Fungal Dioxygenase AsqJ Is Promiscuous and Bimodal: Substrate‐Directed Formation of Quinolones versus Quinazolinones

Previous studies showed that the FeII/α‐ketoglutarate dependent dioxygenase AsqJ induces a skeletal rearrangement in viridicatin biosynthesis in Aspergillus nidulans, generating a quinolone scaffold from benzo[1,4]diazepine‐2,5‐dione substrates. We report that AsqJ catalyzes an additional, entirely...

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Bibliographic Details
Published in:Angewandte Chemie 2021-04, Vol.133 (15), p.8378-8383
Main Authors: Einsiedler, Manuel, Jamieson, Cooper S., Maskeri, Mark A., Houk, Kendall N., Gulder, Tobias A. M.
Format: Article
Language:English
Subjects:
biocatalysis
Biosynthesis
Catalysis
Chemistry
Computer applications
Diketones
Dioxygenase
enzyme mechanism
FeII/α-ketoglutarate dependent dioxygenases
natural products
Quinazolinones
Quinolones
Ring structures
Substrates
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Summary:Previous studies showed that the FeII/α‐ketoglutarate dependent dioxygenase AsqJ induces a skeletal rearrangement in viridicatin biosynthesis in Aspergillus nidulans, generating a quinolone scaffold from benzo[1,4]diazepine‐2,5‐dione substrates. We report that AsqJ catalyzes an additional, entirely different reaction, simply by a change in substituent in the benzodiazepinedione substrate. This new mechanism is established by substrate screening, application of functional probes, and computational analysis. AsqJ excises H2CO from the heterocyclic ring structure of suitable benzo[1,4]diazepine‐2,5‐dione substrates to generate quinazolinones. This novel AsqJ catalysis pathway is governed by a single substituent within the complex substrate. This unique substrate‐directed reactivity of AsqJ enables the targeted biocatalytic generation of either quinolones or quinazolinones, two alkaloid frameworks of exceptional biomedical relevance. AsqJ catalyzes a complex rearrangement sequence in quinolone biosynthesis. We show the AsqJ biocatalytic potential to significantly exceed this natural function. An unprecedented reaction pathway leading to quinazolinones is uncovered, functionally and mechanistically characterized in detail, revealing a unique substrate‐dependent product selectivity in enzyme catalysis.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.202017086