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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Manuel Einsiedler - , Chair of Technical Biochemistry (Author)
  • Cooper S. Jamieson - , University of California at Los Angeles (Author)
  • Mark A. Maskeri - , University of California at Los Angeles (Author)
  • Kendall N. Houk - , University of California at Los Angeles (Author)
  • Tobias A.M. Gulder - , Chair of Technical Biochemistry (Author)

Abstract

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.

Details

Original languageEnglish
Pages (from-to)8297-8302
Number of pages6
JournalAngewandte Chemie - International Edition
Volume60
Issue number15
Publication statusPublished - 6 Apr 2021
Peer-reviewedYes

External IDs

PubMed 33411393

Keywords

ASJC Scopus subject areas

Keywords

  • biocatalysis, biosynthesis, enzyme mechanism, Fe/α-ketoglutarate dependent dioxygenases, natural products