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Bifunctional Substrate Activation via an Arginine Residue Drives Catalysis in Chalcone Isomerases
Salk Inst Biol Studies, Jack H Skirball Ctr Chem Biol & Prote, Howard Hughes Med Inst, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA;Calif State Univ San Bernardino, San Bernardino, CA 92407 USA.
Salk Inst Biol Studies, Jack H Skirball Ctr Chem Biol & Prote, Howard Hughes Med Inst, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA.
Salk Inst Biol Studies, Jack H Skirball Ctr Chem Biol & Prote, Howard Hughes Med Inst, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA;Manus Biosynth, Cambridge, MA USA.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Biology.
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2019 (English)In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 9, no 9, p. 8388-8396Article in journal (Refereed) Published
Abstract [en]

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 combined with 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, share mechanistic similarities with 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.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2019. Vol. 9, no 9, p. 8388-8396
Keywords [en]
Michaelase, asymmetric biocatalysis, arginine general acid, catalytic water, bifunctional guanidine catalysis, enzyme evolution, flavonoid biosynthesis
National Category
Organic Chemistry Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-394690DOI: 10.1021/acscatal.9b01926ISI: 000485090400076OAI: oai:DiVA.org:uu-394690DiVA, id: diva2:1366652
Funder
EU, European Research Council, 30647Knut and Alice Wallenberg Foundation, KAW 2013.0124Available from: 2019-10-30 Created: 2019-10-30 Last updated: 2019-10-30Bibliographically approved

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Pabis, AnnaKamerlin, Shina C. Lynn

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