Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nat Plants. 2019 Aug;5(8):867-878. doi: 10.1038/s41477-019-0474-0. Epub 2019 Jul 22.
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 biosynthetic 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.
卡瓦（Piper methysticum）是原产于波利尼西亚群岛的一种传统药用灌木，具有良好的抗焦虑和镇痛特性。其主要的精神活性成分卡瓦内酯是一种独特的聚酮类化合物，通过与传统精神药物不同的机制与人体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应用。此外，卡瓦还产生 flavokavains，这是一类具有抗癌活性的查尔酮类化合物，在结构上与卡瓦内酯有关。在这里，我们报告了卡瓦内酯和 flavokavain 生物合成网络关键酶的从头阐明。我们提出了一对同源性 stryrylpyrone 合酶进化发展的结构基础，这对合酶建立了卡瓦内酯支架，以及催化机制，该机制具有区域和立体特异性的卡瓦内酯还原酶，产生了一组手性卡瓦内酯。我们进一步证明了在异源宿主中工程 stryrylpyrone 生产的可行性，从而通过合成生物学为开发基于卡瓦内酯的非成瘾性精神治疗药物开辟了道路。
