Reconstitution of biosynthetic pathway for mushroom-derived cyathane diterpenes in yeast and generation of new "non-natural" analogues.

ABSTRACT: 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 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.

SUBMITTER: Ma K 

PROVIDER: S-EPMC8463280 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature