Engineering biosynthesis of the anticancer alkaloid noscapine in yeast.
Engineering biosynthesis of the anticancer alkaloid noscapine in yeast.
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DOI：
10.1038/ncomms12137
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发表时间：
2016-07-05
影响因子：
16.6
通讯作者：
Smolke CD
中科院分区：
文献类型：
--
作者：
Li Y;Smolke CD
诺斯卡品是从罂粟中分离的一种潜在的抗癌药物，最近发现编码负责合成诺斯卡品的酶的基因聚集在罂粟的基因组上。在这里，我们重建的诺斯卡品基因簇在酿酒酵母实现诺斯卡品和相关途径中间体的微生物生产，补充和扩展以前在植物和体外研究。我们的工作提供了裂小檗碱中间体的结构验证和那可托林-4 ′-O-甲基转移酶的描述，表明该活性由独特的异二聚体催化。我们还重建了一个14步的生物合成途径的诺斯卡品从简单的生物碱norlaudanosoline工程酵母菌株表达16异源植物酶，实现了一个复杂的植物途径在微生物宿主重建。其他工程酵母产生以前难以接近的途径中间体和一种新的衍生物，从而推进原小檗碱和诺斯卡品相关药物的发现。 诺斯卡品是一种潜在的抗癌药物，传统上是从罂粟罂粟中分离出来的。在此，Li和Smolke重组了酿酒酵母中的诺斯卡品基因簇，实现了诺斯卡品及相关途径中间体的微生物生产，为诺斯卡品的生物合成提供了新的见解。
Noscapine is a potential anticancer drug isolated from the opium poppy Papaver somniferum, and genes encoding enzymes responsible for the synthesis of noscapine have been recently discovered to be clustered on the genome of P. somniferum. Here, we reconstitute the noscapine gene cluster in Saccharomyces cerevisiae to achieve the microbial production of noscapine and related pathway intermediates, complementing and extending previous in planta and in vitro investigations. Our work provides structural validation of the secoberberine intermediates and the description of the narcotoline-4′-O-methyltransferase, suggesting this activity is catalysed by a unique heterodimer. We also reconstitute a 14-step biosynthetic pathway of noscapine from the simple alkaloid norlaudanosoline by engineering a yeast strain expressing 16 heterologous plant enzymes, achieving reconstitution of a complex plant pathway in a microbial host. Other engineered yeasts produce previously inaccessible pathway intermediates and a novel derivative, thereby advancing protoberberine and noscapine related drug discovery. Noscapine is a potential anticancer drug that is traditionally isolated from the opium poppy Papaver somniferum. Here, Li and Smolke reconstitute the noscapine gene cluster in Saccharomyces cerevisiae, to achieve the microbial production of noscapine and related pathway intermediates, and provide new insights into the biosynthesis of noscapine.