Biosynthesis of the highly oxygenated tetracyclic core skeleton of Taxol.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
15 Mar 2024
15 Mar 2024
Historique:
received:
13
12
2023
accepted:
03
03
2024
medline:
18
3
2024
pubmed:
16
3
2024
entrez:
16
3
2024
Statut:
epublish
Résumé
Taxol is a widely-applied anticancer drug that inhibits microtubule dynamics in actively replicating cells. Although a minimum 19-step biosynthetic pathway has been proposed and 16 enzymes likely involved have been characterized, stepwise biosynthetic reactions from the well-characterized di-oxygenated taxoids to Taxol tetracyclic core skeleton are yet to be elucidated. Here, we uncover the biosynthetic pathways for a few tri-oxygenated taxoids via confirming the critical reaction order of the second and third hydroxylation steps, unearth a taxoid 9α-hydroxylase catalyzing the fourth hydroxylation, and identify CYP725A55 catalyzing the oxetane ester formation via a cascade oxidation-concerted acyl rearrangement mechanism. After identifying a acetyltransferase catalyzing the formation of C7-OAc, the pathway producing the highly-oxygenated 1β-dehydroxybaccatin VI with the Taxol tetracyclic core skeleton is elucidated and its complete biosynthesis from taxa-4(20),11(12)-diene-5α-ol is achieved in an engineered yeast. These systematic studies lay the foundation for the complete elucidation of the biosynthetic pathway of Taxol.
Identifiants
pubmed: 38490987
doi: 10.1038/s41467-024-46583-3
pii: 10.1038/s41467-024-46583-3
pmc: PMC10942993
doi:
Substances chimiques
Paclitaxel
P88XT4IS4D
Taxoids
0
Mixed Function Oxygenases
EC 1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2339Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 31921006
Informations de copyright
© 2024. The Author(s).
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