Discovery of extended product structural space of the fungal dioxygenase AsqJ

Manuel Einsiedler and Tobias A. M. Gulder ()
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Manuel Einsiedler: Technische Universität Dresden
Tobias A. M. Gulder: Technische Universität Dresden

Nature Communications, 2023, vol. 14, issue 1, 1-9

Abstract: Abstract 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. These systematic investigations map the substrate tolerance of AsqJ within its two established pathways, revealing significant promiscuity, especially in the quinolone pathway. Most importantly, two further reactivities leading to new AsqJ product classes are discovered, thus significantly expanding the structural space accessible by this biosynthetic enzyme. Switching AsqJ product selectivity is achieved by subtle structural changes on the substrate, revealing a remarkable substrate-controlled product selectivity in enzyme catalysis. Our work paves the way for the biocatalytic synthesis of diverse biomedically important heterocyclic structural frameworks.

Date: 2023
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DOI: 10.1038/s41467-023-39111-2

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