摘要
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,de novo synthesis of cyathane diterpenes in a geranylgeranyl pyrophosphate engineered Saccharomyces cerevisiae 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,S.cerevisiae strains generating twenty-two cyathane-type diterpenes,including seven"unnatural"cyathane xylosides(12,13,14a,14b,19,20,and 22)are established.Compounds 12-14,19,and 20 show significant neurotrophic effects on PC 12 cells in the dose of 6.3-25.0μmol/L.These studies provide new insights into the divergent biosynthesis of mushroom-originated cyathanes and a straightforward approach to produce bioactive cyathane-type diterpenes.
基金
supported by the grants from the National Key R&D program of China(Grant 2018YFD0400203 and 2017YEE0108200)
the National Natural Science Foundation of China(Grant 21472233)
the“Innovative Cross Team”project,CAS(Grant E0222L01R1,China)
