Ma Ke, Zhang Yuting, Guo Cui, Yang Yanlong, Han Junjie, Yu Bo, Yin Wenbing, Liu Hongwei
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China.
Acta Pharm Sin B. 2021 Sep;11(9):2945-2956. doi: 10.1016/j.apsb.2021.04.014. Epub 2021 May 3.
Mushroom-derived cyathane-type diterpenes possess unusual chemical skeleton and diverse bioactivities. To efficiently supply bioactive cyathanes for deep studies and explore their structural diversity, synthesis of cyathane diterpenes in a geranylgeranyl pyrophosphate engineered is investigated. Aided by homologous analyses, one new unclustered FAD-dependent oxidase EriM accounting for the formation of allyl aldehyde and three new NADP(H)-dependent reductases in the biosynthesis of cyathanes are identified and elucidated. By combinatorial biosynthetic strategy, strains generating twenty-two cyathane-type diterpenes, including seven "unnatural" cyathane xylosides (, , , , , , and ) are established. Compounds -, , and show significant neurotrophic effects on PC12 cells in the dose of 6.3-25.0 μmol/L. These studies provide new insights into the divergent biosynthesis of mushroom-originated cyathanes and a straightforward approach to produce bioactive cyathane-type diterpenes.
蘑菇来源的杯伞烷型二萜具有独特的化学骨架和多样的生物活性。为了高效地提供生物活性杯伞烷用于深入研究并探索其结构多样性，本文研究了在香叶基香叶基焦磷酸工程菌中杯伞烷二萜的合成。借助同源分析，鉴定并阐明了一种新的非聚类FAD依赖性氧化酶EriM，其参与烯丙基醛的形成，以及杯伞烷生物合成中三种新的NADP(H)依赖性还原酶。通过组合生物合成策略，构建了能够产生二十二种杯伞烷型二萜的菌株，其中包括七种“非天然”杯伞烷木糖苷（、、、、、和）。化合物 - 、和 在6.3 - 25.0 μmol/L的剂量下对PC12细胞显示出显著的神经营养作用。这些研究为蘑菇来源的杯伞烷的多样化生物合成提供了新的见解，并为生产生物活性杯伞烷型二萜提供了一种直接的方法。
