Artemisinin Biosynthesis: Control of Transcription

青蒿素生物合成：转录控制

• 批准号: 7251827
• 负责人: PAMELA J WEATHERS
• 金额: $ 20.62万
• 依托单位: WORCESTER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2010-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251827
• 关键词: Abbreviations; Acids; Affect; Anabolism; Antimalarials; Artemisia annua; Artemisinins; Carbon; Complex; Condition; Cytochrome P450; D-xylulose-5-phosphate; Data; Development; Dose; Engineering; Enzymes; FPS-FES Oncogene; Flowers; Fructose; Gene Expression; Genes; Genetic Transcription; Geranyltranstransferase; Glucose; Goals; Growth; Hydroxymethylglutaryl-CoA reductase; Individual; Knowledge; Lactones; Malaria; Metabolic; Molecular; Pathway interactions; Pharmaceutical Preparations; Plants; Production; Protein Isoforms; RNA Interference; Regulation; Regulator Genes; Relative (related person); Role; Seedling; Sesquiterpenes; Source; Squalene Synthetase; Staging; Sterols; Sucrose; Terpenes; Terpenoid Biosynthesis Pathway; Testing; Therapeutic; Transcriptional Regulation; Transgenic Organisms; Vascular Plant; Weight; Work; amorpha-4,11-diene synthase; anti-cancer therapeutic; antimicrobial; arteannuin B; artemisic acid; artemisinine; cost; doxorubicin/mitomycin/vinblastine protocol; drug production; farnesyl pyrophosphate; gibberellic acid; indolepropanol phosphate; isopentenyl pyrophosphate; mevalonate; novel; sugar; tool; trichodiene synthase

DESCRIPTION (provided by applicant): Artemisinin (AN), and its derivatives are proven effective antimalarial therapeutics that also been shown to have effective activity as broad spectrum antimicrobials, and anticancer therapeutics. AN is a complex compound and still best produced by the plant Artemisia annua. Little is known, however, about how AN biosynthesis is regulated, although the following is known about its production: more AN or its precursor, artemisinic acid (AA), is made when plants shift from vegetative growth to flowering, or grown on glucose instead of sucrose (our recent data). Since these conditions strongly affect AN production, we propose to use them to study the transcriptional regulation of AN biosynthetic genes. OUR HYPOTHESES: 1. Artemisinin biosynthesis is regulated at multiple steps in the pathway, both early (pre- FDP) and late (post-FDP). 2. Developmental stage and carbon source regulate the transcription of several genes in this pathway. 3. Coordinate control of artemisinin and sterol production occurs at the level of transcription. TECHNICAL OBJECTIVES: The long-term goal of our work is to develop a fundamental understanding of the regulatory control of terpene production in Artemisia annua so that metabolic manipulation of terpenoid biosynthesis can eventually be developed not only for artemisinin but other therapeutically important plant produced terpenoid drugs. This work has 3 objectives to be accomplished over 2.5 years: 1. To compare the relative expression of the terpenoid biosynthetic genes pre farnesyl diphosphate (FDP), and post FDP leading to AN with levels of both AA, DHAA, and AN production in A. annua seedlings as they are shifted from vegetative growth to conditions that induce flowering. 2. To compare the relative expression of the terpenoid biosynthetic genes pre farnesyl diphosphate (FDP), and post FDP leading to AN with levels of both AA, DHAA, and AN production in A. annua seedlings grown in glucose, fructose, and sucrose. 3. Include analysis of SQS expression in these studies to determine coordinate control of expression. Unfortunately little is still known about how important plant products like AN are produced in the plant and high production of terpenoids in low cost field-grown plants still remains challenging. This information is important because there has been little comprehensive effort to fully understand the regulation of not only this very important therapeutic sesquiterpene, but also other plant-derived terpenes that could have potentially very beneficial medicinal applications. The most potent therapeutic available for curing malaria, artemisinin, is produced in the plant, "Sweet Annie", but at levels too low to be able to provide adequate doses to annually treat the millions of cases that occur worldwide. The proposed study is a first step in helping us understand how to control artemisinin's biosynthesis to ultimately increase the production of this drug, and others that are chemically similar, in low cost field-grown plants.

描述（由申请人提供）：青蒿素（AN）及其衍生物被证明是有效的抗疟疾治疗剂，也被证明具有作为广谱抗微生物剂和抗癌治疗剂的有效活性。AN是一种复杂的化合物，仍然最好由植物黄花蒿产生。然而，关于AN的生物合成是如何调节的知之甚少，尽管以下是关于其生产的已知信息：当植物从营养生长转变为开花时，或在葡萄糖而不是蔗糖上生长时，会产生更多的AN或其前体青蒿酸（AA）（我们最近的数据）。由于这些条件强烈影响AN生产，我们建议使用它们来研究AN生物合成基因的转录调控。我们的假设：1.青蒿素生物合成在途径的多个步骤中受到调节，早期（FDP前）和晚期（FDP后）。2.发育阶段和碳源调节该途径中几个基因的转录。3.青蒿素和甾醇生产的协调控制发生在转录水平。技术支持：我们工作的长期目标是发展对青蒿中萜类化合物生产的调控的基本理解，以便最终不仅可以开发青蒿素而且可以开发其他具有治疗重要性的植物产生的萜类化合物药物的萜类化合物生物合成的代谢操纵。这项工作有三个目标要在2.5年内完成：1。比较法呢基二磷酸（FDP）前和FDP后导致AN的萜类生物合成基因的相对表达与A.当它们从营养生长转变到诱导开花的条件时。2.比较法呢基二磷酸（FDP）前和FDP后导致AN的萜类生物合成基因的相对表达与A.在葡萄糖、果糖和蔗糖中生长的黄花树幼苗。3.在这些研究中包括SQS表达分析，以确定表达的协调控制。不幸的是，关于在植物中产生像AN这样的植物产品的重要性仍然知之甚少，并且在低成本的田间生长的植物中高产量的萜类化合物仍然具有挑战性。这一信息很重要，因为几乎没有全面的努力来充分理解不仅这种非常重要的治疗性倍半萜的调节，而且其他植物来源的萜烯也可能具有潜在的非常有益的医药应用。治疗疟疾最有效的药物青蒿素是在“甜安妮”工厂生产的，但水平太低，无法提供足够的剂量来治疗每年发生在世界各地的数百万病例。这项拟议中的研究是帮助我们了解如何控制青蒿素生物合成的第一步，以最终增加这种药物的产量，以及其他化学性质相似的药物，在低成本的田间种植植物中。