Loss of Hyperconjugative Effects Drives Hydride Transfer during Dihydrofolate Reductase Catalysis
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comunitat-uji-handle3:10234/8638
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Title
Loss of Hyperconjugative Effects Drives Hydride Transfer during Dihydrofolate Reductase CatalysisAuthor (s)
Date
2019-09-23Publisher
American Chemical SocietyISSN
2155-5435Bibliographic citation
Antonio Angelastro, J. Javier Ruiz-Pernía, Iñaki Tuñón, Vicent Moliner, Louis Y. P. Luk, and Rudolf K. Allemann. Loss of Hyperconjugative Effects Drives Hydride Transfer during Dihydrofolate Reductase. Catalysis ACS Catalysis 2019 9 (11), 10343-10349 DOI: 10.1021/acscatal.9b02839Type
info:eu-repo/semantics/articlePublisher version
https://pubs.acs.org/doi/abs/10.1021/acscatal.9b02839Version
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Abstract
Hydride transfer is widespread in nature and has an essential role in applied research. However, the mechanisms of how this transformation occurs in living organisms remain a matter of vigorous debate. Here, we examined ... [+]
Hydride transfer is widespread in nature and has an essential role in applied research. However, the mechanisms of how this transformation occurs in living organisms remain a matter of vigorous debate. Here, we examined dihydrofolate reductase (DHFR), an enzyme that catalyzes hydride from C4′ of NADPH to C6 of 7,8-dihydrofolate (H2F). Despite many investigations of the mechanism of this reaction, the contribution of polarization of the π-bond of H2F in driving hydride transfer remains unclear. H2F was stereospecifically labeled with deuterium β to the reacting center, and β-deuterium kinetic isotope effects were measured. Our experimental results combined with analysis derived from QM/MM simulations reveal that hydride transfer is triggered by polarization at the C6 of H2F. The σ Cβ–H bonds contribute to the buildup of the cationic character during the chemical transformation, and hyperconjugation influences the formation of the transition state. Our findings provide key insights into the hydride transfer mechanism of the DHFR-catalyzed reaction, which is a target for antiproliferative drugs and a paradigmatic model in mechanistic enzymology. [-]
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ACS Catalysis, 2019, vol. 9, no 11Investigation project
UK’s Biotechnology and Biological Sciences Research Council through grants; BB/J005266/1 and BB/L020394/1; Spanish Ministerio de Ciencia, Innovación y Universidades and FEDER funds: Grant PGC2018-094852-B, Spanish Ministerio de Economía y Competitividad: CTQ2015-74523-JIN (AEI/FEDER, UE); Universitat Jaume I: UJI·B2017-31Rights
info:eu-repo/semantics/openAccess
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