An Efficient Chemoenzymatic Synthesis of Dihydroartemisinic Aldehyde.
An Efficient Chemoenzymatic Synthesis of Dihydroartemisinic Aldehyde.
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DOI：
10.1002/anie.201609557
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发表时间：
2017-04-03
期刊：
影响因子：
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通讯作者：
Allemann RK
中科院分区：
文献类型：
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作者：
Demiray M;Tang X;Wirth T;Faraldos JA;Allemann RK
从黄花蒿中提取的青蒿素是治疗疟疾最有效的药物。在植物中，倍半萜环化酶、细胞色素依赖性CYP450和醛还原酶将法尼酯二磷酸（FDP）转化为双氢青蒿醛（DHAAl），后者是青蒿素生物合成的关键中间体，也是其化学合成的半合成前体。在这里，我们报告了一种化学酶过程，该过程能够仅使用精心设计的羟基化FDP衍生物的倍半萜合成酶来传递DHAAl。这一过程逆转了FDP的自然环化顺序和倍半萜烯碳氢化合物的氧化顺序，为DHAAl的合成提供了显著的改进，并展示了底物工程在萜烯合酶介导的高价值天然产物合成中的潜力。
Artemisinin from the plant Artemisia annua is the most potent pharmaceutical for the treatment of malaria. In the plant, the sesquiterpene cyclase amorphadiene synthase, a cytochrome‐dependent CYP450, and an aldehyde reductase convert farnesyl diphosphate (FDP) into dihydroartemisinic aldehyde (DHAAl), which is a key intermediate in the biosynthesis of artemisinin and a semisynthetic precursor for its chemical synthesis. Here, we report a chemoenzymatic process that is able to deliver DHAAl using only the sesquiterpene synthase from a carefully designed hydroxylated FDP derivative. This process, which reverses the natural order of cyclization of FDP and oxidation of the sesquiterpene hydrocarbon, provides a significant improvement in the synthesis of DHAAl and demonstrates the potential of substrate engineering in the terpene synthase mediated synthesis of high‐value natural products.