ArticleBiochemistry2012
Active site hydrophobic residues impact hydrogen tunneling differently in a thermophilic alcohol dehydrogenase at optimal versus nonoptimal temperatures.
Article in Biochemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 36 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
- Accelerated Uptake of COACS applied materials & interfaces · 2025Article
- Hydride Transfer Mechanism of Enzymatic Sugar Nucleotide C2 Epimerization Probed with a Loose-Fit CDP-Glucose Substrate.ACS catalysis · 2022Article
- A Minireview on Temperature Dependent Protein Conformational Sampling.The protein journal · 2021Review
- Hydrogen deuterium exchange defines catalytically linked regions of protein flexibility in the catecholProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Conformational sampling and kinetics changes across a non-Arrhenius break point in the enzyme thermolysin.Structural dynamics (Melville, N.Y.) · 2020Article
- Oscillatory Active-site Motions Correlate with Kinetic Isotope Effects in Formate Dehydrogenase.ACS catalysis · 2019Article
- Moving Through Barriers in Science and Life.Annual review of biochemistry · 2019Article
- Engineered control of enzyme structural dynamics and function.Protein science : a publication of the Protein Society · 2018Review
- Origins of Enzyme Catalysis: Experimental Findings for C-H Activation, New Models, and Their Relevance to Prevailing Theoretical Constructs.Journal of the American Chemical Society · 2017Article
- Hydrostatic Pressure Studies Distinguish Global from Local Protein Motions in C-H Activation by Soybean Lipoxygenase-1.Angewandte Chemie (International ed. in English) · 2016Article
- Dynamically achieved active site precision in enzyme catalysis.Accounts of chemical research · 2015Review
- Evolutionary aspects of enzyme dynamics.The Journal of biological chemistry · 2014Review
- Picosecond-resolved fluorescence studies of substrate and cofactor-binding domain mutants in a thermophilic alcohol dehydrogenase uncover an extended network of communication.Journal of the American Chemical Society · 2014Article
- Yeast alcohol dehydrogenase structure and catalysis.Biochemistry · 2014Article
- Picosecond-resolved fluorescent probes at functionally distinct tryptophans within a thermophilic alcohol dehydrogenase: relationship of temperature-dependent changes in fluorescence to catalysis.The journal of physical chemistry. B · 2014Article
- Binding of NAD+ and L-threonine induces stepwise structural and flexibility changes in Cupriavidus necator L-threonine dehydrogenase.The Journal of biological chemistry · 2014Article
- Kinetic isotope effects as a probe of hydrogen transfers to and from common enzymatic cofactors.Archives of biochemistry and biophysics · 2014Review
- Effects of cavities at the nicotinamide binding site of liver alcohol dehydrogenase on structure, dynamics and catalysis.Biochemistry · 2014Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
A growing body of data suggests that protein motion plays an important role in enzyme catalysis. Two highly conserved hydrophobic active site residues in the cofactor-binding pocket of ht-ADH (Leu176 and V260) have been mutated to a series of hydrophobic side chains of smaller size, as well as one deletion mutant, L176Δ. Mutations decrease k(cat) and increase K(M)(NAD(+)). Most of the observed decreases in effects on k(cat) at pH 7.0 are due to an upward shift in the optimal pH for catalysis; a simple electrostatic model is invoked that relates the change in pK(a) to the distance between the positively charged nicotinamide ring and bound substrate. Structural modeling of the L176Δ and V260A variants indicates the development of a cavity behind the nicotinamide ring without any significant perturbation of the secondary structure of the enzyme relative to that of the wild type. Primary kinetic isotope effects (KIEs) are modestly increased for all mutants. Above the dynamical transition at 30 °C for ht-ADH [Kohen, A., et al. (1999) Nature 399, 496], the temperature dependence of the KIE is seen to increase with a decrease in side chain volume at positions 176 and 260. Additionally, the relative trends in the temperature dependence of the KIE above and below 30 °C appear to be reversed for the cofactor-binding pocket mutants in relation to wild-type protein. The aggregate results are interpreted in the context of a full tunneling model of enzymatic hydride transfer that incorporates both protein conformational sampling (preorganization) and active site optimization of tunneling (reorganization). The reduced temperature dependence of the KIE in the mutants below 30 °C indicates that at low temperatures, the enzyme adopts conformations refractory to donor-acceptor distance sampling.
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