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

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 Saccharomyce...

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Autores principales: Ma, Ke, Zhang, Yuting, Guo, Cui, Yang, Yanlong, Han, Junjie, Yu, Bo, Yin, Wenbing, Liu, Hongwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463280/
https://www.ncbi.nlm.nih.gov/pubmed/34589407
http://dx.doi.org/10.1016/j.apsb.2021.04.014
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author Ma, Ke
Zhang, Yuting
Guo, Cui
Yang, Yanlong
Han, Junjie
Yu, Bo
Yin, Wenbing
Liu, Hongwei
author_facet Ma, Ke
Zhang, Yuting
Guo, Cui
Yang, Yanlong
Han, Junjie
Yu, Bo
Yin, Wenbing
Liu, Hongwei
author_sort Ma, Ke
collection PubMed
description 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.
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spelling pubmed-84632802021-09-28 Reconstitution of biosynthetic pathway for mushroom-derived cyathane diterpenes in yeast and generation of new “non-natural” analogues Ma, Ke Zhang, Yuting Guo, Cui Yang, Yanlong Han, Junjie Yu, Bo Yin, Wenbing Liu, Hongwei Acta Pharm Sin B Original Article 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. Elsevier 2021-09 2021-05-03 /pmc/articles/PMC8463280/ /pubmed/34589407 http://dx.doi.org/10.1016/j.apsb.2021.04.014 Text en © 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Ma, Ke
Zhang, Yuting
Guo, Cui
Yang, Yanlong
Han, Junjie
Yu, Bo
Yin, Wenbing
Liu, Hongwei
Reconstitution of biosynthetic pathway for mushroom-derived cyathane diterpenes in yeast and generation of new “non-natural” analogues
title Reconstitution of biosynthetic pathway for mushroom-derived cyathane diterpenes in yeast and generation of new “non-natural” analogues
title_full Reconstitution of biosynthetic pathway for mushroom-derived cyathane diterpenes in yeast and generation of new “non-natural” analogues
title_fullStr Reconstitution of biosynthetic pathway for mushroom-derived cyathane diterpenes in yeast and generation of new “non-natural” analogues
title_full_unstemmed Reconstitution of biosynthetic pathway for mushroom-derived cyathane diterpenes in yeast and generation of new “non-natural” analogues
title_short Reconstitution of biosynthetic pathway for mushroom-derived cyathane diterpenes in yeast and generation of new “non-natural” analogues
title_sort reconstitution of biosynthetic pathway for mushroom-derived cyathane diterpenes in yeast and generation of new “non-natural” analogues
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463280/
https://www.ncbi.nlm.nih.gov/pubmed/34589407
http://dx.doi.org/10.1016/j.apsb.2021.04.014
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