Chorismic acid conformation

Figure 4.11). This reaction, a Claisen rearrangement, transfers the PEP-derived side-chain so that it becomes directly bonded to the carbocycle, and so builds up the basic carbon skeleton of phenylalanine and tyrosine. The reaction is catalysed in nature by the enzyme chorismate mutase, and, although it can also occur thermally, the rate increases some 106-fold in the presence of the enzyme. The enzyme achieves this by binding the pseudoaxial conformer of chorismic acid, allowing a transition state with chairlike geometry to develop. 

The most favourable conformation for chorismic acid has the substituents pseudo equatorial but the L3,3]-sigmatropic rearrangement cannot take place in that conformation. First, the diaxial conformation must be formed and the chair transition state achieved. Then the required orbitals will be correctly aligned. 

The proton magnetic resonance spectrum of chorismic acid (81) was fully analysed by Edwards and Jackman and this analysis confirmed the structure and relative stereochemistry assigned to the molecule. Fm hermore the magnitude of the coupling constant between the protons Hj and H4. (11.7 Hz) as well as both the allylic coupling constants (1.9 Hz) suggested that the most extensively populated conformation of the molecule in solution is that in which the two substituents at C-3 and C-4 are quasi-equatorial (93). With this information in mind Edwards and Jackman postulated that the role of the enzyme chorismate mutase, which promotes the transformation to prephenic acid (86), is to invert the... 

Schultz and coworkers (Jackson et a ., 1988) have generated an antibody which exhibits behaviour similar to the enzyme chorismate mutase. The enzyme catalyses the conversion of chorismate [49] to prephenate [50] as part of the shikimate pathway for the biosynthesis of aromatic amino acids in plants and micro-organisms (Haslam, 1974 Dixon and Webb, 1979). It is unusual for an enzyme in that it does not seem to employ acid-base chemistry, nucleophilic or electrophilic catalysis, metal ions, or redox chemistry. Rather, it binds the substrate and forces it into the appropriate conformation for reaction and stabilizes the transition state, without using distinct catalytic groups. 

The transition state for the enzymatic reaction has been shown to have a chairlike geometry as well [61], and conformationally constrained compounds that mimic this structure, such as the oxabicyclic dicarboxylic acid 1 (Fig. 3.6), are good inhibitors of chorismate mutase enzymes [62 - 64], How a protein might stabilize this high-energy species has been a matter of some debate. Recently, heavy atom isotope effects were used to characterize the structure of the transition state bound to BsCM [65]. A very... 

Fig. 3.6. Chorismate prefers a pseudodiequatorial conformation in solution. It must adopt a disfavored pseudodiaxial conformation to reach the pericyclic transition state. The conformationally constrained oxabicyclic dicarboxylic acid 1, which mimics the transition state, is a potent inhibitor of natural chorismate mutases [62], Antibodies raised against this compound also catalyze the reaction, albeit 100 to 10,000-times less efficiently than their natural counterparts [39, 41].

Chorismate mutase is an enz3me that promotes a pericyclic reaction by forcing the substrate to assume the conformation needed for the reaction. The product of the pericyclic reaction is prephenate, which is subsequently converted into the amino acids phenylalanine and tyrosine. What kind of a pericyclic reaction does chorismate mutase catalyze ... 

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