Compounds from Chorismic Acid

Dimethylquinazoline is from Triatoma bugs which carry trypanosomiasis parasites, and indole and skatole are evil-smelling compounds found as trail pheromones in ants and defensive secretion of caddis flies (Trichoptera). Methyl anthranilate has been found in the mandibular gland of males of the ant Camponotus nearticus, and is one component of the trail pheromone (with methyl nicotinate) of the ant Aenictus rotundatus. 

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Figure 8.5 Aromatic compounds from chorismic acid. Mechanism a in the top left...

For the aromatic pathway (Figure 30.20), the critical control points are the condensation of phosphoenolpyruvate and erythrose-4-phosphate to 3-deoxy-D-arabinoheptulosonate 7-phosphate, DAHP, by DAHP synthase. For tryptophan, the formation of anthranilic acid from chorismic acid by anthranilate synthase is the second critical control point. The transcriptional regulation was overcome through the use of alternative promoters and allosteric regulation was circumvented by the classical technique of selection for feedback-resistant mutants using toxic analogues of the repressing compounds. 

Experiments on the rate of 2,3-DHBA formation from chorismic acid and the observation that chorismic acid, in the absence of NAD was converted to a compound which could serve as a substrate for 2,3-DHBA formation, indicated that at least two steps were concerned in the conversion of chorismic acid to 2,3-DHBA [84,86]. The first intermediate is isochorismic acid, which is converted to the second intermediate... 

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. 

From chorismic acid, four major pathways lead to essential metabolites tryptophan, phenylalanine and tyrosine, p-aminobenzoic acid and the folate group of coenzymes, and the isoprenoid quinones (Fig. 7.2). Numerous secondary compounds in plants and other organisms are formed from products and intermediates of these pathways. 

Tryptophan is an essential amino acid for most organisms. In plants and bacteria, this compound is derived from chorismic acid. Many groups of secondary compounds are formed from tryptophan among these are several simple amine derivatives and a number of alkaloids. 

In some fungi, salicylic acid (65) and related compounds, such as 6-methylsalicylic acid, are derived from acetate-ma-lonate pathways. In bacterial systems, similar compounds are derived from chorismic acid via isochorismic acid see Chapter 7). Salicylic acid often is found in species of Salix... 

The naphthoquinone nucleus of the above-mentioned compounds originates from chorismic acid and y-hydroxybutyryl-2 -thiamine pyrophosphate ( activated succinylsemialdehyde ) derived from oc-ketoglutarate (C 4). An important intermediate is 2-succinylbenzoic acid. Naphthohydroquinone-2-carboxylic acid is the first naphthalene derivative formed. Juglone is synthesized via a symmetrical intermediate, in contrast to the vitamins K, e.g., phylloquinone, and to lawsone. The side chain of phylloquinone derives from phytol (D 6.3). 

Until recently it was believed that chorismic acid is the branch point compound that links the shikimate pathway to the vitamin K biosynthetic pathway. "" Recent results show that this is not true (vide infra). Since vitamin K was assumed to be derived from chorismic acid, it was concluded that plant quinones which, like vitamin K, are synthesized in plants via the shikimate pathway are also derived from chorismic acid. Since chorismic acid is not the immediate precursor of the benzene ring of vitamin K, it probably is also not the immediate precursor of plant quinones such as alizarin, lucidin, or juglone. ... 

Phylloquinone and menaquinone are derived from chorismic acid, which results from 3-phosphoenolpyruvic acid (a product of glycolysis) and D-erythrose 4-phosphate (a product of the pentose and Calvin cycles) as a starting compound for the biosynthesis of phenylalanine, tyrosine and tryptophan. It is transformed into iso-chorismic acid other carbon atoms are derived from 2-oxoglutaric acid. The side chain is provided by ph)4yl diphosphate or by polyprenyl diphosphates, which are formed from geranylgeranyl diphosphate. The final reaction is a methylation at C-2. 

Chorismic acid (26), thus, represents the first divergence point of pyocyanin from other biosynthetic pathways. The first authentic pyocyanin biosynthetic enzyme is PhzE, which has sequence similarity to anthranilate synthases, which generate anthranilate from chorismate. PhzE is thought to catalyze the conversion of chorismic acid (26) to amine 165. Compound 165 is in turn a substrate for PhzD, an isochorismatase that catalyzes the hydrolysis of the vinyl ether to 166 and pyruvate [188, 189],... 

FIGURE 3.1 The biosynthetic pathway from chorismate to L-phenylalanine in Escherichia coli K12. The mnemonic of the genes involved are shown in parentheses below the enzymes responsible for each step. Compound 1 is L-phenylalanine, 2 is chorisimic acid, 3 is prephenic acid, and 4 is phenylpyruvic acid. 

Thirty-four naturally occurring compounds that incorporate the oxazole moiety have been isolated thus far. The sources are diverse—plants of the families Gramineae and Rutaceae, nudibranch egg masses, and microorganisms, the latter having furnished the majority of the compounds. With three exceptions, the marine and bacterial oxazoles appear to have been formed from peptides of aliphatic amino acids, while the oxazoles of the Gramineae and Rutaceae arise from the chorismic acid-phenylalanine pathway. The oxazoles have not been... 

At the branching point of chorismic acid, either anthranilic acid, the precursor of tryptophan, or prephenic acid, the precursor of phenylalanine, itself the precursor of tyrosine and dopa (3,4-dihydroxy-phenylalanine), is formed (Fig. 10). Phosphorylation at the 3-position, condensation with phosphoenolpyru-vate, and elimination of phosphoric acid yields choris-mate from shikimate. Chorismate is also the precursor of a number of simple, and very important, aromatic compounds, including salicylic acid, 4-amino-benzoic acid (PABA), a constituent of folic acid, and 2,3-dihydroxybenzoic acid, a key acylating group of enterobactin. 

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. 

The naturally occurring naphthoquinones such as lawsone and juglone are products of the shikimic acid pathway to aromatic amino-acids but the path which leads to these naphthoquinones branches from the main pathway before the formation of aromatic compounds, probably no later than chorismic acid.It will be most interesting to see whether the biosynthesis of shihunine also follows this route all the other bases of plant origin which arise from products of the shikimic acid pathway derive from aromatic precursors. 

The three aromatic amino acids that are biosynthesized in the shikimic acid pathway have much in common. The many stereochemical events occurring between the condensation of compounds 288a and 289 derived from carbohydrates to the formation of prephenic acid 296 have been extensively reviewed including a recent review by ourselves (82), and so we have summarized the stereochemistry of the biosynthesis in Scheme 79. Prephenic acid 296 leads to phenylalanine 297 and tyrosine 298. The mem-substituted amino acids 299 are derived from chorismate 295, as is tryptophan 302, as shown. 

Phenolic compounds include a wide range of secondary metabolites that are biosynthesised from carbohydrates through the shikimate pathway [14]. This is the biosynthetic route to the aromatic amino acids, phenylalanine, tyrosine, and tryptophan, and only occurs in microorganisms and plants. In the first step, the glycolytic intermediate phosphoenol pyruvate and the pentose phosphate intermediate erythrose-4-phosphate are condensed to 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP), a step catalysed by DAHP synthase. Intermediates of the shikimate pathway are 3-dehydroquinate, shikimate, and chorismate (Fig. 1). Phenylalanine is biosynthesised from chorismate, and from phenylalanine all the phenylpropanoids. Quinate is produced from 3-dehydroquinate and incorporated into chlorogenic and isochlorogenic acids (caffeoyl quinic acids) by combination with caffeic acid. Gallic acid is produced from shikimate. 

Biosynthesis Like other aromatic amino acids, e.g., Phe and Tyr, Trp is formed on the shikimic acid pathway. There is a branching point at chorismic acid one branch leads to Phe and Tyr, the other to Trp choris-mic acid - anthranilic acid (anthranilic acid synthase, EC 4.1.3.27)- A-(5 -0-phosphoribosyl)-anthranilic acid (anthranilic acid phosphoribosyl transferase, EC 2.4.2.18)- 1 -o-carboxyphenylamino-1 -deoxyribu-lose 5-phosphate [A-(5 -phosphoribosyl)anthranilic acid isomerase]- indole-3-glycerol phosphate (in-dole-3-glycerol phosphate synthase, EC 4.1.1.48) - indole (tryptophan synthase, EC 4.2.1,20)+serine - Trp. Many biologically active indole compounds are derived from Trp, e. g., 5-hydroxytryptophan, 5-hydroxy-tryptamine ( serotonin), and melatonin as well as many indole alkaloids. 

The key intermediate in the formation of these compounds is o-succinylbenzoic acid (OSB) (38) which is formed from wo-chorismic acid and a-ketoglutararic acid (39), a tticarboxylic acid cycle intermediate (Fig. 6.7) (Si-mantiras and Leistner, 1989). a-Ketoglutaric acid can be converted to glutamic acid, which previously was proposed... 

Use of Mutants in Biosynthetic Studies Formation of Chorismic Acid Derivatives of Chorismic Acid Biosynthesis of Tryptophan Indole 3-Acetic Acid Avenalumins from Oats DIMBOA and Related Compounds Biosynthesis of Phenylalanine and Tyrosine Compounds Derived from Shikimic Pathway Intermediates... 

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). 

Another series of compounds that appear to be derived from ijo-chorismic acid are cyclohexene oxides such as cro-tepoxide (36), senepoxide (37), and pipoxide (38) from Croton macrostachys (Euphorbiacee), Uvaria zeylanica (An-nonaceae), and Piper hookeri (Piperaceae), respectively (Fig. 7.13). These compounds have demonstrated antitumor activity (Jolad et al., 1981). 

Phenazines compounds based on the phenazine ring system (Table). All known naturally occurring P. are produced only by bacteria, which excrete them into the growth medium. Both six-membered carbon rings of P. are biosynthesized in the shikimate pathway of aromatic biosynthesis, via chorismic acid (not from anthranilate, as reported earlier). The earliest identified biosynthetic intermediate after chorismate is phenazine 1,6-dicarboxylate, which has been isolated from Pseudomonas phenazinium and from non-... 

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