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Artemisia annua mutant impaired in artemisinin synthesis demonstrates importance of nonenzymatic conversion in terpenoid metabolism

机译:在青蒿素合成中受损的青蒿突变体表明在萜类代谢中非酶促转化的重要性

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摘要

Artemisinin, a sesquiterpene lactone produced by Artemisia annua glandular secretory trichomes, is the active ingredient in the most effective treatment for malaria currently available. We identified a mutation that disrupts the amorpha-4,11-diene C-12 oxidase (CYP71AV1) enzyme, responsible for a series of oxidation reactions in the artemisinin biosynthetic pathway. Detailed metabolic studies of cyp71av1-1 revealed that the consequence of blocking the artemisinin biosynthetic pathway is the redirection of sesquiterpene metabolism to a sesquiterpene epoxide, which we designate arteannuin X. This sesquiterpene approaches half the concentration observed for artemisinin in wild-type plants, demonstrating high-flux plasticity in A. annua glandular trichomes and their potential as factories for the production of novel alternate sesquiterpenes at commercially viable levels. Detailed metabolite profiling of leaf maturation time-series and precursor-feeding experiments revealed that nonenzymatic conversion steps are central to both artemisinin and arteannuin X biosynthesis. In particular, feeding studies using 13C-labeled dihydroartemisinic acid (DHAA) provided strong evidence that the final steps in the synthesis of artemisinin are nonenzymatic in vivo. Our findings also suggest that the specialized subapical cavity of glandular secretory trichomes functions as a location for both the chemical conversion and the storage of phytotoxic compounds, including artemisinin. We conclude that metabolic engineering to produce high yields of novel secondary compounds such as sesquiterpenes is feasible in complex glandular trichomes. Such systems offer advantages over single-cell microbial hosts for production of toxic natural products.
机译:青蒿素是一种由青蒿腺分泌性毛状体产生的倍半萜内酯,是目前最有效的疟疾治疗方法中的活性成分。我们确定了一个突变,该突变破坏了amorpha-4,11-二烯C-12氧化酶(CYP71AV1)酶,该酶负责青蒿素生物合成途径中的一系列氧化反应。 cyp71av1-1的详细代谢研究表明,阻断青蒿素生物合成途径的结果是倍半萜烯代谢重新定向为倍半萜烯环氧化物,我们将其指定为青蒿素X。该倍半萜烯接近野生型植物中所观察到的青蒿素浓度的一半。年青腺毛状体的高通量可塑性及其作为工厂生产具有商业可行性水平的新型倍半萜的潜力。叶片成熟时间序列的详细代谢物分析和前体喂养实验表明,非酶促转化步骤对于青蒿素和青蒿素X生物合成都是至关重要的。特别是,使用13C标记的二氢青蒿酸(DHAA)进行的喂养研究提供了有力的证据,证明合成青蒿素的最终步骤在体内是非酶促的。我们的发现还表明,腺体分泌的毛状体的根尖下腔可作为化学转化和包括青蒿素在内的植物毒性化合物的储存场所。我们得出结论,在复杂的腺毛中,进行代谢工程以产生高收率的新型次生化合物(如倍半萜)是可行的。这样的系统在生产有毒天然产物方面比单细胞微生物宿主更具优势。

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