Chorismate metabolism

Walsh CT, Liu J, Rusnak F, Sakaitani M. Molecular studies on enzymes in chorismate metabolism and the enterobactin biosynthesis pathway. Chem. Rev. 1990 90 1105-1129. 

Studies with isolated enzymes in vitro reveal feedback inhibition of chorismate mutase by phenylalanine and tyrosine. Tryptophan apparently controls its own synthesis by feedback inhibition of anthranilate synthase and furthermore exerts control in the partitioning of chorismate between the two competing routes of chorismate metabolism by its ability to both activate chorismate mutase and relieve the inhibition imposed on this step by phenylalanine and tyrosine. In addition, carbon flux throuch chorismate to prephenate is also sensitive to fluctuations in chorismate concentration due to the allosteric substrate activation of chorismate mutase by chorismate. 

Within the diastereomeric switch sequences, the corresponding trans-diols become accessible either using a Mitsunobu inversion or a reversible Diels-Alder cyclization as key reaction step [249,250]. This synthetic strategy is complementary to an approach involving metabolic engineering of E. coli via the chorismate/ isochorismate pathway [251]. 

The shikimate pathway is the major route in the biosynthesis of ubiquinone, menaquinone, phyloquinone, plastoquinone, and various colored naphthoquinones. The early steps of this process are common with the steps involved in the biosynthesis of phenols, flavonoids, and aromatic amino acids. Shikimic acid is formed in several steps from precursors of carbohydrate metabolism. The key intermediate in quinone biosynthesis via the shikimate pathway is the chorismate. In the case of ubiquinones, the chorismate is converted to para-hydoxybenzoate and then, depending on the organism, the process continues with prenylation, decarboxylation, three hydroxy-lations, and three methylation steps. - ... 

It is interesting to note that the dihydroxybenzoyl nucleus arises from chorismic acid which, in turn, is derived from erythrose phosphate and phosphoenol pyruvate, both of these substances being intermediates in the anaerobic metabolism of carbohydrate (74). Accordingly, the biogenesis of the catechol type ligand is independent of the presence of oxygen gas. 

Chemical properties appropriate to a compound found at a branch point of metabolism are displayed by chorismic acid. Simply warming the compound in acidic aqueous solution yields a mixture of prephen-ate and para-hydroxybenzoate (corresponding to reactions h and l of Fig. 25-1). Note that the latter reaction is a simple elimination of the enolate anion of pyruvate. As indicated in Fig. 25-1, these reactions correspond to only two of several metabolic reactions of the chorismate ion. In E. coli the formation of phe-nylpyruvate (steps h and i, Fig. 25-1) is catalyzed by a single protein molecule with two distinctly different enzymatic activities chorismate mutase and prephenate dehydratase.34-36 However, in some organisms the enzymes are separate.37 Both of the reactions catalyzed by these enzymes also occur spontaneously upon warming chorismic acid in acidic solution. The chorismate mutase reaction, which is unique in its mechanism,373 is discussed in Box 9-E. Stereochemical studies indicate that the formation of phenylpyruvate in Fig. 25-1, step z, occurs via a... 

Microbes and plants synthesize aromatic compounds to meet their needs of aromatic amino acids (L-Phe, L-Tyr and L-Trp) and vitamins. The biosynthesis of these aromatics [69] starts with the aldol reaction of D-erythrose-4-phosphate (E4P) and phosphoenolpyruvate (PEP), which are both derived from glucose via the central metabolism, into DAHP (see Fig. 8.13). DAHP is subsequently converted, via a number of enzymatic steps, into shikimate (SA) and eventually into chorismate (CHA, see later), which is the common intermediate in the biosynthesis of the aromatic amino acids [70] and vitamins. 

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],... 

The Fab fragment of 1F7 has already been shown to function in the cytoplasm of a chorismate mutase-deficient yeast strain [43,44]. When produced at a sufficiently high level, the catalytic antibody is able to replace the missing enzyme and weakly complement the metabolic defect. Conceivably, therefore, it can be placed under selection pressure to identify variants that have higher catalytic efficiency. Preliminary results from such experiments appear quite promising [69]. 

Comparable studies have been performed for the formation of m-cyclo-hexyl fatty acids in Alicydobacillus acidocaldarius and the pathways are identical [100]. A recent publication concerning this later pathway has shown that the final remaining stereochemical ambiguity, the stereochemistry of proton loss at C-6 in the initial 1,4-conjugate elimination of shikimate occurs with loss of the pro-6R proton [102]. This mirrors the stereochemistry of normal shikimate metabolism in the formation of chorismate from 5-enolpyruvyl-shikimate 3-phosphate. 

The thousands of enzyme-catalyzed chemical reactions in living cells are organized into a series of biochemical (or metabolic) pathways. Each pathway consists of a sequence of catalytic steps. The product of the first reaction becomes the substrate of the next and so on. The number of reactions varies from one pathway to another. For example, animals form glutamine from a-ketoglutarate in a pathway that has two sequential steps, whereas the synthesis of tryptophan by Escherichia coli requires 13 steps. Frequently, biochemical pathways have branch points. For example, chorismate, a metabolic intermediate in tryptophan biosynthesis, is also a precursor of phenylalanine and tyrosine. 

In the treated plants the biosynthesis of phenylalanine, more particularly the metabolism of chorismic acid, is inhibited. Similar conclusions were drawn by Roisch and Lingens (1974) in experiments with Escheria coli. 

Chorismic acid is a metabolic intermediate that is the branch point in the synthesis of coenzyme Q and the aromatic amino acids, phenylalanine, tyrosine, and tryptophan (Figure 21.12). 

See also Metabolism of Aromatic Amino Acids and Histidine, Shikimic Acid, Erythrose-4-Phosphate, Phenylalanine, Folate, Chorismate, Coenzyme Q... 

The indole moiety of the terpenoid indole alkaloids originates from tryptophan, an aromatic amino acid, which is derived from chorismate via anthranilate. Chorismate is a major branching point in plant primary and secondary metabolism. Here the shikimate pathway (Fig. 6) branches into different pathways (Fig. 7), among others leading to the aromatic amino acids tyrosine, phenylalanine, and tryptophan. 

The biosynthesis of shikimate, the direct precursor for chorismate, has been reviewed elsewhere 138-141). The shikimate pathway leading to chorismate is located in the plastids. For the two branches from chorismate leading to the aromatic amino acids, it has been postulated that both occur in a plastidial and a cytosolic form 142). The plastidial form is responsible for the aromatic amino acids for primary metabolism, and the cytosolic one for the biosynthesis of the aromatic amino acids used as precursors in secondary metabolism (for a review, see refs. 141,143). 

Fig. 7. Chorismate as major branching point in secondary metabolism.

In this review we have only dealt with alkaloid biosynthesis in C. roseus the biochemistry of this plant has also been studied in detail for other aspects, such as anthocyanin production, phosphate metabolism, cell growth, and cell division cycle (e.g., ref. 362). Unfortunately, most of the studies concerning the primary metabolism are not linked with those of secondary metabolism. However, one may expect that in the future the studies on secondary metabolism, such as chorismate-derived products (an-thocyanins, benzoic acid derivatives, and alkaloids) and terpenoid-derived products such as the alkaloids, will be integrated. This will eventually allow us a much better insight into the overall biochemistry of the plant. All of the available information makes C. roseus an outstanding model system for the study of the regulation of plant metabolism. 

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