Proximity, effect in enzymes

Clearly, proximity and orientation play a role in enzyme catalysis, but there is a problem with each of the above comparisons. In both cases, it is impossible to separate true proximity and orientation effects from the effects of entropy loss when molecules are brought together (described the Section 16.4). The actual rate accelerations afforded by proximity and orientation effects in Figures 16.14 and 16.15, respectively, are much smaller than the values given in these figures. Simple theories based on probability and nearest-neighbor models, for example, predict that proximity effects may actually provide rate increases of only 5- to 10-fold. For any real case of enzymatic catalysis, it is nonetheless important to remember that proximity and orientation effects are significant. 

The kidney contains the major site of renin synthesis, the juxtaglomerular cells in the wall of the afferent arteriole. From these cells, renin is secreted not only into the circulation but also into the renal interstitium. Moreover, the enzyme is produced albeit in low amounts by proximal tubular cells. These cells also synthesize angiotensinogen and ACE. The RAS proteins interact in the renal interstitium and in the proximal tubular lumen to synthesize angiotensin II. In the proximal tubule, angiotensin II activates the sodium/hydrogen exchanger (NHE) that increases sodium reabsorption. Aldosterone elicits the same effect in the distal tubule by activating epithelial sodium channels (ENaC) and the sodium-potassium-ATPase. Thereby, it also induces water reabsotption and potassium secretion. 

In the intramolecular reactions studied by Bruice and Koshland and their co-workers, proximity effects (reduction in kinetic order and elimination of unfavourable ground state conformations) and orientation effects might give rate accelerations of 10 -10 . Hence, these effects can by themselves account for the enhancements seen in most intramolecular reactions. However, a factor of 10 -10 is less than the rate acceleration calculated for many enzyme reactions and certain intramolecular reactions, for example, hydrolysis of benzalde-hyde disalicyl acetal (3 X 10 ) (Anderson and Fife, 1973) and the lactonization reaction of[l] (10 ) where a trimethyl lock has been built into the system. If hydrolysis of tetramethylsuccinanilic acid (Higuchi et al., 1966) represents a steric compression effect (10 rate acceleration), then proximity, orientation, and steric compression... 

The secondary structure of the polypeptide chain in hydrolytic enzymes ensures the spatial proximity of the necessary functional groups, which are responsible for the observed catalytic effect. In synthetic enzyme mimics, it is possible to bring the requisite functionalities into close juxtaposition only if there is a rigid framework to which these groups are attached. It was thus logical to examine cyclic peptides, especially cyclodipeptides, which bear the necessary functional groups for their catalytic activity in ester hydrolysis. 

The secret behind the superb catalytic performance of enzymes is that when an enzyme binds the substrates and cofactors, it turns the uncatalyzed intermolecular readion into an intramolecular reaction [25]. In general, intramolecular reactions are faster than intermolecular ones, because the reading groups are already close to each other. This proximity effect increases the effedive concentration, and with it the rate... 

This article will describe the different chemical strategies used by enzymes to achieve rate acceleration in the reactions that they catalyze. The concept of transition state stabilization applies to all types of catalysts. Because enzyme-catalyzed reactions are contained within an active site of a protein, proximity effects caused by the high effective concentrations of reactive groups are important for enzyme-catalyzed reactions, and, depending on how solvent-exposed the active site is, substrate desolvation may be important also. Examples of acid-base catalysis and covalent (nucleophilic) catalysis will be illustrated as well as examples of "strain" or substrate destabilization, which is a type of catalysis observed rarely in chemical catalysis. Some more advanced topics then will be mentioned briefly the stabilization of reactive intermediates in enzyme active sites and the possible involvement of protein dynamics and hydrogen tunneling in enzyme catalysis. 

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