The biosynthetic origin of psychoactive kavalactones in kava
The biosynthetic origin of psychoactive kavalactones in kava
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DOI：
10.1038/s41477-019-0474-0
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发表时间：
2019-08-01
期刊：
影响因子：
18
通讯作者：
Weng, Jing-Ke
中科院分区：
文献类型：
--
作者：
Pluskal, Tomas;Torrens-Spence, Michael P.;Weng, Jing-Ke
卡瓦胡椒 (Piper methysticum) 是一种原产于波利尼西亚群岛的民族药用灌木，具有良好的抗焦虑和镇痛特性。其主要精神活性成分卡瓦内酯形成一类独特的聚酮化合物，通过与传统精神药物不同的机制与人类中枢神经系统相互作用。然而，未知的生物合成机制和化学合成的困难阻碍了卡瓦内酯的治疗用途。此外，卡瓦还产生黄酮卡瓦苷，这是一种具有抗癌特性的查尔酮类化合物，其结构与卡瓦内酯相关。在这里，我们报告了卡瓦内酯和黄酮卡瓦因生物合成网络的关键酶的从头阐明。我们提出了一对旁系同源苯乙烯吡喃酮合酶的进化发展的结构基础，该合酶建立了卡瓦内酯支架，以及产生手性卡瓦内酯子集的区域和立体特异性卡瓦内酯还原酶的催化机制。我们进一步证明了在异源宿主中工程化苯乙烯吡喃酮生产的可行性，从而开辟了一条通过合成生物学开发基于卡瓦内酯的非成瘾性精神治疗药物的方法。
Kava (Piper methysticum) is an ethnomedicinal shrub native to the Polynesian islands with well-established anxiolytic and analgesic properties. Its main psychoactive principles, kavalactones, form a unique class of polyketides that interact with the human central nervous system through mechanisms distinct from those of conventional psychiatric drugs. However, an unknown bio-synthetic machinery and difficulty in chemical synthesis hinder the therapeutic use of kavalactones. In addition, kava also produces flavokavains, which are chalconoids with anticancer properties structurally related to kavalactones. Here, we report de novo elucidation of the key enzymes of the kavalactone and flavokavain biosynthetic network. We present the structural basis for the evolutionary development of a pair of paralogous styrylpyrone synthases that establish the kavalactone scaffold and the catalytic mechanism of a regio- and stereo-specific kavalactone reductase that produces a subset of chiral kavalactones. We further demonstrate the feasibility of engineering styrylpyrone production in heterologous hosts, thus opening a way to develop kavalactone-based non-addictive psychiatric therapeutics through synthetic biology.