ArticleJournal of the American Chemical Society2014
Protein mass-modulated effects in the catalytic mechanism of dihydrofolate reductase: beyond promoting vibrations.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 61 citations in OpenAlex.
- Free energy relationship analysis for temperature dependence of hydride kinetic isotope effects of NADH/NADChemical science · 2026Article
- Large Temperature Dependence of Large Kinetic Isotope Effects of Multistep Hydride Reduction ofThe Journal of organic chemistry · 2025Article
- Rigidity Analysis of Hydride Tunneling Ready States from Secondary Kinetic Isotope Effects and Hammett Correlations: Relating to the Temperature Dependence of Kinetic Isotope Effects.Journal of physical organic chemistry · 2025Article
- Structural Effects on the Hydride-Tunneling Kinetic Isotope Effects of NADH/NADThe Journal of organic chemistry · 2025Article
- Study of the Effects of Remote Heavy Group Vibrations on the Temperature Dependence of Hydride Kinetic Isotope Effects of the NADH/NADACS omega · 2024Article
- Allosteric activation unveils protein-mass modulation of ATP phosphoribosyltransferase product release.Communications chemistry · 2024Article
- Structural Effects on the Temperature Dependence of Hydride Kinetic Isotope Effects of the NADH/NADThe Journal of organic chemistry · 2024Article
- Correlation of temperature dependence of hydride kinetic isotope effects with donor-acceptor distances in two solvents of different polarities.Organic & biomolecular chemistry · 2023Article
- Comparison of the Role of Protein Dynamics in Catalysis by Dihydrofolate Reductase fromThe journal of physical chemistry. B · 2022Article
- Temperature-Dependent Kinetic Isotope Effects in R67 Dihydrofolate Reductase from Path-Integral Simulations.The journal of physical chemistry. B · 2021Article
- Protein Mass-Modulated Effects in Alkaline Phosphatase.Biochemistry · 2021Article
- Monoclonal antibody stability can be usefully monitored using the excitation-energy-dependent fluorescence edge-shift.The Biochemical journal · 2020Article
- Effect of Protein Isotope Labeling on the Catalytic Mechanism of Lactate Dehydrogenase.The journal of physical chemistry. B · 2019Article
- Heavy Enzymes and the Rational Redesign of Protein Catalysts.Chembiochem : a European journal of chemical biology · 2019Article
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- Why are some Enzymes Dimers? Flexibility and Catalysis inACS catalysis · 2019Article
- Active-Site Glu165 Activation in Triosephosphate Isomerase and Its Deprotonation Kinetics.The journal of physical chemistry. B · 2019Article
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- Engineered control of enzyme structural dynamics and function.Protein science : a publication of the Protein Society · 2018Review
- Contribution of buried distal amino acid residues in horse liver alcohol dehydrogenase to structure and catalysis.Protein science : a publication of the Protein Society · 2018Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The role of fast protein dynamics in enzyme catalysis has been of great interest in the past decade. Recent "heavy enzyme" studies demonstrate that protein mass-modulated vibrations are linked to the energy barrier for the chemical step of catalyzed reactions. However, the role of fast dynamics in the overall catalytic mechanism of an enzyme has not been addressed. Protein mass-modulated effects in the catalytic mechanism of Escherichia coli dihydrofolate reductase (ecDHFR) are explored by isotopic substitution ((13)C, (15)N, and non-exchangeable (2)H) of the wild-type ecDHFR (l-DHFR) to generate a vibrationally perturbed "heavy ecDHFR" (h-DHFR). Steady-state, pre-steady-state, and ligand binding kinetics, intrinsic kinetic isotope effects (KIEint) on the chemical step, and thermal unfolding experiments of both l- and h-DHFR show that the altered protein mass affects the conformational ensembles and protein-ligand interactions, but does not affect the hydride transfer at physiological temperatures (25-45 °C). Below 25 °C, h-DHFR shows altered transition state (TS) structure and increased barrier-crossing probability of the chemical step compared with l-DHFR, indicating temperature-dependent protein vibrational coupling to the chemical step. Protein mass-modulated vibrations in ecDHFR are involved in TS interactions at cold temperatures and are linked to dynamic motions involved in ligand binding at physiological temperatures. Thus, mass effects can affect enzymatic catalysis beyond alterations in promoting vibrations linked to chemistry.
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