An ortho-Quinone Methide Mediates Disulfide Migration in the Biosynthesis of Epidithiodiketopiperazines.
Alkaloids
Biosynthesis
Disulfides
FAD-Dependent Thioredoxin Oxygenase
Fungi
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:
10 07 2023
10 07 2023
Historique:
received:
24
03
2023
medline:
5
7
2023
pubmed:
9
5
2023
entrez:
9
5
2023
Statut:
ppublish
Résumé
The transannular disulfide functions as a key structural element imparting diverse biological activities to epidithiodiketopiperazines (ETPs). Although mechanisms were proposed in previous studies, α,β'-disulfide formation in ETPs is not well-determined owing to the failure to identify the hypothetical intermediate. Herein, we characterize the key ortho-quinone methide (o-QM) intermediate and prove its involvement in the carbon-sulfur migration from an α,α'- to an α,β'-disulfide by elucidating pretrichodermamide A biosynthesis, which is catalyzed by a FAD-dependent thioredoxin oxygenase TdaE harboring a noncanonical CXXQ motif. Biochemical investigations of recombinant TdaE and mutants demonstrated that the construction of the α,β'-disulfide was initiated by Gln140 triggering proton abstraction for generation of the essential o-QM intermediate, accompanied by β'-acetoxy elimination. Subsequent attack on the α,α'-disulfide by Cys137 led to disulfide migration and spirofuran formation. This study expands the biocatalytic toolbox for transannular disulfide formation and sets the stage for the targeted discovery of bioactive ETPs.
Identifiants
pubmed: 37157140
doi: 10.1002/anie.202304252
doi:
Substances chimiques
quinone methide
138230-21-4
Disulfides
0
epidithiodiketopiperazine
0
Indolequinones
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202304252Informations de copyright
© 2023 Wiley-VCH GmbH.
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