瑞士苏黎世联邦理工学院Piel, Jrn团队报道了来自植物相关细菌具有强力细胞毒素，janustatins基于基因组的发现和完全合成。相关研究成果发表在2022年9月5日出版的《自然—化学》。

宿主相关细菌越来越多地被认为是，具有前所未有的化学支架的生物活性天然产物的未充分开发的来源。最近确定的一个例子是与植物根相关的海洋细菌Gynuella sunshinyii，属于化学上未被充分开发的海洋螺目。它的基因组包含至少22个生物合成基因簇，这表明它具有丰富的且大部分没有特征的特殊代谢。

该文中，研究人员对非标准聚酮合酶簇的硅化预测导致了janustatins的发现，Janustatin是一种结构上前所未有的聚酮生物碱，具有极强的细胞毒性，产量极小。综合MS和二维NMR实验、¹³C化学位移的密度泛函理论计算，和横向旋转框架悬置效应光谱数据的半定量解释来确定相对构型，从而实现对映体的全合成和绝对构型的分配。Janustatins具有一种以前未知的吡啶二氢吡喃酮杂环和一种不寻常的生物活性，包括亚毫摩尔浓度下的延迟同步细胞死亡。

附：英文原文

Title: Genome-based discovery and total synthesis of janustatins, potent cytotoxins from a plant-associated bacterium

Author: Ueoka, Reiko, Sondermann, Philipp, Leopold-Messer, Stefan, Liu, Yizhou, Suo, Rei, Bhushan, Agneya, Vadakumchery, Lida, Greczmiel, Ute, Yashiroda, Yoko, Kimura, Hiromi, Nishimura, Shinichi, Hoshikawa, Yojiro, Yoshida, Minoru, Oxenius, Annette, Matsunaga, Shigeki, Williamson, R. Thomas, Carreira, Erick M., Piel, Jrn

Issue&Volume: 2022-09-05

Abstract: Host-associated bacteria are increasingly being recognized as underexplored sources of bioactive natural products with unprecedented chemical scaffolds. A recently identified example is the plant-root-associated marine bacterium Gynuella sunshinyii of the chemically underexplored order Oceanospirillales. Its genome contains at least 22 biosynthetic gene clusters, suggesting a rich and mostly uncharacterized specialized metabolism. Here, in silico chemical prediction of a non-canonical polyketide synthase cluster has led to the discovery of janustatins, structurally unprecedented polyketide alkaloids with potent cytotoxicity that are produced in minute quantities. A combination of MS and two-dimensional NMR experiments, density functional theory calculations of 13C chemical shifts and semiquantitative interpretation of transverse rotating-frame Overhauser effect spectroscopy data were conducted to determine the relative configuration, which enabled the total synthesis of both enantiomers and assignment of the absolute configuration. Janustatins feature a previously unknown pyridodihydropyranone heterocycle and an unusual biological activity consisting of delayed, synchronized cell death at subnanomolar concentrations.

DOI: 10.1038/s41557-022-01020-0

Source: https://www.nature.com/articles/s41557-022-01020-0