Biosynthesis of Phomactin Platelet Activating Factor Antagonist Requires a Two-Enzyme Cascade.
Biosynthesis
Cytochrome P450 Enzymes
Heterologous Expression
Phomactins
Terpene Cyclase
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
20 11 2023
20 11 2023
Historique:
received:
02
09
2023
medline:
16
11
2023
pubmed:
8
10
2023
entrez:
7
10
2023
Statut:
ppublish
Résumé
Phomactin diterpenoids possess a unique bicyclo[9.3.1]pentadecane skeleton with multiple oxidative modifications, and are good platelet-activating factor (PAF) antagonists that can inhibit PAF-induced platelet aggregation. In this study, we identified the gene cluster (phm) responsible for the biosynthesis of phomactins from a marine fungus, Phoma sp. ATCC 74077. Despite the complexity of their structures, phomactin biosynthesis only requires two enzymes: a type I diterpene cyclase PhmA and a P450 monooxygenase PhmC. PhmA was found to catalyze the formation of the phomactatriene, while PhmC sequentially catalyzes the oxidation of multiple sites, leading to the generation of structurally diverse phomactins. The rearrangement mechanism of the diterpene scaffold was investigated through isotope labeling experiments. Additionally, we obtained the crystal complex of PhmA with its substrate analogue FGGPP and elucidated the novel metal-ion-binding mode and enzymatic mechanism of PhmA through site-directed mutagenesis. This study provides the first insight into the biosynthesis of phomactins, laying the foundation for the efficient production of phomactin natural products using synthetic biology approaches.
Identifiants
pubmed: 37804495
doi: 10.1002/anie.202312996
doi:
Substances chimiques
Platelet Activating Factor
0
Diterpenes
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202312996Informations de copyright
© 2023 Wiley-VCH GmbH.
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