Chorismic acid synthesis

Wood, H.B., Buser, H.-P., and Ganem, B., Phosphonate analogues of chorismic acid. Synthesis and evaluation as mechanism-hased inactivators of chorismate mutase, J. Org. Chem., 57, 178, 1992. 

A further series of prochiral bicydic [2.2.1] substrates have also been studied by Taschner and coworkers and lead generally to lactones of high enantiomeric purity. One of these is a valuable precursor for chorismic acid synthesis[97]. 

Feedback Inhibition Regulating Chorismic Acid Synthesis... 

Wood, H. B. Ganem, B. Short Chemical Synthesis of (-)-Chorismic Acid from (-)-Shikimic Acid, J. Am. Chem. Soc. 1990,112, 8907. 

Insertion into an O—H bond is generally favored over cyclopropanation, and consequently protection of hydroxy functionality is normally required. The ease of O—H insertion is nicely illustrated in a recent synthesis of chorismic acid derivatives, where the alkene functionality in (20) was totally unaffected by the carbenoid (Scheme 4).48... 

Until pyruvates. In connection with a synthesis of chorismic acid (1) McGowan and Hcrchiold1 developed a new synthesis of cnol pyruvates, as outlined in chart (I). 

Campbell, M.M. et al. The Biosynthesis and Synthesis of Shikimic Acid, Chorismic Acid, and Related Compounds. 1993 [45]... 

The quinone ring is derived from isochorismic acid, formed by isomerization of chorismic acid, an intermediate in the shikirnic acid pathway for synthesis of the aromatic amino acids. The first intermediate unique to menaquinone formation is o-succinyl benzoate, which is formed by a thiamin pyrophosphate-dependent condensation between 2-oxoglutarate and chorismic acid. The reaction catalyzed by o-succinylbenzoate synthetase is a complex one, involving initially the formation of the succinic semialdehyde-thiamin diphosphate complex by decarboxylation of 2-oxoglutarate, then addition of the succinyl moiety to isochorismate, followed by removal of the pyruvoyl side chain and the hydroxyl group of isochorismate. 

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). 

In contrast to E. coli, Flavobacterium [112] is unable to grow anaerobically and does not seem to produce a catechol siderophore from isochorismic acid. Regulation of isochorismic acid synthesis is therefore likely to be completely different. The relative high K , value of isochorismate synthase for chorismic acid, compared to E. coli, may prevent drainage of substrates into isochorismic acid-utilizing reactions. This may indicate that isochorismate synthesis is controlled not only at the level of transcription, as is the case in E. coli, but also at enzyme level [112]. 

When a P. aeruginosa mutant (PALS 128) was grown under iron rich conditions, the specific activity of the SA-forming enzymes was below the limits of detection [79]. Liu et al. [88], suggest that entC gene expression may be limited at the translational level as well, even when the operon is induced under iron deficiency. This may be understandable because chorismic acid is an essential metabolite for Phe, Trp, Tyr, folate and ubiquinone synthesis. In B. subtilis it was shown that the accumulation of 2,3-DHBA(Glycine) was influenced by the levels of aromatic amino acids and anthranilic acid. Anthranilic acid inhibited the synthesis of DHBA from chorismic acid [117]. It seemed that the reduction in phenolic acid accumulation caused by aromatic amino acids is a consequence of enzyme repression [121]. The synthesis of 2,3-DHBA in B. subtilis is also reduced by other phenolic acids, such as m-substimted benzoic acids. Inhibition of accumulation of phenolic acid by other phenolic acids, would indicate a fairly specific effect on phenolic acid synthesis, but not on the accumulation of coproporphyrin that also accumulates in iron-deficient cultures oiB. subtilis [121]. 

A feedback inhibition has been detected in B. subtilis, using the ferrisiderophore reductase. This enzyme reduces iron from the ferrisiderophore. The rate at which the ferrisiderophore reductase reduces iron from ferrisiderophores may signal the aromatic pathway about the demand for chorismic acid for 2,3-DHBA synthesis [128,129]. The reductase may have a regulatory effect on chorismate synthase activity. Chorismate synthase may have oxidizable sulfhydryl groups that, when oxidized, may slow the synthesis of chorismic acid [128-130]. There seemed to be no repression or inhibitory effect of 2,3-DHBA or SA on its own biosynthesis [78,121]. Also the endproduct mycobactin (sole endproduct) does not inhibit SA biosynthesis [78]. 

Candicidin production by Streptomyces griseus was inhibited by inorganic phosphate, which suppressed the biosynthesis of p-aminobenzoate, the starter unit for the synthesis of this 38-membered heptaene macrolide antibiotic [95]. P-aminobenzoic acid synthase (PABA synthase) catalyses the conversion of chorismic acid to PABA, which is a precursor to candicidin. 

Figure 4. Enzymes of Rhizobium (a) and Lemna (b) proposed as sites of glyphosate inhibition of aromatic amino acid synthesis. Abbreviations CM, chorismate mutase PDH, prephenate dehydrogenase and PD, prephenate dehydratase.

Chorismate is an intermediate in the biosynthesis of the aromatic amino acids tryptophan, phenylalanine, and tyrosine. Mammals do not synthesize these amino acids bom chorismate. Instead, they obtain the essential aromatic amino acids tryptophan and phenylalanine from the diet, and they can synthesize tyrosine from phenylalanine. Glyphosate is an effective herbicide because it prevents synthesis of aromatic amino acids in plants. But the compound has no effect on mammals because they have no active pathway for de novo aromatic amino acid synthesis. 

The pivotal position occupied by chorismic acid in the shikimic acid pathway has been established in several higher plants as well as microorganisms (Fig. 2) (Edwards and Jackman, 1965 Cotton and Gibson, 1968 Schmit and Zalkin, 1969 Gilchrist et al., 1972). By action of chorismate mutase [Fig. 3 (8)], chorismate is converted to prephenate which is subsequently metabolized by two independent pathways [Fig. 3 (9 and 11)] to form phenylalanine and tyrosine. Alternatively, chorismate serves as a substrate for anthranilate synthase, the first enzyme in the pathway branch leading to the synthesis of tryptophan [Fig. 4 (13)]. 

Because shikimic acid does not enter into mammalian metabolism, its synthesis and use are clear targets at which to aim selective toxicity. In bacteria, shikimic acid arises by cyclization of the carbohydrate 3-deoxy-2-oxo-D- mAzVzoheptulosonic acid 7-phosphate, which is formed by the condensation of erythrose 4-phosphate and phosphoenolpyruvic acid. Shikimic acid undergoes biosynthesis to chorismic acid (4.55) which is the enolpyruvic ether of raw5-3,4-dihydroxy cyclohexa-1,5-diene-1-carboxylic acid. As its name indicates, this acid sits at a metabolic fork, the branches of which lead to prephenic acid, to phenylalanine (and hence to tyrosine), to anthranilic acid (and hence tryptophan), to ubiquinone, vitamin K, and/ -aminobenzoic acid (and hence folic acid). 

The biosynthesis of compounds derived from shikimic acid is closely linked to that of isomers of vitamin K (35) (Fig. 6.7). In plants and in microorganisms, die aromatic ring is formed via the shikimate pathway, which does not exist in animals. Only recently has it been established that vitamin K synthesis branches from wo-chorismic acid (36) and not from chorismic acid (37). fro-Chorismic acid (36) is derived from shikimic acid (see Chapter 7) (Leistner, 1986). Both of the cyclization steps leading to naphthoquinones and vitamin K are unusual in plants. 

Although the formation of p-aminobenzoic acid (36) (Fig. 7.12) can be explained by amination and loss of pyruvate from w<7-chorismic acid, enzyme extracts from Enterobacter aerogenes and two Streptomyces species contain p-amino-benzoate synthase and /5< -chorismate synthase activity. Kinetic data suggest that synthesis of p-aminobenzoic acid occurs from chorismic acid (Johanni et al., 1989). p-Aminobenzoic acid is important in the formation of folic acid in fungi and bacteria (Haslam, 1974). 

The first step in the formation of tryptophan involves conversion of chorismate (9) to anthranilate (11) (Fig. 7.4). Although the reaction is not well understood, it is catalyzed by the enzyme anthranilate synthase and utilizes L-gluta-mine. By means of specifically labeled chorismic acid, it was determined that the protonation involved in the formation of anthranilic acid had occurred from the re face (Figure 4) (Floss, 1986). Anthranilic acid (11) also serves as an intermediate for the synthesis of a number of secondary compounds and occurs free and as various derivatives in many plants and other organisms (Dewick, 1989). 

The synthesis of tryptophan in microorganisms is affected at several levels by end-product inhibition. Thus, end-product feedback inhibition partly regulates the synthesis of chorismic acid which is the final product of the common aromatic pathway and serves as a substrate for the first reaction in the tryptophan-synthesizing branch pathway (see Fig. 2). Regulation of the common aromatic pathway was recently reviewed by Doy [72]. The first enzyme of the common aromatic pathway, 3-deoxy-D-flrah/>jo-heptulosonate 7-phosphate synthetase (DAHPS), has been reported to exist as at least three isoenzymes, each specifically susceptible to inhibition by one of the aromatic amino acid end products (tyrosine, phenylalanine, and tryptophan), in E. coli (see reference [3]). It should be noted that many reports have indicated that in E. coli the DAHPS (trp), the isoenzyme whose synthesis is repressed specifically by tryptophan, was not sensitive to end-product inhibition by tryptophan. Recently, however, tryptophan inhibition of DAHPS (trp) activity has been demonstrated in E. coli [3,73,74]. The E. coli pattern, therefore, represents an example of enzyme multiplicity inhibition based on the inhibition specificity of isoenzymes. It is interesting to note the report by Wallace and Pittard [75] that even in the presence of an excess of all three aromatic amino acids enough chorismate is synthesized to provide for the synthesis of the aromatic vitamins whose individual pathways branch from this last common aromatic intermediate. In S. typhimurium, thus far, only two DAHPS isoenzymes, DAHPS (tyr) and DAHPS (phe) have been identified as sensitive to tyrosine and phenylalanine, respectively [76]. 

The feedback inhibition control described above provides one form of regulation of the synthesis of chorismic acid which serves as a substrate in the first reaction specific to the tryptophan branch pathway. In the same reaction glutamine serves as the amino donor [80,81] in the... 

End-product inhibition of AS activity by tryptophan appears to be a rather common control mechanism among microorganisms. Nester and Jensen [71] described tryptophan inhibition of B. subtilis AS activity as the first step in sequential feedback control. Excess tryptophan would result in inhibition of the conversion of chorismate to anthrani-late. The consequent accumulation of chorismic acid would then serve as a feedback inhibitor of the DAMPS, the first enzyme in the pathway leading to chorismate synthesis. Bacillus alvei has an anthranilate synthetase which is extremely sensitive to inhibition by tryptophan [98]. In contrast to the mode of AS feedback inhibition in E. coli and S. typhimurium, the B. alvei AS is inhibited by tryptophan noncom-petitively with respect to chorismate and uncompetitively with respect to glutamine. It is the only Bacillus species, among 21 studied, which did not exhibit a sequential feedback control pattern [79]. 

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