Transition state, stabilization

Enzymes recognize and stabilize atomic features that are present in the transition state for the catalyzed reaction but that are not present in the substrate or product. The enzyme is more complementary to the transition state than to the reactants of products. 

A common theme of all the preceding mechanisms of catalysis is that the enzyme does something to assist the reaction in reaching the transition state. The structure of the transition state for a chemical reaction is slightly different from the structure of either the reactants or products. Some chemical bonds are at different angles and lengths, and charges are distributed differently. The enzyme can stabilize those features that occur 

The STRAIN AND DISTORTION model for catalysis involves pushing, pulling, or twisting a bond that is to be made or broken during the reaction. Parts of the substrate not involved directly in the chemical reaction are required to hold the substrate on the enzyme in the distorted form. The distortion and strain make it easier to reach the transition state. 

The STRUCTURE OF THE TRANSITION STATE is different from that of the substrate with respect to charge and shape. Because it looks different, the enzyme can recognize specific features of the transition state and stabilize them. This makes it easier to reach the transition state and makes the reaction faster. 

There are other parts of the substrate, not involved in the reaction, that don t change structure during the reaction— like the R groups. These 

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Transition-state stabilization in subtilisin is dissected by protein engineering... 

A structural anomaly in subtilisin has functional consequences Transition-state stabilization in subtilisin is dissected by protein engineering Catalysis occurs without a catalytic triad Substrate molecules provide catalytic groups in substrate-assisted catalysis Conclusion Selected readings... 

Calculations at several levels of theory (AMI, 6-31G, and MP2/6-31G ) find lower activation energies for the transition state leading to the observed product. The transition-state calculations presumably reflect the same structural features as the frontier orbital approach. The greatest transition-state stabilization should arise from the most favorable orbital interactions. As discussed earlier for Diels-Alder reactions, the-HSAB theory can also be applied to interpretation of the regiochemistry of 1,3-dipolar cycloaddi-... 

The hypothesis that electron-pair donation from the a atom will stabilize this transition state leads to the difficulty that the attacking atom must carry more bonds than conventional valence bond symbolism admits. Despite this problem, the general idea is expressed by 7 and its relationship to 6 by resonance. It is possible that transition state stabilization can be obtained in this way by rehybridization of the entire molecule. Klopman et al. suggest that the a effect arises from... 

Cecil, T. R., et al., 1992. RNA catalysis by a group I ribozyme Developing a model for transition-state stabilization. Journal of Biological Chemistry... 

Transition-state stabilization in chymotrypsin also involves the side chains of the substrate. The side chain of the departing amine product forms stronger interactions with the enzyme upon formation of the tetrahedral intermediate. When the tetrahedral intermediate breaks down (Figure 16.24d and e), steric repulsion between the product amine group and the carbonyl group of the acyl-enzyme intermediate leads to departure of the amine product. 

Transition-State Stabilization and Transition-State Analogs... 

Figure 6.16 The hypothetical structure of a transition state for alkene protonalion. The transition slate is closer in both energy and structure to the carbocation than to the alkene. Thus, an increase in carbocation stability (lower AG°) also causes an increase in transition-state stability (lower AG >, thereby increasing the rate of its formation.

Since equatorial attack is roughly antiperiplanar to two C-C bonds of the cyclic ketone, an extended hypothesis of antiperiplanar attack was proposed39. Since the incipient bond is intrinsically electron deficient, the attack of a nucleophile occurs anti to the best electron-donor bond, with the electron-donor order C—S > C —H > C —C > C—N > C—O. The transition state-stabilizing donor- acceptor interactions are assumed to be more important for the stereochemical outcome of nucleophilic addition reactions than the torsional and steric effects suggested by Felkin. 

The observed stereoselectivity was much higher than in the absence of the sulfide moiety which is explained by a cyclic transition state stabilized by chelation. 

Wang, X. and Andrews, L. (2002) Infrared Spectra and DFT Calculations for the Gold Hydrides AuH, (H2)AuH, and the AuHs Transition State Stabilized in (H2) AuHs. The Journal of Physical Chemistry A, 106, 3744-3748. 

The differences in the rate constant for the water reaction and the catalyzed reactions reside in the mole fraction of substrate present as near attack conformers (NACs).171 These results and knowledge of the importance of transition-state stabilization in other cases support a proposal that enzymes utilize both NAC and transition-state stabilization in the mix required for the most efficient catalysis. Using a combined QM/MM Monte Carlo/free-energy perturbation (MC/FEP) method, 82%, 57%, and 1% of chorismate conformers were found to be NAC structures (NACs) in water, methanol, and the gas phase, respectively.172 The fact that the reaction occurred faster in water than in methanol was attributed to greater stabilization of the TS in water by specific interactions with first-shell solvent molecules. The Claisen rearrangements of chorismate in water and at the active site of E. coli chorismate mutase have been compared.173 It follows that the efficiency of formation of NAC (7.8 kcal/mol) at the active site provides approximately 90% of the kinetic advantage of the enzymatic reaction as compared with the water reaction. 

The structural and chemical mechanisms used by enzymes to achieve transition state stabilization have been reviewed in detail elsewhere (e.g., see Jencks, 1969, Warshel, 1998, Cannon and Benkovic, 1998, Copeland, 2000, Copeland and Anderson, 2002 and Kraut et al., 2003). Four of the most common strategies used by enzymes for transition state stabilization—approximation, covalent catalysis, acid/base catalysis, and conformational distortion—are discussed below. 

Figure 2.3 Schematic representation of the induced strain model of transition state stabilization. Source Redrawn from Copeland (2000).

In this chapter we have seen that enzymatic catalysis is initiated by the reversible interactions of a substrate molecule with the active site of the enzyme to form a non-covalent binary complex. The chemical transformation of the substrate to the product molecule occurs within the context of the enzyme active site subsequent to initial complex formation. We saw that the enormous rate enhancements for enzyme-catalyzed reactions are the result of specific mechanisms that enzymes use to achieve large reductions in the energy of activation associated with attainment of the reaction transition state structure. Stabilization of the reaction transition state in the context of the enzymatic reaction is the key contributor to both enzymatic rate enhancement and substrate specificity. We described several chemical strategies by which enzymes achieve this transition state stabilization. We also saw in this chapter that enzyme reactions are most commonly studied by following the kinetics of these reactions under steady state conditions. We defined three kinetic constants—kai KM, and kcJKM—that can be used to define the efficiency of enzymatic catalysis, and each reports on different portions of the enzymatic reaction pathway. Perturbations... 

Wild-type and mutant enzymes Main a-linkage in glucan products Amino acid sequence around transition-state stabilizer D627 in GTFR... 

Mutations are shown in italics the putative transition-state stabilizer is shown in bold. 

Strain and Distortion Transition-State Stabilization Transition-State Analogs Chemical Catalysis... 

W. Jones, L. C. Kurz, and R. Wolfenden, Transition-state stabilization by adenosine... 

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