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      Biosynthesis of ursolic acid and oleanolic acid in Saccharomyces cerevisiae

      Author(s): 1 , 1 , 1 , 1 , 1 , 2 , 3
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      Journal: AIChE Journal
      Publisher: Wiley

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          Abstract

          Ursolic acid and oleanolic acid are pentacyclic triterpenoid compounds with a variety of biological activities. A mixture of ursolic acid and oleanolic acid has higher antitumor activity than the individual acids. We have developed a simultaneous biosynthesis pathway for different proportions of ursolic acid and oleanolic acid in Saccharomyces cerevisiae . The ScLCZ08 strain produced 175.15 mg/L of the ursolic acid precursor α‐amyrin, the highest amount reported. Ursolic and oleanolic acid titers and proportions were optimized using Medicago truncatula amyrin C‐28 oxidase and Arabidopsis thaliana cytochrome P450 reductase. Using glucose and ethanol fed‐batch fermentation strategies, the final ursolic acid and oleanolic acid titers were 123.27 and 155.58 mg/L, respectively, demonstrating 4.77‐fold and 4.95‐fold higher production than the parent strain. The ScLCZ11 strain displayed the highest ursolic acid production obtained via microbial fermentation in fed‐batch culture to date. © 2018 American Institute of Chemical Engineers AIChE J, 64: 3794–3802, 2018

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          Production of the antimalarial drug precursor artemisinic acid in engineered yeast.

          Dae-Kyun Ro, Eric M Paradise, Mario Ouellet … (2006)
          Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers. 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. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l(-1)) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid. 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. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.
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            High-level semi-synthetic production of the potent antimalarial artemisinin.

            C Paddon, P. J. Westfall, D Pitera … (2013)
            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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              DNA assembler, an in vivo genetic method for rapid construction of biochemical pathways

              Zengyi Shao, Ruo-Hua Zhao, Huimin Zhao (2009)
              The assembly of large recombinant DNA encoding a whole biochemical pathway or genome represents a significant challenge. Here, we report a new method, DNA assembler, which allows the assembly of an entire biochemical pathway in a single step via in vivo homologous recombination in Saccharomyces cerevisiae. We show that DNA assembler can rapidly assemble a functional d-xylose utilization pathway (∼9 kb DNA consisting of three genes), a functional zeaxanthin biosynthesis pathway (∼11 kb DNA consisting of five genes) and a functional combined d-xylose utilization and zeaxanthin biosynthesis pathway (∼19 kb consisting of eight genes) with high efficiencies (70–100%) either on a plasmid or on a yeast chromosome. As this new method only requires simple DNA preparation and one-step yeast transformation, it represents a powerful tool in the construction of biochemical pathways for synthetic biology, metabolic engineering and functional genomics studies.
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                Author and article information

                Contributors
                Journal
                Title: AIChE Journal
                Abbreviated Title: AIChE Journal
                Publisher: Wiley
                ISSN (Print): 0001-1541
                ISSN (Electronic): 1547-5905
                Publication date Created: November 2018
                Publication date (Electronic): August 27 2018
                Publication date (Print): November 2018
                Volume: 64
                Issue: 11
                Pages: 3794-3802
                Affiliations
                [1 ] Dept. of Biological Engineering School of Chemical Engineering and Technology, Tianjin University Tianjin 300072 China
                [2 ] Key Laboratory of system bioengineering (Tianjin University), Ministry of Education Tianjin 300072 China
                [3 ] Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) Tianjin 300072 China
                Article
                DOI: 10.1002/aic.16370
                SO-VID: 391b0943-0dbb-4e60-8838-6dbad02dfc0d
                Copyright © © 2018
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                http://onlinelibrary.wiley.com/termsAndConditions#vor

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