Rate prediction, ester hydrolysi

Many of the 60 known reactions catalyzed by monoclonal antibodies involve kinetically favored reactions e.g., ester hydrolysis), but abzymes can also speed up kinetically disfavored reactions. Stewart and Benkovic apphed transition-state theory to analyze the scope and limitations of antibody catalysis quantitatively. They found the observed rate accelerations can be predicted from the ratio of equilibrium binding constants of the reaction substrate and the transition-state analogue used to raise the antibody. This approach permitted them to rationalize product selectivity displayed in antibody catalysis of disfavored reactions, to predict the degree of rate acceleration that catalytic antibodies may ultimately afford, and to highlight some differences between the way that they and enzymes catalyze reactions. 

Under physiological conditions (pH 7.4), cocaine (pJCa 8.6) exists mainly as the protonated amine. The reaction pathways discussed above for the ester hydrolysis of neutral cocaine predict similar rates of reaction for methyl ester... 

Collette, T.W. (1990) Ester hydrolysis rate constant prediction from infrared interferograms. Environ. Sci. Technol. 24, 1671-1676. 

The data and mechanistic conclusions summarized above come from work with aryl phosphomonoesters as predicted by the steep jSlg value, alkyl ester dianions react at very slow rates. A recent study of methyl phosphate found the rate of the dianion hydrolysis to be below the threshold of detectability, with an estimated rate constant of 2 x 10 20 s 1 at 25 °C.3 Since this value is close to the rate predicted from an extrapolation of the Bronsted plot of aryl phosphomonoester dianions, a similar mechanism is likely to be followed for alkyl and aryl esters. 

Zhang, H Qu, X. and Ando, H. (2005) A simple method for reaction rate prediction of ester hydrolysis./. Mol. Struct. (Theochem), 725, 31-37. 

The rate determining step is the formation of a carbonium ion and as expected, substituents that are able to stabilize the carbonium ion will strongly accelerate the hydrolysis reaction. This effect is shown in Table 1. However, as also shown in Table 1, this is not true for ortho esters where substituent effects are much smaller than would be predicted by analogy with acetal or ketal hydrolysis, and in some cases are in the opposite direction. These data are consistent with the hypothesis that in ortho ester hydrolysis, there is very little carbonium ion character in the transition state and that in the hydrolysis of ortho esters, addition of a proton is concerted with the breaking of a C-O bond. 

This value is close to the rate predicted from an extrapolation of the Br0nsted plot of aryl phosphomonoester dianions, suggesting that the alkyl and aryl esters likely follow a similar hydrolysis mechanism. 

Cyclodextrins have had valuable industrial uses for a considerable time, particularly as agents to bind or release volatile molecules. Accurate predictions concerning the selectivity and stability of cyclodextrin-guest complexes are therefore of considerable interest both academically and practically." MD was used to simulate cyclodextrin hydrates" as a test of the applicability of the GROMOS program package to systems beyond proteins and nucleic acids. Other early MD simulations focused on interactions with guests such as enantiomers of methyl-2-chloropropionate. Comparisons between calculated thermodynamic properties for complexes formed by O -cyclodextrin with para-substituted phenols and the results of MM simulations led to improvements in force fields that described the interactions. MM2 simulations were used to support NMR data for the -cyclodextrin inclusion complex with benzoic acid. " The well-known catalytic effect of cyclodextrins has been modeled. For example, the relative rate increase of hydrolysis of S over R phenyl ester stereoisomers in the presence of -cyclodextrin... 

Kindler [Twi., 450( 1), 1926] has studied the alkaline hydrolysis of the ethyl esters of a number of substituted benzoic acids. The m-nitro compound was found to have a rate constant 63.5 times as fast as the unsubstituted compound. What relative rate constant is predicted for the reaction of p-methoxybenzoate by the Hammett equation The value based on experimental results is 0.214. 

Detailed studies on the lipase-catalyzed polymerization of divinyl adipate and 1,4-butanediol were performed [41-44]. Bulk polymerization increased the reaction rate and molecular weight of the polymer however, the hydrolysis of the terminal vinyl ester significantly limited the formation of the polyester with high molecular weight. A mathematical model describing the kinetics of this polymerization was proposed, which effectively predicts the composition (terminal structure) of the polyester. 

Unfortunately, the size of the crystallographic problem presented by elastase coupled with the relatively short lifedme of the acyl-enzyme indicated that higher resolution X-ray data would be difficult to obtain without use of much lower temperatures or multidetector techniques to increase the rate of data acquisition. However, it was observed that the acyl-enzyme stability was a consequence of the known kinetic parameters for elastase action on ester substrates. Hydrolysis of esters by the enzyme involves both the formation and breakdown of the covalent intermediate, and even in alcohol-water mixtures at subzero temperatures the rate-limidng step is deacylation. It is this step which is most seriously affected by temperature, allowing the acyl-enzyme to accumulate relatively rapidly at — 55°C but to break down very slowly. Amide substrates display different kinetic behavior the slow step is acylation itself. It was predicted that use of a />-nitrophenyl amid substrate would give the structure of the pre-acyl-enzyme Michaelis complex or even the putadve tetrahedral intermediate (Alber et ai, 1976), but this experiment has not yet been carried out. Instead, over the following 7 years, attention shifted to the smaller enzyme bovine pancreatic ribonuclease A. 

Unfortunately, there is presently only a very tentative bit of evidence available to substantiate this prediction. In one experiment at an acid pH, the overall rate of hydrolysis of the n-octyl ester of 2,4-D was measured in a sediment/water slurry in which a substantial fraction of the ester was sorbed. The rate was observed to be substantially faster than the predicted aqueous phase rate. Though this is an indication that the above prediction is correct, much more experimental work is needed to substantiate and quantify this predicted rate enhancement. 

---