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Artemisinic acid and arteannuin B are biogenetic precursors of artemisinin, ..

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Although total synthesis of artemisinin is difficult and costly, 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 artemisinin.

Another alternate production procedure is the total synthesis of artemisinin

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.

Continuous synthesis of artemisinin-derived ..

Home > News > Continuous synthesis of artemisinin-derived medicines

Chris Paddon is a Principal Scientist at Amyris, Inc. in Emeryville, CA. He was project leader for the Semi-Synthetic Artemisinin project, and subsequently led a number of projects at Amyris using synthetic biology for the production of natural products. He received his Bachelor's degree in Microbiology from The University of Surrey (UK), and doctorate in Biochemistry from Imperial College (London, UK). Following postdoctoral work at The National Institutes for Health (Bethesda, MD) he joined the pharmaceutical industry, working for GSK (London, UK). He subsequently worked for Affymax (Palo Alto, CA) and Xenoport (Santa Clara, CA) before joining Amyris.

As the world's population and economies grow, the demand for a wide variety of specialty, commodity, and pharmaceutical chemicals will outpace the supply available from current sources. There is an urgent need to develop alternative, sustainable sources of many existing chemicals and to develop abundant sources of currently scarce chemicals with novel beneficial properties. Synthetic biology and industrial fermentation, combined with synthetic chemistry, will be an increasingly important source of chemicals in the decades ahead; artemisinin and β-farnesene provide good examples of this relatively new approach to chemical production. Brazil's plentiful sugar cane feedstock and fermentation expertise make it an excellent location for this type of manufacturing, which can expand and diversify the nation's industrial base and international importance.

drug precursor artemisinic acid in ..

Advances in Artemisinin Production | Malaria | Biosynthesis

The rationale for developing microbial isoprenoid production using large-scale fermentation of microbes engineered to manufacture these compounds is that the product will cost less, supply will be more reliable and plentiful, and production will be more ecologically sustainable. An example of this strategy is provided by the semi-synthetic artemisinin project. Artemisinin is a sesquiterpene lactone endoperoxide () with potent anti-malarial activity produced by the plant Artemisia annua. It is the key component of artemisinin combination therapies (ACTs), recommended in 2004 by the World Health Organization (WHO) for the first line treatment of malaria. Following the adoption of ACTs by the WHO, the price of plant-derived artemisinin increased dramatically and has fluctuated ever since between ca. $1,000 per kg and less than $200 per kg, with supply shortages in some years. An alternative to the plant-derived production of artemisinin was desired to stabilize the supply and reduce the price of this essential drug. Total chemical synthesis is infeasible within the economics required for a medicine used broadly in the developing world. Thus, a plan was developed to produce artemisinin using biotechnology, specifically by fermentation using engineered microbes. The metabolic pathway for the production of artemisinic acid, a presumed late-stage precursor of artemisinin in A. annua, was elucidated during the 2000s, leading to a decision to first produce amorphadiene, the alkene precursor of artemisinin, then to develop the three-step oxidation of amorphadiene to artemisinic acid in yeast followed by chemical conversion to artemisinin (Figure 1). The path followed by the semi-synthetic artemisinin project, with particular emphasis on the development of fermentative production of late-stage precursors has been recently reviewed.

The antimalarial drug artemisinin and the specialty chemical β-farnesene are examples of natural product isoprenoids that can help solve global challenges, but whose usage has previously been limited by supply and cost impediments. This review describes the path to commercial production of these compounds utilizing fermentation of engineered yeast. Development of commercially viable yeast strains was a substantial challenge that was addressed by creation and implementation of an industrial synthetic biology pipeline. Using the engineered strains, production of β-farnesene from Brazilian sugarcane offers several environmental advantages. Among the many commercial applications of β-farnesene, its use as a feedstock for making biodegradable lubricants is highlighted. This example, along with others, highlight a powerful new suite of technologies that will become increasingly important for production of chemicals, spanning from pharmaceuticals through commodity chemicals.

Recent Advances in Artemisinin Production ..
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  • ARTEMISININ: THE BIOSYNTHETIC PATHWAY AND ITS ..

    Extraction of artemisinin and artemisinic acid: preparation of artemether and new analogues Richard K

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Production of artemisinic acid or β-farnesene by engineered yeast

The reactor we used in the original study cost €50,000. We have further refined the process so that the new reactor now costs about €10,000 and requires a lot less energy and space. One such reactor can make about 800g of artemisinin per day. In theory, by running 400 such reactors continuously for a year we could make the entire world supply of the drug for a one-time investment of around €4m. We are looking at working with people who are isolating artemisinin from plants and who have plenty of waste product, or companies like Amyris and Sanofi who are experimenting with engineering yeast to produce artemisinic acid directly. The key here is to make as much artemisinin as the world needs at the lowest possible price. With the right partner, we could have commercial production up and running in six months.

acid to artemisinin and artemisinic acid to ..

Two recent schemes for conversion of artemisinic acid to artemisinin have been described, both based on the original synthesis by Roth and Acton. Amyris chemists published a non-photochemical route with a lab-scale yield of 23%, though the process was not optimized. However, the industrial conversion used by Sanofi uses large-scale photo-Schenk ene-chemistry with specially designed and constructed large-scale photoreactors. The final optimized process delivered a 55% total yield of pure isolated artemisinin on a batch scale starting with 600 kg of pure fermentation-derived artemisinic acid. This process was used for production of 35 t of semi-synthetic artemisinin in 2013 and 60 t in 2014. The reaction scheme is described in .

Artemisinic acid - Stanford Chemicals

Although it was first synthesised in 1982, in practice it has been very difficult to scale up the process, hence our continued dependence on the plant product. However, we knew from the work of other researchers that two of the byproducts of the plant – artemisinic acid and dihydroartemisinic acid – were good starting points for synthesis. At present, these compounds are thrown away. Our idea was to see if we could make artemisinin from artemisinic acid using reactive molecules called singlet oxygen and the process of flow chemistry.

Custom Synthesis; Laboratory Equipment; News ..

Semi-synthetic artemisinin is a pharmaceutical with a price point comparable to plant-derived artemisinin, namely above $150 per kg. β-Farnesene, however, is a specialty chemical with multiple uses (more details below); most specialty and commodity chemicals have significantly lower price points, often below $10 per kg. For these product categories, it is of paramount importance that fermentative production be as efficient as possible, with high yields (namely, grams of product made per gram of feed substrate), productivities (grams of product/liter of culture/hour) and concentration (also known as titer; grams of product per liter of culture). Developing yeast strains capable of the yield, productivity and titer required for chemical production requires extensive development, and has been enabled over the last decade by the new discipline of synthetic biology. Synthetic biology seeks to extend approaches and concepts from engineering and computation to redesign biology for a chosen function; recent advances in the application of design automation, i.e., the use of software, hardware and robotics have enabled the creation and screening of hundreds of thousands of strain variants (created by both design and random mutagenesis) for the properties required for commercial production of β-farnesene. Notable enabling technologies developed for routine usage include rapid and reliable assembly of large (i.e., multiple kilobase) deoxyribonucleic acid (DNA) constructs;- high throughput, cost effective, verification of structural DNA assemblies by both initial restriction digest and by low-cost DNA sequencing; and whole genome sequencing of yeast strains. In addition, there is a need to effectively identify the best new strains (akin to panning for gold!) through high throughput, rapid, and accurate methods to screen thousands of strains. Further, the results of small-scale ( 50,000 liter) production. Development and implementation of these technologies required considerable investment by Amyris. The outcome is a robust pipeline for efficient, cost-effective strain generation allied with screening for the properties required for commercial production of β-farnesene by fermentation (i.e., at a price point required for its use as a specialty chemical). A video compilation summarizing the uses and benefits of the above technologies is available online.

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