Multienzymatic cascades are responsible for the biosynthesis of natural products and represent a source of inspiration for synthetic chemists. The Fe(II)/α-ketoglutarate-dependent dioxygenase AsqJ from Aspergillus nidulans is outstanding because it stereoselectively catalyzes both a ferryl-induced desaturation reaction and epoxidation on a benzodiazepinedione. Interestingly, the enzymatically formed spiro epoxide spring-loads the 6,7-bicyclic skeleton for non-enzymatic rearrangement into the 6,6-bicyclic scaffold of the quinolone alkaloid 4'-methoxyviridicatin. Herein, we report different crystal structures of the protein in the absence and presence of synthesized substrates, surrogates, and intermediates that mimic the various stages of the reaction cycle of this exceptional dioxygenase.
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Discovery of extended product structural space of the fungal dioxygenase AsqJ.
Nat Commun
June 2023
Chair of Technical Biochemistry, Faculty of Chemistry and Food Chemistry, Technische Universität Dresden, Bergstraße 66, 01069, Dresden, Germany.
The fungal dioxygenase AsqJ catalyses the conversion of benzo[1,4]diazepine-2,5-diones into quinolone antibiotics. A second, alternative reaction pathway leads to a different biomedically important product class, the quinazolinones. Within this work, we explore the catalytic promiscuity of AsqJ by screening its activity across a broad range of functionalized substrates made accessible by solid-/liquid-phase peptide synthetic routes.
View Article and Find Full Text PDFPeroxy Intermediate Drives Carbon Bond Activation in the Dioxygenase AsqJ.
J Am Chem Soc
August 2022
Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
Dioxygenases catalyze stereoselective oxygen atom transfer in metabolic pathways of biological, industrial, and pharmaceutical importance, but their precise chemical principles remain controversial. The α-ketoglutarate (αKG)-dependent dioxygenase AsqJ synthesizes biomedically active quinolone alkaloids via desaturation and subsequent epoxidation of a carbon-carbon bond in the cyclopeptin substrate. Here, we combine high-resolution X-ray crystallography with enzyme engineering, quantum-classical (QM/MM) simulations, and biochemical assays to describe a peroxidic intermediate that bridges the substrate and active site metal ion in AsqJ.
View Article and Find Full Text PDFHarnessing the Substrate Promiscuity of Dioxygenase AsqJ and Developing Efficient Chemoenzymatic Synthesis for Quinolones.
ACS Catal
June 2021
Department of Chemistry, North Carolina State University, Raleigh, NC.
Nature has developed complexity-generating reactions within natural product biosynthetic pathways. However, direct utilization of these pathways to prepare compound libraries remains challenging due to limited substrate scopes, involvement of multiple-step reactions, and moderate robustness of these sophisticated enzymatic transformations. Synthetic chemistry, on the other hand, offers an alternative approach to prepare natural product analogs.
View Article and Find Full Text PDFFungal Dioxygenase AsqJ Is Promiscuous and Bimodal: Substrate-Directed Formation of Quinolones versus Quinazolinones.
Angew Chem Int Ed Engl
April 2021
Department of Chemistry and Food Chemistry, Chair of Technical Biochemistry, Technical University of Dresden, Bergstraße 66, 01069, Dresden, Germany.
Previous studies showed that the Fe /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.
View Article and Find Full Text PDFOn how the binding cavity of AsqJ dioxygenase controls the desaturation reaction regioselectivity: a QM/MM study.
J Biol Inorg Chem
July 2018
Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek 8, 30239, Kraków, Poland.
The Fe(II)/2-oxoglutarate-dependent dioxygenase AsqJ from Aspergillus nidulans catalyses two pivotal steps in the synthesis of quinolone antibiotic 4'-methoxyviridicatin, i.e., desaturation and epoxidation of a benzodiazepinedione.
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