Biosynthesis and biotechnological production of the anti-obesity agent celastrol.
Journal
Nature chemistry
ISSN: 1755-4349
Titre abrégé: Nat Chem
Pays: England
ID NLM: 101499734
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
24
09
2022
accepted:
19
05
2023
medline:
1
9
2023
pubmed:
27
6
2023
entrez:
26
6
2023
Statut:
ppublish
Résumé
Obesity is a major health risk still lacking effective pharmacological treatment. A potent anti-obesity agent, celastrol, has been identified in the roots of Tripterygium wilfordii. However, an efficient synthetic method is required to better explore its biological utility. Here we elucidate the 11 missing steps for the celastrol biosynthetic route to enable its de novo biosynthesis in yeast. First, we reveal the cytochrome P450 enzymes that catalyse the four oxidation steps that produce the key intermediate celastrogenic acid. Subsequently, we show that non-enzymatic decarboxylation-triggered activation of celastrogenic acid leads to a cascade of tandem catechol oxidation-driven double-bond extension events that generate the characteristic quinone methide moiety of celastrol. Using this acquired knowledge, we have developed a method for producing celastrol starting from table sugar. This work highlights the effectiveness of combining plant biochemistry with metabolic engineering and chemistry for the scalable synthesis of complex specialized metabolites.
Identifiants
pubmed: 37365337
doi: 10.1038/s41557-023-01245-7
pii: 10.1038/s41557-023-01245-7
doi:
Substances chimiques
celastrol
L8GG98663L
Triterpenes
0
Anti-Obesity Agents
0
Pentacyclic Triterpenes
0
Cytochrome P-450 Enzyme System
9035-51-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1236-1246Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
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