? Yes Discussion and Conclusions ● Are the results discussed from multiple angles and placed into context without being over interpreted? Yes ● Do the conclusions answer the aims of the study? To some extent ● Are the conclusions supported by references or results? Yes ● Are the limitations of the study fatal or are they opportunities to inform future research? Needs Future Research.

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  • Abstract, title and references ● Is the aim clear? Yes ● Is it clear what the study found and how they did it? Yes ● Is the title informative and relevant? Yes ● Are the references: ● Relevant? Yes ● Recent? Yes ● Referenced correctly? Yes ● Are appropriate key studies included? Yes Introduction/ background ● Is it clear what is already known about this topic? Yes ● Is the research question clearly outlined? Yes ● Is the research question justified given what is already known about the topic? Yes Methods ● Is the process of subject selection clear? Yes ● Are the variables defined and measured appropriately? Yes ● Are the study methods valid and reliable? To some Extent ● Is there enough detail in order to replicate the study? Yes Results ● Is the data presented in an appropriate way? Yes ● Tables and figures relevant and clearly presented? Yes ● Appropriate units, rounding, and number of decimals? Yes ● Titles, columns, and rows labelled correctly and clearly? Yes ● Categories grouped appropriately? Yes ● Does the text in the results add to the data or is it repetitive? repetitive ● Are you clear about what is a statistically significant result? Yes ● Are you clear about what is a practically meaningful result? Yes Discussion and Conclusions ● Are the results discussed from multiple angles and placed into context without being over interpreted? Yes ● Do the conclusions answer the aims of the study? To some extent ● Are the conclusions supported by references or results? Yes ● Are the limitations of the study fatal or are they opportunities to inform future research? Needs Future Research.

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