The Nucleophilic Reactivity of Alcoholate Anions Toward p-Nitrophenyl Acetate

Jencks, William P.; Gilchrist, Mary.

doi:10.1021/ja00874a013

Cited by 45 publications

(22 citation statements)

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“…The energy of the proton‐transfer step in water was determined from the p K a values (∼16 for Ser and ∼ 7 for His) and is found to be 12 kcal mol −1 . The energy of forming the tetrahedral intermediate was determined by using the rate constant of the uncatalyzed reaction, in water, of the methanol with p ‐nitrophenyl acetate (600 M −1 s −1 25) and extrapolating it to 55 M (this guarantees the presence of OH − in the solvent cage). The resulting rate constant ( k cage ) is around 3.3 .…”

Section: Resultsmentioning

confidence: 99%

Towards Quantitative Computer‐Aided Studies of Enzymatic Enantioselectivity: The Case of Candida antarctica Lipase A

Frushicheva

Warshel

2011

ChemBioChem

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The prospect for consistent computer aided refinement of stereoselective enzymes is explored by simulating of the hydrolysis of enantiomers of an α-substituted ester by the wild type and mutants of CALA, using several strategies. In particular we focus on the use of the empirical valence bond (EVB) method in a quantitative screening for enantioselectivity, evaluating both kcat and kcat/KM in the R and S stereoisomers. It is found that an extensive sampling is essential for obtaining converging results. This requirement points out towards possible problems with approaches that use a limited conformational sampling. However, performing the proper sampling appears to give encouraging results and to offer a powerful tool for computer aided design of enantioselective enzymes. We also explore faster strategies for identifying mutations that will help in augmenting directed evolution experiments but these approaches requires further refinement.

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Section: Resultsmentioning

confidence: 99%

Towards Quantitative Computer‐Aided Studies of Enzymatic Enantioselectivity: The Case of Candida antarctica Lipase A

Frushicheva

Warshel

2011

ChemBioChem

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“…A crude extrapolation provided a second-order rate constant for alcoholysis of 3 of kRoH 1O-4 to 1O-5 M-1 min' at 230C (on the basis that Ea = 25 kcal/mol). The low concentration of the required alkoxide is responsible for the virtually undetectable observed background rates (20,21).…”

Section: ' 11mentioning

confidence: 99%

An Unexpectedly Efficient Catalytic Antibody Operating by Ping-Pong and Induced Fit Mechanisms

Wirsching¹,

Ashley²,

Benkovic³

et al. 1991

Science

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A transition state analogue was used to produce a mouse antibody that catalyzes transesterification in water. The antibody behaves as a highly efficient catalyst with a covalent intermediate and the characteristic of induced fit. While some features of the catalytic pathway were programmed when the hapten was designed and reflect favorable substrate-antibody interactions, other features are a manifestation of the chemical potential of antibody diversity. The fact that antibodies recapitulate mechanisms and pathways previously thought to be a characteristic of highly evolved enzymes suggests that once an appropriate binding cavity is achieved, reaction pathways commensurate with the intrinsic chemical potential of proteins ensue.

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“…This enhanced reactivity is observed for substrates of intermediate reactivity such as fw-iitrophenyl acetate which is about as reactive as our substrate towards amines. 18 In those cases, the ratedetermining step is believed to be the breakdown of the intermediate. This means that, in the intermediate T,, imidazole is a better leaving group than DMAP.…”

Section: T!: Schemementioning

confidence: 99%

Reactivity of some nucleophiles and amino-acid derivatives towards 4-dimethylamino-1-methoxycarbonylpyridinium chloride

Guillot-Edelheit¹,

Laloi-Diard²,

Guibé-Jampel³

et al. 1979

J. Chem. Soc., Perkin Trans. 2

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The kinetics of the reaction of 4-dimethylamino-1 -methoxycarbonylpyridinium chloride (MeOCOPy+NMe,) with water and nucleophiles have been examined as a model reaction of 1 -acyl-4-dimethylaminopyridinium ions with amino-acid residues of proteins.Second-order rate constants determined for a series of 11 L-amino-acids allow the calculation of the relative reactivity of the different functional groups as well as the prediction of the selectivity of the reagent at various pH values (thiol, phenol, and imidazole functions are much more reactive than primary amines).The reagent MeQCOPy+NMe, is particularly insensitive to hydrolysis in the pH range 5-7, a region in which hydrolysis is often competitive with nucleophilic reactions. A Bronsted correlation is observed with primary amines; the slope is (3 = 1, a value which is usually interpreted as a rate-determining breakdown of the tetrahedral intermediate. For thiol and phenol functional groups, the attack is the rate-determining step.A comparison with AclmH+ reactivity shows a similar behaviour for both substrates although MeOCOPy+NMe, is much less reactive.

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The Nucleophilic Reactivity of Alcoholate Anions Toward p-Nitrophenyl Acetate

Cited by 45 publications

References 0 publications

Towards Quantitative Computer‐Aided Studies of Enzymatic Enantioselectivity: The Case of Candida antarctica Lipase A

Towards Quantitative Computer‐Aided Studies of Enzymatic Enantioselectivity: The Case of Candida antarctica Lipase A

An Unexpectedly Efficient Catalytic Antibody Operating by Ping-Pong and Induced Fit Mechanisms

Reactivity of some nucleophiles and amino-acid derivatives towards 4-dimethylamino-1-methoxycarbonylpyridinium chloride

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