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      Advances in biotechnological production of santalenes and santalols

      review-article
      Author(s): a , b , a , b , *
      Publication date (Electronic):
      Journal: Chinese Herbal Medicines
      Publisher: Elsevier
      Keywords: biosynthesis, biotechnological production, sandalwood oil, santalenes, santalols

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          Abstract

          Sandalwood essential oil has been widely used not only as natural medicines but also in perfumery and food industries, with sesquiterpenoids as its major components including ( Z)- α-santalol and ( Z)- β-santalol and so on. The mature heartwoods of Santalum album, Santalum austrocaledonicum and Santalum spicatum are the major plant resources for extracting sandalwood essential oil, which have been overexploited. Synthetic biology approaches have been successfully applied to produce natural products on large scale. In this review, we summarize biosynthetic enzymes of santalenes and santalols, including various santalene synthases (STSs) and cytochrome P450 monooxygenases (CYPs), and then highlight the advances of biotechnological production of santalenes and santalols in heterologous hosts, especially metabolic engineering strategies for constructing santalene- and santalol-producing Saccharomyces cerevisiae.

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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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              The Ehrlich pathway for fusel alcohol production: a century of research on Saccharomyces cerevisiae metabolism.

              Lucie Hazelwood, Jean-Marc G Daran, Antonius van Maris … (2008)
              Article 0 comments Cited 184 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jia-chen Zi
                Journal
                Journal ID (nlm-ta): Chin Herb Med
                Journal ID (iso-abbrev): Chin Herb Med
                Title: Chinese Herbal Medicines
                Publisher: Elsevier
                ISSN (Print): 1674-6384
                ISSN (Electronic): 2589-3610
                Publication date PMC-release: 01 December 2020
                Publication date Collection: January 2021
                Publication date (Electronic): 01 December 2020
                Volume: 13
                Issue: 1
                Pages: 90-97
                Affiliations
                [a ]Biotechnological Institute of Chinese Materia Medica, Jinan University, Guangzhou 510632, China
                [b ]College of Pharmacy, Jinan University, Guangzhou 510632, China
                Author notes
                [* ]Corresponding author. jiachen_zi@ 123456163.com
                Article
                Publisher Item ID: S1674-6384(20)30116-7
                DOI: 10.1016/j.chmed.2020.11.002
                PMC ID: 9476758
                SO-VID: cf5874f3-ba7a-4891-946c-c8af23005226
                Copyright © © 2020 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 11 June 2020
                Date revision received : 17 July 2020
                Date accepted : 27 July 2020
                Categories
                Subject: Review

                Keywords: biosynthesis,biotechnological production,sandalwood oil,santalenes,santalols
                Data availability:
                Keywords: biosynthesis, biotechnological production, sandalwood oil, santalenes, santalols

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