Catalysis proximity effects

Transition State Theory for Enzyme Catalysis Proximity Effects... 

Other approaches have been developed to generate catalytic antibodies including covalent catalysis, proximity effects, and general acid-base catalysis [7]. In addition, strategies have been developed to directly select immu-... 

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. 

FIGURE 16.14 All example of proximity effects in catalysis, (a) The imidazole-catalyzed hydrolysis of j nitrophenylacetate is slow, but the corresponding intramolecular reaction is 24-fold faster (assuming [imidazole] = 1 Min [a]). 

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 importance of the proximity effect in cyclodextrin catalysis has been discussed on the basis of the structural data. Harata et al. 31,35> have determined the crystal structures of a-cyclodextrin complexes with m- and p-nitrophenols by the X-ray method. Upon the assumption that m- and p-nitrophenyl acetates form inclusion complexes in the same manner as the corresponding nitrophenols, they estimated the distances between the carbonyl carbon atoms of the acetates and the adjacent second-... 

Proximity Effects and Enzyme Catalysis Thomas C. Bruice... 

Several broad themes recur frequently in enzymatic reaction mechanisms. Among the most important of these are (1) proximity effects, (2) general-acid and general-base catalysis, (3) electrostatic effects, (4) nucleophilic or electro-philic catalysis by enzymatic functional groups, and... 

Several studies have tackled the structure of the diketopiperazine 1 in the solid state by spectroscopic and computational methods [38, 41, 42]. De Vries et al. studied the conformation of the diketopiperazine 1 by NMR in a mixture of benzene and mandelonitrile, thus mimicking reaction conditions [43]. North et al. observed that the diketopiperazine 1 catalyzes the air oxidation of benzaldehyde to benzoic acid in the presence of light [44]. In the latter study oxidation catalysis was interpreted to arise via a His-aldehyde aminol intermediate, common to both hydrocyanation and oxidation catalysis. It seems that the preferred conformation of 1 in the solid state resembles that of 1 in homogeneous solution, i.e. the phenyl substituent of Phe is folded over the diketopiperazine ring (H, Scheme 6.4). Several transition state models have been proposed. To date, it seems that the proposal by Hua et al. [45], modified by North [2a] (J, Scheme 6.4) best combines all the experimentally determined features. In this model, catalysis is effected by a diketopiperazine dimer and depends on the proton-relay properties of histidine (imidazole). R -OH represents the alcohol functionality of either a product cyanohydrin molecule or other hydroxylic components/additives. The close proximity of both R1-OH and the substrate aldehyde R2-CHO accounts for the stereochemical induction exerted by RfOH, and thus effects the asymmetric autocatalysis mentioned earlier. 

One of the reasons for the present interest in micellar catalysis is the analogy with enzymatic catalysis. For example, with respect to the proximity effect discussed above, such an analogy seems fruitful, but it should be kept in mind that there... 

Kleij, A.W., Gossage, R.A., Gebbink, R.J.M.K., Brinkmann, N., Reijerse, E.J., Kragl, U., Lutz, M., Spek, A.L. and van Koten, G. (2000) A dendritic effect in homogeneous catalysis with carbosilane-supported arylnickel(II) catalysts observation of active-site proximity effects in atom-transfer radical addition. J. Am. Chem. Soc., 122, 12, 112. 

Pericyclic processes comprise a broad and important class of concerted reactions of both theoretical and practical interest. These transformations, which are especially useful in the construction of carbon-carbon bonds,93 include electrocyclic reactions, sigmatropic rearrangements, and cycloadditions. Because they are not typically subject to general acid-general base chemistry but can be highly sensitive to strain and proximity effects, they are attractive targets for antibody catalysis. 

This result, caused by the proximity effect between peripheral catalytic sites, can translate into higher or lower catalytic activity of the metallodendrimer in homogeneous catalysis, and is commonly termed the dendritic effect. In the above case, a negative dendritic effect is observed. An interesting example of a positive dendritic effect on catalyst activity was reported by Jacobsen et al. in the hydrolytic kinetic resolution of terminal epoxides by peripherally Co(salen)-substituted PAMAM dendrimers [39]. 

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. 

Enzymes use the same catalytic mechanisms as nonenzymatic catalysts. Several factors contribute to enzyme catalysis proximity and strain effects, electrostatic effects, acid-base catalysis, and covalent catalysis. Combinations of these factors affect enzyme mechanisms. 

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. 

The basis of the catalysis of the splitting of the disulfide is presumably the formation of a charge-transfer complex between the two-electron donor NADPH (equivalent to a hydride anion) and the acceptor flavin combined with proximity effects. Both coenzymes, NADPH and FAD, are bound to the protein by adenosine phosphate-protein interactions, the substrate is loosely bound at the cleft between the units of a protein dimer (Fig. 9.6.12) (Schulz, 1983 Douglas, 1987). 

Enzyme-substrate complex Polyfunctional catalysis Proximity Medium effects... 

Another important pioneering work in CyD chemistry was reported by Breslow and Campbell [7] on the chlorination of anisole with HOCl. In the presence of a-CyD, the chlorination occurs exclusively at the para-position of anisole. This reaction also takes advantage of covalent catalysis. Here, HOCl first reacts with the secondary OH group of CyD, and the chlorine atom is selectively transferred to the para-position of anisole. Since the anisole penetrates into the cavity with the methoxy group first, the para-position of anisole is located near the secondary OH group (and thus near the CyD-OCl group). Apparently, the product selectivity comes from a proximity effect , as is often observed in enzymatic reactions. 

Methyl transfer reactions play a significant part in the modifications of aromatic polyketides, both of the polyketide core [61,62] as well as of several of the sugar moieties [44,53]. In Streptomyces, more than 20 amino acid sequences have been found that may represent enzymes involved in methyl transfer reactions in the biosynthesis of aromatic polyketides [149]. One of these enzymes, the S-adenosyl-L-methionine-dependent DnrK, is involved in the methylation of the C-4 hydroxyl group in daunorubicin/doxorubicin biosynthesis (Scheme 10, step 12). The subunit of the homo-dimeric enzyme displays a fold typical for small-molecule methyltransferases. The structure of the ternary complex with bound products S-adenosyl-L-homocysteine and 4-methoxy-8-rhodomycin provided insights into the structural basis of substrate recognition and catalysis [149]. The position and orientation of the substrates suggest an Sn2 mechanism for methyl transfer, and mutagenesis experiments show that there is no catalytic base in the vicinity of the substrate. Rate enhancement is thus most likely due to orientational and proximity effects [149]. 

J. Venkatraman, K. Aggarwal, and P. Balaram, Helical peptide models for protein glycation Proximity effects in catalysis of the Amadori rearrangement, Chem. Biol, 8 (2001) 611-625. 

---