Miettinen Karel, Dong Lemeng, Navrot Nicolas, Schneider Thomas, Burlat Vincent, Pollier Jacob, Woittiez Lotte, van der Krol Sander, Lugan Raphaël, Ilc Tina, Verpoorte Robert, Oksman-Caldentey Kirsi-Marja, Martinoia Enrico, Bouwmeester Harro, Goossens Alain, Memelink Johan, Werck-Reichhart Danièle
1] Sylvius Laboratory, Institute of Biology Leiden, Leiden University, Sylviusweg 72, PO Box 9505, Leiden 2300 RA, The Netherlands [2].
1] Laboratory of Plant Physiology, Wageningen University, Droevendaalsesteeg 1, Wageningen 6708 PB, The Netherlands [2].
Nat Commun. 2014 Apr 7;5:3606. doi: 10.1038/ncomms4606.
The (seco)iridoids and their derivatives, the monoterpenoid indole alkaloids (MIAs), form two large families of plant-derived bioactive compounds with a wide spectrum of high-value pharmacological and insect-repellent activities. Vinblastine and vincristine, MIAs used as anticancer drugs, are produced by Catharanthus roseus in extremely low levels, leading to high market prices and poor availability. Their biotechnological production is hampered by the fragmentary knowledge of their biosynthesis. Here we report the discovery of the last four missing steps of the (seco)iridoid biosynthesis pathway. Expression of the eight genes encoding this pathway, together with two genes boosting precursor formation and two downstream alkaloid biosynthesis genes, in an alternative plant host, allows the heterologous production of the complex MIA strictosidine. This confirms the functionality of all enzymes of the pathway and highlights their utility for synthetic biology programmes towards a sustainable biotechnological production of valuable (seco)iridoids and alkaloids with pharmaceutical and agricultural applications.
（裂环）环烯醚萜及其衍生物、单萜吲哚生物碱（MIAs）构成了两大类源自植物的生物活性化合物，具有广泛的高价值药理活性和驱虫活性。用作抗癌药物的MIAs长春碱和长春新碱，由长春花产生的水平极低，导致市场价格高昂且供应不足。它们的生物技术生产因对其生物合成的零碎了解而受到阻碍。在此，我们报告了（裂环）环烯醚萜生物合成途径中最后四个缺失步骤的发现。在另一种植物宿主中表达编码该途径的八个基因，以及两个促进前体形成的基因和两个下游生物碱生物合成基因，能够异源生产复杂的MIA长春花苷。这证实了该途径中所有酶的功能，并突出了它们在合成生物学计划中的效用，以实现具有医药和农业应用价值的（裂环）环烯醚萜和生物碱的可持续生物技术生产。
