Update 1 of: Tunneling and Dynamics in Enzymatic Hydride Transfer

Nagel, Zachary D.; Klinman, Judith P.

doi:10.1021/cr1001035

Cited by 111 publications

(297 citation statements)

References 170 publications

(415 reference statements)

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“…Experimental and theoretical studies of the temperature dependence of KIEs in a variety of enzymatic systems suggested that fast dynamics of the reactive complex directly affect the reaction coordinate (25,27,38,39). It is important to note that in this study, the term "dynamics" refers to only these fast motions of the active site that directly affect the catalyzed hydride transfer.…”

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confidence: 92%

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confidence: 99%

“…This method has been previously used extensively for ecDHFR and its mutants (8, 9, 12-14) and many other enzymes (25)(26)(27)(28)(29). The advantage of this experimental method is that the temperature dependence of KIEs is highly sensitive to the changes in the hydrogen donor and acceptor distance (DAD), which can modulate the degree of the nuclear wave function overlap between the donor and acceptor states of the hydride being transferred (27,30). As suggested by several phenomenological models, referred to here as Marcus-like models, temperature-independent KIEs indicate a short and narrow distribution of DADs, whereas temperature-dependent KIEs are associated with longer and broader DAD distributions with lower fluctuation frequency (27,(31)(32)(33)(34).…”

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confidence: 99%

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Preservation of Protein Dynamics in Dihydrofolate Reductase Evolution

Francis

Stojković

Kohen

2013

Journal of Biological Chemistry

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Background: "Humanized" mutants of bacterial dihydrofolate reductase were examined to relate protein dynamics with enzyme evolution. Results: Effects on enzyme dynamics alter the catalyzed C-H3 C step, but the nature of that step was retained along evolution. Conclusion: Protein dynamics evolved to optimize the catalyzed reaction. Significance: Evolutionary conservation of functional dynamics implicates their role in the catalyzed hydride transfer reaction.

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confidence: 92%

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confidence: 99%

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confidence: 99%

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Preservation of Protein Dynamics in Dihydrofolate Reductase Evolution

Francis

Stojković

Kohen

2013

Journal of Biological Chemistry

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“…The functional roles of such conformational changes include, but are not limited to, the allosteric regulation of enzyme function [2,3], motion necessary to access catalytically competent conformations [4], order-disorder transitions that can be necessary to facilitate efficient chemistry [5,6], and, in the case of catalytically promiscuous enzymes, conformational changes that allow for the catalysis of multiple reactions in the same enzyme [7,8]. The extent to which such functionally important conformational dynamics play a role in promoting enzyme catalysis has been the topic of vigorous debate [9][10][11][12][13][14][15][16][17][18][19]. Even more cryptic is the extent to which conformational diversity plays a role in allowing for enzyme evolvability [20,21], either through the repurposing of existing active sites, or through the emergence of completely new active sites in old enzymes.…”

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confidence: 99%

Conformational dynamics and enzyme evolution

Petrović

Risso

Kamerlin

et al. 2018

J. R. Soc. Interface.

151

172

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Enzymes are dynamic entities, and their dynamic properties are clearly linked to their biological function. It follows that dynamics ought to play an essential role in enzyme evolution. Indeed, a link between conformational diversity and the emergence of new enzyme functionalities has been recognized for many years. However, it is only recently that state-ofthe-art computational and experimental approaches are revealing the crucial molecular details of this link. Specifically, evolutionary trajectories leading to functional optimization for a given host environment or to the emergence of a new function typically involve enriching catalytically competent conformations and/or the freezing out of non-competent conformations of an enzyme. In some cases, these evolutionary changes are achieved through distant mutations that shift the protein ensemble towards productive conformations. Multifunctional intermediates in evolutionary trajectories are probably multi-conformational, i.e. able to switch between different overall conformations, each competent for a given function. Conformational diversity can assist the emergence of a completely new active site through a single mutation by facilitating transition-state binding. We propose that this mechanism may have played a role in the emergence of enzymes at the primordial, progenote stage, where it was plausibly promoted by high environmental temperatures and the possibility of additional phenotypic mutations.

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“…While the overall catalytic turnover rates for enzymes are commonly in the millisecond time scale, the lifetimes of enzymatic transitionstate structures exist on the femtosecond time scale (1,2). The role of protein dynamics has been brought into question with the suggestion that electrostatic preorganization is the sole force responsible for the catalytic prowess of enzymes (3).…”

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Femtosecond dynamics coupled to chemical barrier crossing in a Born-Oppenheimer enzyme

Silva

Murkin

Schramm

2011

Proc. Natl. Acad. Sci. U.S.A.

114

199

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Contributions of fast (femtosecond) dynamic motion to barrier crossing at enzyme catalytic sites is in dispute. Human purine nucleoside phosphorylase (PNP) forms a ribocation-like transition state in the phosphorolysis of purine nucleosides and fast protein motions have been proposed to participate in barrier crossing. In the present study, 13 C−, 15 N−, 2 H−labeled human PNP (heavy PNP) was expressed, purified to homogeneity, and shown to exhibit a 9.9% increase in molecular mass relative to its unlabeled counterpart (light PNP). Kinetic isotope effects and steady-state kinetic parameters were indistinguishable for both enzymes, indicating that transition-state structure, equilibrium binding steps, and the rate of product release were not affected by increased protein mass. Single-turnover rate constants were slowed for heavy PNP, demonstrating reduced probability of chemical barrier crossing from enzyme-bound substrates to enzyme-bound products. In a second, independent method to probe barrier crossing, heavy PNP exhibited decreased forward commitment factors, also revealing mass-dependent decreased probability for barrier crossing. Increased atomic mass in human PNP alters bond vibrational modes on the femtosecond time scale and reduces on-enzyme chemical barrier crossing. This study demonstrates coupling of enzymatic bond vibrations on the femtosecond time scale to barrier crossing. femtosecond motions | kinetic isotope effect | transition state structure | enzymatic catalysis | protein dynamics

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Update 1 of: Tunneling and Dynamics in Enzymatic Hydride Transfer

Cited by 111 publications

References 170 publications

Preservation of Protein Dynamics in Dihydrofolate Reductase Evolution

Preservation of Protein Dynamics in Dihydrofolate Reductase Evolution

Conformational dynamics and enzyme evolution

Femtosecond dynamics coupled to chemical barrier crossing in a Born-Oppenheimer enzyme

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