Details
| Originalsprache | Englisch |
|---|---|
| Aufsatznummer | 6367 |
| Fachzeitschrift | Nature Communications |
| Jahrgang | 16 |
| Ausgabenummer | 1 |
| Publikationsstatus | Veröffentlicht - 10 Juli 2025 |
Abstract
Withanolides are steroidal lactones from nightshade (Solanaceae) plants with untapped drug potential due to limited availability of minor representatives caused by lack of biosynthetic pathway knowledge. Here, we combine phylogenomics with metabolic engineering to overcome this limitation. By sequencing the genome of the medicinal plant ashwagandha (Withania somnifera) and comparing it with nine Solanaceae species, we discover a conserved withanolide biosynthesis gene cluster, consisting of two sub gene clusters with differing expression patterns. We establish metabolic engineering platforms in yeast (Saccharomyces cerevisiae) and the model plant Nicotiana benthamiana to reconstitute the first five oxidations of withanolide biosynthesis, catalysed by the cytochrome P450 monooxygenases CYP87G1, CYP88C7, and CYP749B2 and a short-chain dehydrogenase/reductase, producing the aglycone of withanoside V. Enzyme functions are conserved within both sub gene clusters in W. somnifera and between W. somnifera and Physalis pruinosa. Our work sets the basis for biotechnological withanolide production to unlock their pharmaceutical potential.
ASJC Scopus Sachgebiete
- Chemie (insg.)
- Allgemeine Chemie
- Biochemie, Genetik und Molekularbiologie (insg.)
- Allgemeine Biochemie, Genetik und Molekularbiologie
- Physik und Astronomie (insg.)
- Allgemeine Physik und Astronomie
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in: Nature Communications, Jahrgang 16, Nr. 1, 6367, 10.07.2025.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - Phylogenomics and metabolic engineering reveal a conserved gene cluster in Solanaceae plants for withanolide biosynthesis
AU - Hakim, Samuel Edward
AU - Choudhary, Nancy
AU - Malhotra, Karan
AU - Peng, Jian
AU - Bültemeier, Arne
AU - Arafa, Ahmed
AU - Friedhoff, Ronja
AU - Bauer, Maximilian
AU - Eikenberg, Jessica
AU - Witte, Claus Peter
AU - Herde, Marco
AU - Heretsch, Philipp
AU - Pucker, Boas
AU - Franke, Jakob
N1 - Publisher Copyright: © The Author(s) 2025.
PY - 2025/7/10
Y1 - 2025/7/10
N2 - Withanolides are steroidal lactones from nightshade (Solanaceae) plants with untapped drug potential due to limited availability of minor representatives caused by lack of biosynthetic pathway knowledge. Here, we combine phylogenomics with metabolic engineering to overcome this limitation. By sequencing the genome of the medicinal plant ashwagandha (Withania somnifera) and comparing it with nine Solanaceae species, we discover a conserved withanolide biosynthesis gene cluster, consisting of two sub gene clusters with differing expression patterns. We establish metabolic engineering platforms in yeast (Saccharomyces cerevisiae) and the model plant Nicotiana benthamiana to reconstitute the first five oxidations of withanolide biosynthesis, catalysed by the cytochrome P450 monooxygenases CYP87G1, CYP88C7, and CYP749B2 and a short-chain dehydrogenase/reductase, producing the aglycone of withanoside V. Enzyme functions are conserved within both sub gene clusters in W. somnifera and between W. somnifera and Physalis pruinosa. Our work sets the basis for biotechnological withanolide production to unlock their pharmaceutical potential.
AB - Withanolides are steroidal lactones from nightshade (Solanaceae) plants with untapped drug potential due to limited availability of minor representatives caused by lack of biosynthetic pathway knowledge. Here, we combine phylogenomics with metabolic engineering to overcome this limitation. By sequencing the genome of the medicinal plant ashwagandha (Withania somnifera) and comparing it with nine Solanaceae species, we discover a conserved withanolide biosynthesis gene cluster, consisting of two sub gene clusters with differing expression patterns. We establish metabolic engineering platforms in yeast (Saccharomyces cerevisiae) and the model plant Nicotiana benthamiana to reconstitute the first five oxidations of withanolide biosynthesis, catalysed by the cytochrome P450 monooxygenases CYP87G1, CYP88C7, and CYP749B2 and a short-chain dehydrogenase/reductase, producing the aglycone of withanoside V. Enzyme functions are conserved within both sub gene clusters in W. somnifera and between W. somnifera and Physalis pruinosa. Our work sets the basis for biotechnological withanolide production to unlock their pharmaceutical potential.
UR - http://www.scopus.com/inward/record.url?scp=105010382200&partnerID=8YFLogxK
U2 - 10.1038/s41467-025-61686-1
DO - 10.1038/s41467-025-61686-1
M3 - Article
AN - SCOPUS:105010382200
VL - 16
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 6367
ER -