Mechanistic Aspects of Enzyme Catalysis

The tmparaUeled catalytic power of enzymes has sparked numerous studies on mechanistic theories to provide a molecular tmderstanding of enzyme catalysis for almost a century. Among the numerous theories and rationales, the most illustrative models for the organic chemist are discussed here [91-93]. 

The first proposal for a general mechanism of enzymatic action was developed by E. Fischer in 1894 [94,95]. It assumes that an enzyme and its substrate mechanistically interact hke a lock-and-key fashion (Fig. 1.2). Although this assumption was quite sophisticated at that time, it assumes a completely rigid enzyme structure. 

it cannot explain why many enzymes do act on larger substrates, while they are inactive on smaller coxmterparts. Given Fischer s rationale, small substrates should be transformed at even higher rates than larger substrates since the access to the active site would be easier. Furthermore, the hypothesis cannot explain why many enzymes are able to convert not only their natural substrates but also numerous nonnatural compounds possessing different structural features. Consequently, a more sophisticated model had to be developed. 

A precise orientation of catalytic groups is required for enzyme action the substrate may cause an appreciable change in the three-dimensional relationship of the amino acids at the active site, and the changes in protein structure caused by a substrate will bring the catalytic groups into proper orientation for reaction, whereas a non-substrate will not. See [96]. 

More recently, M.J.S. Dewar developed a different rationale [99] in attempting to explain the high conversimi rates of enzymatic reactions, which are generally substantially faster than the chemically catalyzed equivalent processes. This so-called desolvation theory assumes that the kinetics of enzyme reactions have much in common with those of gas-phase reactions. If a substrate enters the active site of the enzyme, it replaces all of the water molecules at the active site of the enzyme. Then, a formal gas-phase reaction can take place which mimics two reaction partners interacting without a disturbing solvent. In solution, the water molecules impede the approach of the partners, hence the reaction rate is reduced. This theory would, inter alia, explain why small substrate molecules are often more slowly converted than larger analogues, since the former are unable to replace all the water molecules at the active site. 

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