Chorismate uncatalyzed reaction

It has been shown that both the catalyzed and the uncatalyzed reaction proceed through a chairlike transition state, stabilized in polar media59 60-143 262-263. Compound 1, an analog of the transition-state structure, proved to be a potent inhibitor of E. coli chorismate mutase-prephenate dehydrogenase204-255. For a discussion of the mechanism and structural requirements of the enzyme see refs 266 and 267. 

Chorismate mutase (CM) catalyzes the Claisen rearrangement of chorismate to prephenate in the shikimic acid pathway used in the biosynthesis of aromatic amino acids. It represents a reference enzyme to explore the fundamentals of catalysis and has been the subject of extensive experimental and computational research. These have shown both that catalysis proceeds without covalent binding of the substrate to the enzyme, and that the uncatalyzed reaction in water proceeds by the same mechanism. This makes CM a particularly convenient target for QM/MM studies. 

Experimental results for the CM-catalyzed and uncatalyzed reaction, as weU as structural information for chorismate mutase, have been extensively discussed in two previous reviews [2, 3]. There has been a rapid growth of literature in computational studies of chorismate mutase in the last few years. In this chapter, we shall begin by summarizing some key experimental data related to the Claisen rearrangement along with existing structural information for chorismate mutase. We will then review the results of computational studies of chorismate mutase and discuss different proposals that have been suggested for the mechanism of the CM[Pg.1]

The activation parameters for the CM-catalyzed and uncatalyzed Claisen rearrangement are listed in Table 1.2 [20, 21, 26, 42]. For the uncatalyzed reaction, the activation barrier (AG ) is 24.5 kcal/mol. Chorismate mutase is able to reduce the activation barrier by 7-10 kcal/mol. Table 1.2 shows that the rate acceleration is due to a reduction in the entropy of activation to near zero and a decrease in the enthalpy of activation by about 5 kcal/mol the only exception is the BsCM-catalyzed reaction for which there is a significant unfavorable AS. However, the reliability of these data has been called into question [44], and it was suggested [44] that both the substrate binding and product leaving are expected to show large solvent compensation effects involving AH and AS [45, 46). 

Why is 1F7 10 -times iess active than chorismate mutase The antibody molecule s distinctive architecture does not appear to impose intrinsic structural limitations on catalysis. Indeed, comparison of the active sites of the antibody and the monofunctional enzyme from Bacillus subtilis [26] suggests that the differences between them are more a matter of degree than of kind. Upon complex formation, the hapten is buried to a similar extent in both proteins, and similar types of interactions are available for orienting the flexible substrate correctly for reaction. Furthermore, the enzyme and the antibody seem to promote the rearrangement of chorismate via the same concerted transition state as the uncatalyzed reaction. Other formal mechanistic possibilities, such as a two-step heterolytic process assisted by an enzymic nucleophile, can be ruled out by the lack of appropriate functional groups in the respective active sites [25,26]. 

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