Acyl substituent effects on ester aminolysis

Knowlton, Robert C.; Byers, Larry D.

doi:10.1021/jo00251a041

Cited by 23 publications

(6 citation statements)

References 6 publications

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“…The solid line is drawn of slope 1.0 and through the origin. The numbers associated with the points refer to the phosphonates 12-15 and 17. has been taken from the results of Knowlton and Byers (1988) as appropriate for a neutral nucleophile. Changes in this parameter (±1) do not affect the subsequent analysis and conclusions.…”

Section: Discussionmentioning

confidence: 99%

Characterization of covalently bound enzyme inhibitors as transition-state analogs by protein stability measurements: Phosphonate monoester inhibitors of .beta.-lactamase

Rahil

Pratt²

1994

Biochemistry

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An experimental method is described for determining whether a covalent enzyme-inhibitor complex has the properties expected of a transition-state analog. The method involves a comparison of the noncovalent interaction energies between the enzyme and the inhibitor on one hand (determined from protein denaturation thermodynamics) and the analogous transition state on the other (determined from kinetic measurements). These two quantities should presumably be large (in comparison with the interaction energies of substrates or reaction intermediates) and close to equal for a good transition state analog; the former is seen dramatically in a large increase in protein stability. The method is absolute in the sense that it does not require a crystal structure of the inhibited enzyme or any preconceptions as to the mechanism of action of the enzyme except those which led to adoption of the potential transition state analog and which might turn out to be right or wrong. In this paper the method is quantitatively applied to the inhibition of the Staphylococcus aureus PC1 beta-lactamase by phosphonate monoesters. It is concluded that the enzyme-inhibitor complex in this case is likely to be a good transition-state mimic. Therefore, mechanistic interpretation of the crystal structure of the complex can be made with more confidence. A semiquantitative assessment of the situation with serine proteinases is also made. It is concluded, in agreement with predictions based on the generally accepted mechanism and on crystal structures, that anionic, but not neutral, phosph(or/on)yl derivatives are good transition-state analogs.

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Section: Discussionmentioning

confidence: 99%

Characterization of covalently bound enzyme inhibitors as transition-state analogs by protein stability measurements: Phosphonate monoester inhibitors of .beta.-lactamase

Rahil

Pratt²

1994

Biochemistry

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“…4-Nitrophenyl acetate ( p -NPA) was purchased from Acros. p -Nitrophenyl-methoxy-acetate ( p -NPMA) was synthesized according to the previous report, while p -nitrophenyl-(2-phenyl)-propanoate ( p -NPP) was prepared using the method described in the literature . Mass spectra were obtained by MALDI-TOF-MS spectrometer (Bruker Daltonics Autoflex III Smartbeam LRF200-CID spectrometer).…”

Section: Methodsmentioning

confidence: 99%

Conjugating Catalytic Polyproline Fragments with a Self-Assembling Peptide Produces Efficient Artificial Hydrolases

Huang

Horng

2020

Biomacromolecules

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A polyproline fragment containing a catalytic dyad of His–His or Ser–His was coupled with a self-assembling peptide MAX1 to design new hydrolases (H2H5 and H2S5) for catalyzing ester hydrolysis. Circular dichroism measurements indicated that the peptides change their conformation from random coils to β-sheets when pH increases from 5 to 10. IR spectra also displayed the vibration modes corresponding to their β-structures at pH 9.0. Transmission electron microscopy (TEM) and atomic force microscopy (AFM) measurements showed that in solution, the designed peptides self-assemble into network fibrils having a significantly increased catalytic efficiency on ester hydrolysis. On p-nitrophenyl acetate (p-NPA) substrate, the designed peptides exhibit high catalytic efficiency at pH 9.0 (k cat/K M = 12.1 M–1 s–1 for H2H5, 13.3 M–1 s–1 for H2S5), and their efficiency is even better at pH 10.0 (k cat/K M = 24.3 M–1 s–1 for H2H5, 99.4 M–1 s–1 for H2S5). Additionally, H2H5 and H2S5 also display good activity on catalyzing the hydrolysis of p-nitrophenyl-(2-phenyl)-propanoate (p-NPP) and p-nitrophenyl methoxyacetate (p-NPMA). Combining the polyproline-based catalytic scaffold with a self-assembling peptide generates an efficient hydrolase, providing a new design for effective artificial enzymes.

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“…Scheme I), or if the intermediate is too unstable to exist, the reaction may follow a concerted mechanism. A stepwise addition-elimination mechanism through an addition intermediate has been shown for the pyridinolysis of 2,4-dinitrophenyl acetate [23]. Consequently, it can be reasonably concluded that also the reaction of imidazole with the present substituted phenyl esters, possessing only moderately good leaving groups, follows a stepwise rather than a concerted reaction mechanism.…”

Section: On the Mechanism Of The Reaction First-order In Imidazolementioning

confidence: 68%

On the relative leaving group abilities of imidazole and the substituted phenoxide ions. The effect of the acyl group

Neuvonen

1996

Ber Bunsenges Phys Chem

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Rate coefficients for the imidazole‐catalysed hydrolysis of substituted phenyl acetates, chloroacetates and dichloroacetates have been determined in 40% (v/v) acetonitrile‐water. It is shown that the increasing electron‐withdrawal by the acyl group makes the general base‐catalysed nucleophilic reaction of imidazole detectable beside the uncatalysed nucleophilic attack of the amine. This is attributed to the acyl group‐induced change of the partitioning ratio of imidazole and the ester leaving group. A kinetic evidence is obtained of a change in the rate‐limiting step with increasing imidazole concentration for the imidazole‐catalysed reactions of 4‐chloro‐ and 4‐methoxyphenyl dichloroacetates.

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Acyl substituent effects on ester aminolysis

Cited by 23 publications

References 6 publications

Characterization of covalently bound enzyme inhibitors as transition-state analogs by protein stability measurements: Phosphonate monoester inhibitors of .beta.-lactamase

Characterization of covalently bound enzyme inhibitors as transition-state analogs by protein stability measurements: Phosphonate monoester inhibitors of .beta.-lactamase

Conjugating Catalytic Polyproline Fragments with a Self-Assembling Peptide Produces Efficient Artificial Hydrolases

On the relative leaving group abilities of imidazole and the substituted phenoxide ions. The effect of the acyl group

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