Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
Université de Tours, EA2106 Biomolécules et Biotechnologies Végétales, Parc de Grandmont 37200 Tours, France.
Science. 2018 Jun 15;360(6394):1235-1239. doi: 10.1126/science.aat4100. Epub 2018 May 3.
Vinblastine, a potent anticancer drug, is produced by (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.
长春碱是一种有效的抗癌药物，少量存在于（马达加斯加长春花）中，异源重建长春碱的生物合成可以为这种药物提供额外的来源。然而，长春碱合成的化学基础使得鉴定生物合成基因具有挑战性。在这里，我们确定了这种植物中长春碱生物合成所必需的两种缺失酶：一种氧化酶和一种还原酶，它将茎嘧啶乙酸转化为二氢前康拉定乙酸，然后通过本文中描述的两种水解酶脱乙酰基和环化生成长春质碱或文多灵。该途径展示了植物如何创造化学多样性，也为基于茎嘧啶的生物活性化合物的异源生成平台的发展提供了可能。
