马克斯·普朗克化学生态学研究所Sarah E. O’Connor团队的最新研究提出了金鸡纳生物碱的生物合成。这一研究成果于2026年3月18日发表在国际顶尖学术期刊《自然》上。

在这里，研究人员报告了基因的发现负责独特的金鸡纳生物碱的喹啉-喹啉支架的生物合成。同位素标记、基因沉默、单核RNA测序和比较转录组学的结合揭示了一些意想不到的生物合成转化的参与。研究团队还描述了一种以前未报道的季胺中间体，它是通过非酶环化产生的。本研究表明，当这些基因异源表达时，可以产生二氢奎宁(二)酮、二氢辛可宁(二)酮及辛可宁(二)酮。

更进一步，该异源表达平台还能将非天然的氟代/氯代色胺底物转化为二氢辛可宁(二)酮类似物，这表明这些生物合成酶可以用来生产卤化金鸡纳生物碱衍生物。这些发现揭示了金鸡纳生物碱支架是如何生物合成的长期谜团，并突出了通过代谢工程方法获得这些化合物的前景。

据介绍，金鸡纳生物碱，已经被研究了250多年。植物衍生的天然产物对医学和基础科学产生了重大影响。其代表性化合物包括历史上重要的抗疟药物奎宁，以及工艺化学中广泛使用的手性催化剂辛可尼丁。然而，植物如何合成这些众所周知的化合物在很大程度上仍然是未知的。

附：英文原文

Title: Biosynthesis of cinchona alkaloids

Author: Lombe, Blaise Kimbadi, Zhou, Tingan, Kang, Gyumin, Wood, Joshua C., Hamilton, John P., Gase, Klaus, Nakamura, Yoko, Alam, Ryan M., Dirks, Ron P., Caputi, Lorenzo, Robin Buell, C., OConnor, Sarah E.

Issue&Volume: 2026-03-18

Abstract: Cinchona alkaloids, which have been studied for more than 250years, are plant-derived natural products that have collectively had a substantial impact in medicine and basic science1,2,3,4,5. Examples of cinchona alkaloids include quinine, a historically important antimalarial drug, and cinchonidine, a chiral catalyst widely used in process chemistry. However, it is still largely unknown how plants synthesize these well-known compounds. Here we report the discovery of genes responsible for the biosynthesis of the distinctive quinoline–quinuclidine scaffold of cinchona alkaloids. A combination of isotopic labelling, gene silencing, single-nucleus RNA sequencing and comparative transcriptomics revealed the involvement of several unexpected biosynthetic transformations. We also describe a previously unreported quaternary amine intermediate that is generated through an unusual enzymatic cyclization. We show that dihydroquini(di)none, dihydrocinchoni(di)none and cinchoni(di)none can be produced when these genes are heterologously expressed in Nicotiana benthamiana. Furthermore, we demonstrate that this N.benthamiana expression platform can convert non-native fluorinated and chlorinated tryptamine substrates into dihydrocinchoni(di)none analogues, which suggests that these biosynthetic enzymes can be leveraged to produce halogenated cinchona alkaloid derivatives. These discoveries uncover the long-standing mystery of how the cinchona alkaloid scaffold is biosynthesized and highlight prospects for access to these compounds through metabolic engineering approaches.

DOI: 10.1038/s41586-026-10227-x

Source: https://www.nature.com/articles/s41586-026-10227-x