Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle
Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle
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DOI：
10.1126/science.aat4100
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发表时间：
2018-06-15
期刊：
影响因子：
56.9
通讯作者：
O'Connor, Sarah E.
中科院分区：
文献类型：
--
作者：
Caputi, Lorenzo;Franke, Jakob;O'Connor, Sarah E.
长春碱是一种有效的抗癌药物，由长春花（马达加斯加长春花）少量产生，长春碱生物合成的异源重建可以提供这种药物的额外来源。然而，长春碱合成的化学基础使得生物合成基因的鉴定具有挑战性。在这里，我们确定了在这种植物中长春碱生物合成所必需的两种缺失的酶：氧化酶和还原酶，其将stemmadenine乙酸酯异构化为二氢precondylocarpine乙酸酯，然后通过本文表征的两种水解酶将其脱乙酰氧基化并环化为长春质碱或他勃松碱。这些途径显示了植物如何产生化学多样性，并且还能够开发用于产生stemadenine衍生的生物活性化合物的异源平台。
Vinblastine, a potent anticancer drug, is produced by Catharanthus roseus (Madagascar periwinkle) in small quantities, and heterologous reconstitution of vinblastine biosynthesis could provide an additional source of this drug. However, the chemistry underlying vinblastine synthesis makes identification of the biosynthetic genes challenging. Here we identify the two missing enzymes necessary for vinblastine biosynthesis in this plant: an oxidase and a reductase that isomerize stemmadenine acetate into dihydroprecondylocarpine acetate, which is then deacetoxylated and cyclized to either catharanthine or tabersonine via two hydrolases characterized herein. The pathways show how plants create chemical diversity and also enable development of heterologous platforms for generation of stemmadenine-derived bioactive compounds.