Shikimic acid pathway Claisen rearrangement

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. 

Claisen rearrangement of chorismic acid 1 to prephenic acid 2 (Scheme 1), which is catalyzed by the enzyme chorismate mutase, can be considered as the key step in the biosynthesis of aromatic compounds, that is the so-called shikimic acid pathway. The chair-like transition state geometry 3 was proved by double isotope-labeling experiments [2]. However, in the laboratory this particular reaction can be accelerated not only by enzymes but also by catalytic antibodies [3]. For the generation of such antibodies haptenes such as 4 were used, that is, molecules whose structure is very similar to the transition state of the particular reaction and which are tightly bound by the antibody. 

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. 

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. 

C,oH oOg, Mu 226.19. P. is unstable in the free form and undergoes decarboxylation with elimination of water to give phenylpyruvic acid. It is an intermediate in the biosynthesis of many aromatic natural products by the shikimate pathway (see chorismic acid, shi-kimic acid). The biosynthesis of P. proceeds from chorismic acid by enzyme-catalyzed [3,3]sigmatropic rearrangement (Claisen rearrangement) under the action of chorismate mutase (EC 5.4.99.5). 

The rearrangement of 122 to 123 is a key reaction along the shikimate biosynthetic pathway for generating aromatic amino acids in plant, fungal, and bacterial systems, and it is catalyzed by the enzyme chorismate mutase more than a millionfold. This has stimulated an in-depth investigation of the mechanism of the Claisen rearrangement. ... 

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