Catalysis proximity factor

Several factors contribute to enzyme catalysis. The most important of these are (1) proximity and strain effects, (2) electrostatic effects, (3) acid-base catalysis, and (4) covalent catalysis. Each factor will be described briefly. 

Many examples of proximity effects are known. In general, whenever an intramolecular acid or base is invoked in acid-base catalysis, proximity effects can be a factor. Further, when any catalyst holds a substrate near a catalytic group at its active site, or holds two separate substrates next to each other, proximity effects can be relevant. Proximity effects are definitely prevalent in organometallic catalysis, as we will see in Chapter 12. Hence, proximity effects are key to many forms of catalysis. 

The study of both carbonyl and carbon acid participation in ester hydrolysis has been used by Bowden and Last (1971) to evaluate certain of the factors suggested for important roles in enzymic catalysis. A first model concerns a comparison of the three formyl esters and shows that the proximity of the formyl to the ester group and internal strain increase in passing along the series, 1,2-benzoate, 1,8-naphthoate and 4,5-phenanthroate. The very large rate enhancements result from the proximity of the internal nucleophile once formed and from internal strain. Strain is increased or induced by the primary... 

The factors — or at least some of them — which control reactivity in intramolecular reactions are relevant to enzyme catalysis, which also involves reactions between functional groups brought together in close and precisely defined proximity (Kirby, 1980). This has been an area of lively discussion in the recent literature [for a brief summary and leading references see Paquette et al. (1990)]. The main difficulty in making generalizations about the dependence of reactivity on geometry based on results from systems in which proximity is covalently enforced lies in the constraints imposed by particular systems. These may well affect reactivity... 

In terms of enzyme catalysis, the following factors are likely to influence the magnitude of the rate enhancement in enzymatic processes (a) proximity and orientation effects (b) electrostatic complementarity of the enzyme s active site with respect to the reactant s stabilized transition state configuration (c) enzyme-bound metal ions that serve as template, that alter pK s of catalytic groups, that facilitate nucleophilic attack, and that have... 

Samuelsson (1966) concluded, on the basis of his studies, that the close proximity of a copper-protein complex to the phospholipids which are also associated with the fat globule membrane is an important consideration in the development of an oxidized flavor in fluid milks. Haase and Dunkley (1970) stated that although some aspects of catalysis of oxidative reactions in milk by copper still appear anomalous... the mechanism of oxidized flavor development with copper as catalyst involves a specific grouping of lipoprotein-metal complexes in which the spatial orientation is a critical factor. ... 

Catalysis by lysozyme is caused by three main factors (Figure 1) (1) general acid catalysis by glutamic acid residue 35, located in the proximity of the glycosidic bond, initiates the formation of a carbonium... 

C-H and C-C bond activations by ruthenium complexes have formed the focus of this chapter, and consequently other important reactions to cleave chemical bonds such as dihydrogen, C-S and M-R have not been described. Today, ruthenium is regarded as a powerful tool for cleaving a variety of both activated and unactivated chemical bonds under homogeneous conditions. Important factors that provide these activities include 1) coordinative unsaturation of the ruthenium center 2) a close proximity of the bond to the ruthenium metal and 3) kinetic preference and thermodynamic stability of the products. It is likely that the combined use of ruthenium complexes and modern strategies in organic synthesis and catalysis will provide many opportunities for the creation of new reaction processes in the futtue. 

In order to bypass the problem of designing a pocket from scratch, Bolon and Mayo [27] introduced a catalytically active His residue in thioredoxin, a well-defined 108-residue protein for which much structural and functional information was available. The design was based on the well-known reaction mechanism of p-nitrophenyl acetate hydrolysis and thioredoxin was redesigned by computation to accommodate a histidine with an acylated side chain to mimic transition state stabilization. The thioredoxin mutant was catalytically active and the reaction followed saturation kinetics with a k at of 4.6 x 10 s and a Km of 170 xM. The catalytic efficiency, after correction for differential protonation and nucleophilicity, can be estimated to be a factor of 50 greater than that of 4-methylimidazole, due to nucleophilic catalysis and proximity effects, see Section 5.2.3. 

Synthetases and ligases are not classified as nucleotidyltransferases and phosphotransferases, but those that utilize ATP to activate a substrate for ligation catalyze nucleotidyl transfers or phospho transfers in activation steps. The mechanistic questions regarding these steps are analogous but not identical to those for the simple transferases. The chemical aspects of the adenylyl and phospho transfer steps should be the same for ATP-dependent synthetases and ligases as for the simpler transferases. However, enzymic catalysis frequently involves factors other than purely chemical rate enhancement of a single step. In the case of ATP-dependent synthetases and ligases, these factors include the requirement to bind several substrates in close proximity or the involvement of two or more sites in a polymer. In a few cases the complications imposed by the interactions... 

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