Chorismate-prephenate rearrangement

Figure 11 Chorismate-prephenate rearrangement catalyzed by antibody 1F7 raised against a bicyciic hapten that mimics the chair conformation of the transition state of the reaction and X-ray structure of the corresponding antibody 1 F7-hapten compiex.

Wiest, O. Honk, K. N. Stabilization of the transition state of the chorismate-prephenate rearrangement An ab initio study of enzyme and antibody catalysis, J. Am. Chem. Soc. 1995,117, 11628-11639. 

Hur S, TC Bruice (2003c) Just a near attack conformer for catalysis (chorismate to prephenate rearrangements in water, antibody, enzymes, and their mutants). J. Am. Chem. Soc. 125 (35) 10540-10542... 

Epoxide opening by benzeneselenolate anion gave the rphenyl selenide with high regioselectivity (Table 8, entry 4)22. Oxidation and rearrangement yielded (+)- ra/t. -2-cyclohexene-1,4-diol. A similar approach was the key step in the synthesis of a ( + )-chorismate-prephenate analog (Table 8, entry 5)24. 

The reaction in the shikimic acid pathway is, of course, the [3,3]-sigmatropic shift in which chorismic acid rearranges to prephenic acid on the way to aromatic rings (p. 1403). The simpler reaction given here is one of the family of reactions from Chapter 36 (pp. 944-6) using an allylic alcohol and an enol derivative of a carbonyl compound. In this case we have the enol ether of a ketone. We must combine these to make an allyl vinyl ether for rearrangement. 

Enzymatic studies with chorismate mutase prephenate dehydrogenase from Escherichia coli show that the chorismate prephenate analog 7 is not a substrate for chorismate mutase65. Both 7 and 8 are moderately competitive inhibitors for chorismate mutase. Ester derivatives 4 and 5, as well as 6, readily undergo Claisen rearrangements in organic solvents. 

In this contribution, we describe work from our group in the development and application of alternatives that allow the explicit inclusion of environment effects while treating the most relevant part of the system with full quantum mechanics. The first methodology, dubbed MD/QM, was used for the study of the electronic spectrum of prephenate dianion in solution [18] and later coupled to the Effective Fragment Potential (EFP) [19] to the study of the Claisen rearrangement reaction from chorismate to prephenate catalyzed by the chorismate mutase (CM) enzyme [20]. 

The Shikimate pathway is responsible for biosynthesis of aromatic amino acids in bacteria, fungi and plants [28], and the absence of this pathway in mammals makes it an interesting target for designing novel antibiotics, fungicides and herbicides. After the production of chorismate the pathway branches and, via specific internal pathways, the chorismate intermediate is converted to the three aromatic amino acids, in addition to a number of other aromatic compounds [29], The enzyme chorismate mutase (CM) is a key enzyme responsible for the Claisen rearrangement of chorismate to prephenate (Scheme 1-1), the first step in the branch that ultimately leads to production of tyrosine and phenylalanine. 

Chorismate mutase catalyzes the Claisen rearrangement of chorismate to prephenate at a rate 106 times greater than that in solution (Fig. 5.5). This enzyme reaction has attracted the attention of computational (bio)chemists, because it is a rare example of an enzyme-catalyzed pericyclic reaction. Several research groups have studied the mechanism of this enzyme by use of QM/MM methods [76-78], It has also been studied with the effective fragment potential (EFP) method [79, 80]. In this method the chemically active part of an enzyme is treated by use of the ab initio QM method and the rest of the system (protein environment) by effective fragment potentials. These potentials account... 

Claisen rearrangement chorismic acid to prephenic acid... 

The hydrophobic effects between the apolar gronps involved in the Diels-Alder reaction also occnr when the apolar gronps belong to the same molecules, and thus should also be beneficial to the Claisen rearrangement. The nonenzymatic rearrangement of chorismate to prephenate occurs 100 times faster in water than in methanol (Copley and Knowles, 1987 Grieco et al., 1989). 

Claisen rearrangement plays an important part in the biosynthesis of several natural products. For example, the chorismate ion is rearranged to the prephenate ion by the Claisen rearrangement, which is catalysed by the enzyme chorismate mutase. This prephenate ion is a key intermediate in the shikimic acid pathway for the biosynthesis of phenylalanine, tyrosine and many other biologically important natural products. 

FIGURE 22-19 Biosynthesis of phenylalanine and tyrosine from chorismate in bacteria and plants. Conversion of chorismate to prephenate is a rare biological example of a Claisen rearrangement. 

Chorismate mutase (CM) catalyzes conversion of chorismate into prephenate in a Claisen rearrangement prephenate is a precursor in the biosynthesis of both i-phenylalanine (i-Phe) and i-tyrosine (i-Ttyr). CM occurs as a dimer for structural studies, the monomer was needed (MacBeath, 1998). The assay for CM activity was based on growth of the colonies in the absence of i-Phe and L-Tyr and thus was based on selection, not screening. One resulting mutant was found to be a monomer and to contain a somewhat polar Ala-Arg-Trp-Pro-Trp-Ala sequence. 

A thoroughly investigated reaction on the biosynthetic pathway to aromatics is the [3+3]-sigmatropic Claisen rearrangement from chorismic acid to prephenic acid (Figure 18.8). 

Figure 18.8 Claisen rearrangement from chorismate to prephenate catalyzed by antibodies.

Returning to the main course of the shikimate pathway, a singular rearrangement process occurs transforming chorismic acid into prephenic acid... 

The Claisen rearrangement has attracted special attention because of the pronounced solvent dependence of the reaction [92] and the biochemically important Claisen rearrangement of chorismate to prephenate in the shikimic add pathway [93] (Fig. 12). Both aspects of the reaction have been studied recently using DFT methods. 

Chorismate mutase catalyses the Claisen rearrangement of chorismate to form prephenate. It is an excellent system for analysing catalysis because the same reaction occurs in solution with the same reaction mechanism no covalent catalysis by the... 

Woodcock HL, M Hodoscek, P Sherwood, YS Lee, HF Schaefer, BR Brooks (2003) Exploring the quantum mechanical/molecular mechanical replica path method a pathway optimization of the chorismate to prephenate Claisen rearrangement catalyzed by chorismate mutase. Theor. Chem. Acc. 109 (3) 140-148... 

Before we embark on our journey into the world of six-membered transition states, I would like to speak briefly about one reaction, to illustrate how a transition state is drawn throughout the book. The enzyme-catalyzed transformation of chorsimate (2) to prephenate (3) is a classic example of a [3,3]-sigmatropic Claisen rearrangement6 (Scheme IV). As an old bond is being broken and at the same time a new bond is formed in the transition state, the transition state for the Claisen rearrangement of chorismate to prephenate would look more like transistion state A than like B. Still, for the convenience of following the bond connection event clearly, I prefer to draw the transition state like B. 

Under conditions in which all of (-)-chorismate rearranges, only half of the racemic substrate is converted to prephenate by 1F7 (37). The kcat value for ( )-chorismate is the same as that measured for the pure (-)-isomer, but its apparent is twice larger. Because the kcat value determined for the racemate is unchanged relative to the optically pure material, (+)-chorismate can be treated as a competitive inhibitor. From our data, the term O.SKn/Ki must be much less than 1, indicating that binding of the (+)-isomer to the antibody is at least one or two orders of magnitude weaker than that of (-)-chorismate. 

The utilization of evolutionary strategies in the laboratory can be illustrated with proteins that catalyze simple metabolic reactions. One of the simplest such reactions is the conversion of chorismate to prephenate (Fig. 3.3), a [3,3]-sigmatropic rearrangement. This transformation is a key step in the shikimate pathway leading to aromatic amino acids in plants and lower organisms [28, 29]. It is accelerated more than a million-fold by enzymes called chorismate mutases [30],... 

Fig. 3.3. Shikimate pathwayforthe biosynthesis of aromatic amino acids in plants and lower organisms. The [3,3]-sigmatropic rearrangement of chorismate into prephenate is shown in the box. PEP, phosphoenolpyruvate.

Andrews, P. R. Smith, G. D. Yonng, I. G. Transition-state stabilization and enzymic catalysis. Kinetic and molecular orbital studies of the rearrangement of chorismate to prephenate, Biochemistry 1973,12, 3492-3498. 

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