Catalytic mechanism and molecular engineering of quinolone biosynthesis in dioxygenase AsqJ

Sophie L. Mader, Alois Bräuer, Michael Groll () and Ville R. I. Kaila ()
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Sophie L. Mader: Technische Universität München
Alois Bräuer: Technische Universität München
Michael Groll: Technische Universität München
Ville R. I. Kaila: Technische Universität München

Nature Communications, 2018, vol. 9, issue 1, 1-8

Abstract: Abstract The recently discovered FeII/α-ketoglutarate-dependent dioxygenase AsqJ from Aspergillus nidulans stereoselectively catalyzes a multistep synthesis of quinolone alkaloids, natural products with significant biomedical applications. To probe molecular mechanisms of this elusive catalytic process, we combine here multi-scale quantum and classical molecular simulations with X-ray crystallography, and in vitro biochemical activity studies. We discover that methylation of the substrate is essential for the activity of AsqJ, establishing molecular strain that fine-tunes π-stacking interactions within the active site. To rationally engineer AsqJ for modified substrates, we amplify dispersive interactions within the active site. We demonstrate that the engineered enzyme has a drastically enhanced catalytic activity for non-methylated surrogates, confirming our computational data and resolved high-resolution X-ray structures at 1.55 Å resolution. Our combined findings provide crucial mechanistic understanding of the function of AsqJ and showcase how combination of computational and experimental data enables to rationally engineer enzymes.

Date: 2018
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DOI: 10.1038/s41467-018-03442-2

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