Electrostatic Basis for Enzyme Catalysis

Warshel, Arieh; Sharma, Pramod Kumar; Kato, Mitsunori; Xiang, Yun; Liu, Hanbin; Olsson, Mats H. M.

doi:10.1021/cr0503106

Cited by 1,191 publications

(1,264 citation statements)

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“…Therefore, understanding how these enzymes not only identify their native substrates but also select for and discriminate between their promiscuous substrates holds a key to understanding evolution of function within enzyme superfamilies. Prior to attempting to understand the enzyme catalyzed reactions, however, it is important to have a clear understanding of the corresponding reference reactions in solution 9,49 , not only in order to obtain a thorough understanding of the basic chemistry of the reaction in the absence of the enzyme and to be able to quantify the catalytic proficiency of the enzyme, but also, where relevant, for the calibration and validation of the theoretical approaches that are being used with which to probe the corresponding enzyme catalyzed reaction. Experimental data on aryl sulfates [37][38][39]55 , particularly linear free energy relationships (LFER), would suggest that the mechanism of hydrolysis of sulfate monoester anions is similar to that of phosphate monoester dianions 33,56 .…”

Section: Introductionmentioning

confidence: 99%

Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Kamerlin

2011

J. Org. Chem.

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Both phosphoryl and sulfuryl transfer are ubiquitous in biology, being involved in a wide range of processes, ranging from cell division to apoptosis. Additionally, it is becoming increasingly clear that enzymes that can catalyze phosphoryl transfer can often cross-catalyze sulfuryl-transfer (and vice versa).However, while there have been extensive experimental and theoretical studies performed on phosphoryl transfer, the body of available research on sulfuryl transfer is comparatively much smaller.The present work presents a direct theoretical comparison of p-nitrophenyl phosphate and sulfate monoester hydrolysis, both of which are considered prototype systems for probing phosphoryl and sulfuryl transfer respectively. Specifically, free energy surfaces have been generated using density functional theory, by initial geometry optimization in PCM using the 6-31+G* basis set and the B3LYP density functional, followed by single point calculations using the larger 6-311+G** basis set and the COSMO continuum model. The resulting surfaces have been then used to identify the relevant transition states, either by further unconstrained geometry optimization, or from the surface itself where possible.Additionally, configurational entropies were evaluated using a combination of the quasiharmonic approximation and the restraint release approach and added to the calculated activation barriers as a correction. Finally, the overall activation entropy was estimated by approximating the solvent contribution to the total activation entropy using the Langevin dipoles solvation model. We have reproduced both the experimentally observed activation barriers and the observed trend in the activation entropies with reasonable accuracy, as well providing a comparison of calculated and observed 15 N and 18 O kinetic isotope effects. We demonstrate that, counterintuitively, the hydrolysis of the p-nitrophenyl sulfate proceeds through a more expa show that the solvation effects upon moving from the ground state to the transition state are quite different for both reactions, suggesting that the enzymes that catalyze these reactions would need active 4 sites with quite different electrostatic preorganization for the efficient catalysis of either reaction (despite which many enzymes can catalyze both phosphoryl and sulfuryl transfer). We believe that such a comparative study is an important foundation for understanding the molecular basis for phosphatesulfate cross promiscuity within members of the alkaline phosphatase superfamily.

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Section: Introductionmentioning

confidence: 99%

Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Kamerlin

2011

J. Org. Chem.

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“…The nature and magnitude of these forces remains an active area of research. [10][11][12][13][14][15] Enzymes have evolved to create elaborate active sites containing precise arrangements of hydrogen-bonding networks, electrostatic interactions, and functional group availability specifically aimed at increasing the reactivity of bound substrates. While the development of synthetic host-guest systems has not reached the level of enzyme specificity, the characteristics of each synthetic assembly, such as the size, shape, charge, and functional group availability, greatly influence the guest-binding characteristics and have led to remarkable and often unexpected reactivity.…”

Section: Introductionmentioning

confidence: 99%

Spin Equilibria in Monomeric Manganocenes: Solid-State Magnetic and EXAFS Studies

et al. 2009

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A water-soluble self-assembled supramolecular host molecule catalyzes the hydrolysis of orthoformates in basic solution. Comparison of the rate constants of the catalyzed and uncatalyzed reactions for hydrolysis displays rate accelerations of up to 3900 for tri-n-propyl orthoformate. Kinetic analysis shows that the mechanism of hydrolysis with the supramolecular host obeys the Michaelis-Menten model.Mechanistic studies, including 13 C-labeling experiments, revealed that the resting state of the catalytic system is the neutral substrate encapsulated in the host. Activation parameters for the k cat step of the reaction revealed that upon encapsulation in the assembly, the entropy of activation becomes more negative in contrast to the uncatalyzed reaction. Furthermore, solvent isotope effects reveal a normal k(H 2 O)/k(D 2 O) = 1.6, confirming that proton transfer is occurring in the transition state and is rate limiting in the catalyzed reaction. In comparison to the uncatalyzed reaction, which operates by an A-1 mechanism in which the decomposition of the protonated substrate is rate limiting, the encapsulated reaction proceeds through an A-S E 2 mechanism in which proton transfer from protonated water to the substrate is rate limiting.

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“…[1][2][3][4][5][6][7][8]. There are currently compelling evidences that electrostatic effects give the largest catalytic contributions (e.g., refs.…”

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“…The problem in rationalizing this enormous rate acceleration is the fact that we are dealing with a radical reaction, which would not provide a simple way for the enzyme to exert electrostatic effects for stabilizing the transition state (TS). This presents a major problem to the view that enzymes catalyze reactions mainly by electrostatic effects, and that other factors cannot give large contributions (2). In fact, B 12 enzymes have been originally assumed to present what is perhaps the best support for the popular idea (e.g., refs.…”

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A new paradigm for electrostatic catalysis of radical reactions in vitamin B ₁₂ enzymes

Sharma

Chu²,

Olsson³

et al. 2007

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

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The catalytic power of enzymes containing coenzyme B12 cofactor has been, in some respects, the ''last bastion'' for the strain hypothesis. The present work explores the origin of this effect by using simulation methods that overcome the sampling difficulties of previous energy minimization studies. It is found that the major part of the catalytic effect is due to the electrostatic interaction between the ribose and the protein, and that the strain contribution is very small. Remarkably, enzymes can use electrostatic effects even in a radical process, when the charge distribution of the reacting fragments does not change significantly during the reaction. Electrostatic catalysis can, in such cases, be obtained by attaching a polar group to the leaving fragment and designing an active site that interacts more strongly with this group in the product state than in the reactant state. The finding that evolution had to use this trick provides further evidence to the observation that it is extremely hard to catalyze enzymatic reactions by nonelectrostatic factors. The trick used by B12 enzymes may, in fact, be a very powerful new strategy in enzyme design.simulation of enzymatic reactions ͉ strain effect ͉ transition state stabilization

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Electrostatic Basis for Enzyme Catalysis

Cited by 1,191 publications

References 236 publications

Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Spin Equilibria in Monomeric Manganocenes: Solid-State Magnetic and EXAFS Studies

A new paradigm for electrostatic catalysis of radical reactions in vitamin B ₁₂ enzymes

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Electrostatic Basis for Enzyme Catalysis

Cited by 1,191 publications

References 236 publications

Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Spin Equilibria in Monomeric Manganocenes: Solid-State Magnetic and EXAFS Studies

A new paradigm for electrostatic catalysis of radical reactions in vitamin B 12 enzymes

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A new paradigm for electrostatic catalysis of radical reactions in vitamin B ₁₂ enzymes