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

文献信息 ​

DOI10.1038/nature12051
PMID23575629
期刊Nature
影响因子48.5
JCR 分区Q1
发表年份2013
被引次数679
关键词青蒿素, 半合成生产, 合成生物学, 酿酒酵母, 抗疟疾
文献类型Journal Article, Research Support, Non-U.S. Gov't
ISSN0028-0836
页码528-32
期号496(7446)
作者C 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

一句话小结 ​

本研究利用合成生物学开发出一种高产青蒿酸的酵母菌株，实现了每升25克青蒿酸的发酵产量，并建立了一种高效的化学工艺将青蒿酸转化为青蒿素，解决了青蒿素供应不稳定的问题。这一成果为降低抗疟药物成本、增强发展中国家治疗疟疾的能力提供了可行的工业生产方案，具有重要的公共卫生意义。

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青蒿素 · 半合成生产 · 合成生物学 · 酿酒酵母 · 抗疟疾

摘要 ​

在2010年，全球有超过2亿例疟疾病例，至少导致65.5万人死亡。世界卫生组织建议使用基于青蒿素的联合疗法（ACTs）来治疗由恶性疟原虫（Plasmodium falciparum）引起的无并发症疟疾。青蒿素是一种具有强效抗疟特性的倍半萜内过氧化物，由植物青蒿（Artemisia annua）生产。然而，植物来源的青蒿素供应不稳定，导致短缺和价格波动，给ACT制造商的生产计划带来复杂性。因此，需要一个稳定且价格合理的青蒿素来源。在此，我们利用合成生物学开发了高产青蒿酸（青蒿素的前体）生物生产的酵母菌株（酿酒酵母，Saccharomyces cerevisiae）。以往尝试生产具有商业相关浓度的青蒿酸均以失败告终，仅能生产每升1.6克的青蒿酸。在这项研究中，我们展示了完整的生物合成途径，包括发现了一种植物脱氢酶和第二种细胞色素，这为青蒿酸提供了一条高效的生物合成途径，发酵产量达每升25克青蒿酸。此外，我们开发了一种实用、高效且可扩展的化学工艺，用于将青蒿酸转化为青蒿素，采用化学来源的单重氧，从而避免了对专用光化学设备的需求。这里描述的菌株和工艺构成了生产半合成青蒿素的可行工业过程的基础，以稳定青蒿素的供应，以便将其衍生化为活性药物成分（例如青蒿琥酯），并纳入ACTs中。由于所有知识产权均已免费提供，这项技术有潜力以降低的年度平均价格，增加对发展中国家一线抗疟治疗的供应。

英文摘要 ​

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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主要研究问题 ​

  1. 半合成青蒿素生产过程中使用的酵母菌株有哪些特性，使其在高产率方面表现优异？
  2. 在提高青蒿酸的发酵产量方面，发现的植物脱氢酶和第二个细胞色素的具体作用是什么？
  3. 该研究中的化学过程如何有效地避免使用专门的光化学设备，具体步骤是什么？
  4. 半合成青蒿素的工业生产如何帮助稳定青蒿素的供应，并对全球抗疟疾治疗产生何种影响？
  5. 在抗疟疾药物的生产中，如何评估新技术对降低成本和提高可及性的实际效果？

核心洞察 ​

1. 研究背景和目的 ​

据世界卫生组织统计，2010年全球有超过2亿例疟疾病例，造成至少65.5万人死亡。针对由恶性疟原虫（Plasmodium falciparum）引起的无并发症疟疾，世界卫生组织推荐使用基于青蒿素的联合疗法（ACTs）。青蒿素是一种由植物青蒿（Artemisia annua）生产的强效抗疟药物。然而，由于青蒿素的植物来源供应不稳定，导致其短缺和价格波动，给ACT制造商的生产计划带来了挑战。因此，本研究旨在利用合成生物学开发一种稳定、经济的青蒿素来源，以满足市场需求并降低生产成本。

2. 主要方法和发现 ​

研究团队使用合成生物学技术，开发了高产的酿酒酵母（Saccharomyces cerevisiae）菌株，以生物合成青蒿酸（青蒿素的前体）。之前的研究中，青蒿酸的产量仅为每升1.6克，未能满足商业需求。本研究首次展示了完整的生物合成途径，并发现了一种植物脱氢酶和第二种细胞色素，显著提高了青蒿酸的生物合成效率，最终实现了每升25克青蒿酸的发酵产量。此外，研究团队还开发了一种高效且可扩展的化学转化工艺，利用单态氧将青蒿酸转化为青蒿素，避免了对专门光化学设备的需求。

3. 核心结论 ​

本研究实现了青蒿酸的高效生物合成和青蒿素的简化转化过程，为工业化生产半合成青蒿素奠定了基础。这一过程的可行性将有助于稳定青蒿素的供应，进而为ACT的活性药物成分（如阿莫地喹）提供原材料。此外，由于所有知识产权免费提供，该技术有潜力降低抗疟治疗在发展中国家的平均年度价格。

4. 研究意义和影响 ​

该研究的成功开发不仅为全球抗疟疾治疗提供了一个稳定、经济的青蒿素来源，还可能改变目前依赖植物提取的生产模式，降低了对自然资源的依赖，从而提升了生产的可持续性。此外，该技术的普及预计将增强发展中国家对一线抗疟疾治疗的可及性，有助于降低疟疾相关的死亡率和疾病负担，促进公共健康的改善。

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  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)

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