Prephenate, intermediates shikimic acid pathway

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. 

Fig. 2 (1)]. A key intermediate in the pathway is chorismate from which branched pathways lead to tryptophan, phenylalanine, tyrosine, 4-amino benzoate, isoprenoid quinones, and metacarboxyphenylalanine. A secondary branch also occurs at prephenate leading to phenylalanine and tyrosine. A representative number of non amino acid compounds in relation to their shikimic acid pathway precursors are shown in Fig. 1. One side branch leads to quinate which participates in the formation of depsides. 

Basically, the shikimic acid pathway involves initial condensation of phosphoenolpyruvate (PEP) from the glycolysis process with erythrose-4-phosphate derived from the oxidative pentose phosphate cycle. A series of reactions leads to shikimic acid, which is then phosphorylated. The phosphorylated shikimic acid combines with a second molecule of PEP to yield prephenic acid via chorismic acid intermediate. Prephenic acid is then decarboxylated to form phenyl-pyruvate or p-hydroxyphenylpyruvate. On transamination, these two compounds yield phenylalanine and tyrosine, respectively. 

Danishefsky and Hirama have published a neat total synthesis of the disodium salt of prephenic acid (24), a central intermediate in the shikimic acid biosynthetic pathway.The key step involves a Diels-Alder reaction between the diene (22) and the unsaturated lactone (23). A crucial feature of this synthesis is the simultaneous protection of both the C-lO-carboxy and C-8-keto functions as a methoxy-lactone, allowing umasking in a single step by alkaline hydrolysis. 

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. 

Aryl side chain containing L-a-amino acids, such as phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp), are derived through the shikimate pathway. The enzymatic transformation of phosphoenolpyr-uvate (PEP) and erythro-4-phosphate, through a series of reactions, yields shikimate (Scheme 2). Although shikimate is an important biosynthetic intermediate for a number of secondary metabolites, this chapter only describes the conversion of shikimate to amino acids containing aryl side chains. In the second part of the biosynthesis, shikimate is converted into chorismate by the addition of PEP to the hydroxyl group at the C5 position. Chorismate is then transformed into prephenate by the enzyme chorismate mutase (Scheme 3). 

The Claiscn rearrangement of chorismate 1, the last common intermediate in the biosynthesis of aromatic amino acids via the shikimate pathway, to prephenate 2 proceeds readily without catalysis263 and is greatly accelerated by a factor of 1.9 xlO6 by the enzyme chorismate mutase655-656. 

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