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Artemisinin Biosynthesis: Role of Reactive Oxygen

青蒿素生物合成：活性氧的作用

基本信息

批准号：
7778392
负责人：
PAMELA J WEATHERS
金额：
$ 22.37万
依托单位：
WORCESTER POLYTECHNIC INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2013-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Artemisinin (AN), produced by the plant Artemisia annua L., is a proven therapeutic for treating malaria and also for treatment of a large range of bacterial, viral and parasitic diseases, and cancers. While AN has high value as a therapeutic, its production is only cost effective when harvested from field grown plants. Understanding biosynthetic control of this important terpenoid drug is crucial to meeting the growing worldwide demand. Recently we showed that plants subjected to reactive oxygen stress produce higher levels of AN and its precursors. Since this phenomenon has the potential to link a variety of established AN elicitors in a unified model, we propose investigating reactive oxygen stress as a key regulator of AN biosynthesis. Our 3 objectives are: 1. Investigation of the relative expression levels of early (HMGR, FPS) and late dedicated (ADS, CYP71AV1, DBR2, ALDH1) genes as plants are subjected to diverse sources of oxidative stress, including photo, drought, and chemically induced oxidation. These data would serve to identify a transcriptional basis for ROS induction of AN production. 2. Compare metabolic profiles and the redox state of plants under normal and oxygen stressed growing conditions. Measuring key metabolic intermediates allows us to form a preliminary metabolic balance map showing key points of change upon ROS-induced perturbations to help further elucidate the ROS role in the putative non-enzymatic last step of AN biosynthesis and metabolite balance control not readily identifiable through transcript analysis. 3. Investigate and demonstrate in soil-grown plants a process for increasing AN production through the induction of oxidative stress by both biotic and abiotic means that will allow for optimizing production of AN while simultaneously allowing for maximum plant growth. This will further correlate potentially simple methods that could be employed immediately to induce mild oxidative stress for over production of artemisinin in soil-grown plants. These results will further our fundamental understanding of the biosynthesis of artemisinin in A. annua and will further our ability to enhance its production to meet the ever growing therapeutic demand. PUBLIC HEALTH RELEVANCE: Malaria and the neglected tropical diseases addressed in our proposal account for >500 million infections and upwards of 2 million deaths. Artemisinin has been shown to be effective against all of these diseases, but the drug is in desperately short supply to treat even malaria. Our studies on reactive oxygen will facilitate a better understanding of the last steps in the biosynthetic pathway thereby enhancing the potential to increase the drug produced in the plant.

描述（由申请人提供）：青蒿素（AN）由植物黄花蒿（Artemisia annua L.）生产，是一种经证实的治疗疟疾的药物，也可用于治疗多种细菌、病毒和寄生虫病以及癌症。虽然AN具有很高的治疗价值，但它的生产只有在从田间种植的植物中收获时才具有成本效益。了解这种重要萜类药物的生物合成控制对于满足日益增长的全球需求至关重要。最近我们发现，植物受到活性氧胁迫产生更高水平的AN及其前体。由于这种现象有可能将各种已建立的AN激发子连接在一个统一的模型中，我们建议研究活性氧应激作为AN生物合成的关键调节因子。我们的三个目标是：1。研究植物在不同来源的氧化胁迫下，早期（HMGR， FPS）和后期专用（ADS, CYP71AV1, DBR2, ALDH1）基因的相对表达水平，包括光、干旱和化学诱导氧化。这些数据将有助于确定ROS诱导AN产生的转录基础。2. 比较植物在正常和缺氧生长条件下的代谢特征和氧化还原状态。测量关键代谢中间体使我们能够形成一个初步的代谢平衡图，显示ROS引起的扰动的关键变化点，有助于进一步阐明ROS在AN生物合成的非酶最后一步和代谢物平衡控制中的作用，这些作用不易通过转录物分析确定。3. 在土壤生长的植物中，研究并证明通过生物和非生物方式诱导氧化应激来增加AN产量的过程，这将允许优化AN的生产，同时允许最大限度的植物生长。这将进一步将潜在的简单方法联系起来，这些方法可以立即用于诱导土壤种植植物中过度生产青蒿素的轻度氧化应激。这些结果将进一步加深我们对青蒿素生物合成的基本理解，并将进一步提高我们的生产能力，以满足日益增长的治疗需求。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The flavonoids casticin and artemetin are poorly extracted and are unstable in an Artemisia annua tea infusion.

DOI：
10.1055/s-0032-1314949
发表时间：
2012-06
期刊：
Planta medica
影响因子：
2.7
作者：
Weathers PJ;Towler MJ
通讯作者：
Towler MJ

Trichomes + roots + ROS = artemisinin: regulating artemisinin biosynthesis in Artemisia annua L.

DOI：
10.1007/s11627-011-9343-x
发表时间：
2011-06
期刊：
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-PLANT
影响因子：
2.6
作者：
Nguyen, Khanhvan T.;Arsenault, Patrick R.;Weathers, Pamela J.
通讯作者：
Weathers, Pamela J.

DMSO triggers the generation of ROS leading to an increase in artemisinin and dihydroartemisinic acid in Artemisia annua shoot cultures.

DOI：
10.1007/s00299-009-0807-y
发表时间：
2010-02
期刊：
PLANT CELL REPORTS
影响因子：
6.2
作者：
Mannan, Abdul;Liu, Chunzhao;Arsenault, Patrick R.;Towler, Melissa J.;Vail, Dan R.;Lorence, Argelia;Weathers, Pamela J.
通讯作者：
Weathers, Pamela J.

Biomass production of hairy roots of Artemisia annua and Arachis hypogaea in a scaled-up mist bioreactor.