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Bifunctional Substrate Activation via an Arginine Residue Drives Catalysis in Chalcone Isomerases

By Jason R. Burke, James J. La Clair, Ryan N Philippe, Anna Pabis, Joseph M. Jez, George A Cortina, Miriam Kaltenbach, Marianne E Bowman, Gordon V Louie, Katherine B Woods, Andrew T Nelson, Dan S. Tawfik, Shina CL Kamerlin, Joseph P. Noel

Posted 30 Oct 2018
bioRxiv DOI: 10.1101/457440 (published DOI: 10.1021/acscatal.9b01926)

Chalcone isomerases are plant enzymes that perform enantioselective oxa-Michael cyclizations of 2-hydroxychalcones into flavanones. An X-ray crystal structure of an enzyme-product complex and molecular dynamics simulations reveal an enzyme mechanism wherein the guanidinium ion of a conserved arginine positions the nucleophilic phenoxide and activates the electrophilic enone for cyclization through Bronsted and Lewis acid interactions. The reaction terminates by asymmetric protonation of the carbanion intermediate syn to the guanidinium. Interestingly, bifunctional guanidine- and urea-based chemical reagents, increasingly used for asymmetric organocatalytic applications, are synthetic counterparts to this natural system. Comparative protein crystal structures and molecular dynamics simulations further demonstrate how two active site water molecules coordinate a hydrogen bond network that enables expanded substrate reactivity for 6-deoxychalcones in more recently evolved type-2 chalcone isomerases.

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