Phosphoenolpyruvate, shikimic acid pathway

Alkaloid biosynthesis needs the substrate. Substrates are derivatives of the secondary metabolism building blocks the acetyl coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid and 1-deoxyxylulose 5-phosphate (Figure 21). The synthesis of alkaloids starts from the acetate, shikimate, mevalonate and deoxyxylulose pathways. The acetyl coenzyme A pathway (acetate pathway) is the source of some alkaloids and their precursors (e.g., piperidine alkaloids or anthraniUc acid as aromatized CoA ester (antraniloyl-CoA)). Shikimic acid is a product of the glycolytic and pentose phosphate pathways, a construction facilitated by parts of phosphoenolpyruvate and erythrose 4-phosphate (Figure 21). The shikimic acid pathway is the source of such alkaloids as quinazoline, quinoline and acridine. 

The specific and proximate precursor of the mCyN unit in ansamycin polyketides is 3-amino-5-hydroxybenzoic acid 59 (AHBA) [94]. The biosynthesis of AHBA has recently been described by Floss and co-workers from the initial branch point of the shikimic acid pathway prior to 3-deoxy-D-flra/jzno-heptulo-sonic acid 7-phosphate (DAHP) [95]. The pathway shown in Scheme 25 was delineated by feedings of the proposed AHBA precursors, in labelled forms, to cell-free extracts of both the rifamycin B producer A. mediterranei S699 and the ansatrienin A producer S. collinus Tul892. In these experiments each of the compounds 61-64 was converted into AHBA with generally increasing efficiency. Most importantly the shikimate pathway compound DAHP cannot replace phosphoenolpyruvate 61 and erythrose 4-phosphate 60, or aminoDAHP 62 as the precursor of AHBA 59. 

Besides showing the unbranched pathway from erythrose-4-phosphate and phosphoenolpyruvate to shikimic acid. Figure 2L13 also shows the sequence of reactions from shikimic acid to chorismate, the first major branch point in the synthesis of the aromatic amino acids and histidine. The sixth reaction of the shikimic acid pathway is inhibited specifically by glyphosate (see here), which is the active ingredient in the broad spectrum herbicide known as Roundup. 

The unbranched pathways from erythrose-4-phosphate and phosphoenolpyruvate through shikimic acid to chorismate is shown in Figure 21.13. The sixth reaction of the shikimic acid pathway is... 

The shikimic acid (or shikimate) pathway can be divided into three parts condensation of erythrose-4-phosphate and phosphoenolpyruvate and the subsequent cyclization and production of shikimic acid (Fig. 7.1), alteration of shiki-mate-3-phosphate to chorismic acid (Fig. 7.1), and the conversion of chorismate into other products (Fig. 7.2). The shikimic acid pathway might more appropriately be called the chorismic acid pathway, as that compound is the key intermediate and branching point for most plant secondary compounds produced. 

The starting materials for the shikimic acid pathway, erythrose-4-phosphate (1) and phosphoenolpyruvate (2) are both involved in the primary metabolism of sugars and have key roles in the carbon assimilation cycle of photosynthesis, a process principally found in higher plants and algae (Bonner and Varner, 1976). 

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. 

The two starting materials of the shikimic acid pathway, phosphoenolpyruvate (a product of glycolysis) and erythrose 4-phosphate (a product of pentose... 

The shikimic acid pathway begins with phosphoenolpyruvate which is obtained from glycolysis, and D-erythrose-4-phosphate, which comes from the pentose phosphate cycle. The two are linked to form an intermediate with 7 C atoms which cyclizes to 5-dehydroquinic acid. The latter exists in equilibrium with quinic acid. The pathway proceeds via 5-dehydroshikimic acid and shikimic acid to 5-phosphoshikimic acid. An additional phosphoenolpyruvate unit is now attached to the last-mentioned compound. The product of this reaction is converted, in several steps, to chorismic acid. 

This route, often called the shikimic acid pathway involves the condensation of phosphoenolpyruvate (2) and a 4-carbon sugar erythrose-4-phosphate (1) which is derived from the pentose phosphate pathway. The product of this reaction is converted to shikimic acid (3). Phosphorylation of shikimic acid to yield 5-phosphoshikimic acid (4) is followed by the addition of another molecule of phospho-enol pyruvate (2) which results in the synthesis of prephenic acid (5). Aromatization of the prephenic acid can give rise to phenylpyruvic acid (6) which upon transamination becomes phenylalanine. The carbon skeletons of the other aromatic amino acids, tryptophane and tyrosine are also synthesised via the shikimic acid pathway as is lignin and many of the aromatic secondary products described in Chapter 6. 

The initial step in the pathway is the condensation of erythrose-4-phosphale with phosphoenolpyruvate, yielding dehydroquinic acid, which by elimination of the elements of water affords dehydroshikimic acid reduction of the 3-keto group to hydroxyl gives shikimic acid. 

The shikimate pathway begins with a coupling of phosphoenolpyruvate (PEP) and D-erythrose 4-phosphate to give the seven-carbon 3-deoxy-D-arabino-heptulo-sonic acid 7-phosphate (DAHP) through an aldol-type condensation. Elimination of phosphoric acid from DAHP, followed by an intramolecular aldol reaction, generates the first carbocyclic intermediate, 3-dehydroquinic acid. Shikimic acid (394) is... 

The biosynthetic pathway through shikimic acid (5.7) to aromatic amino acids, outlined in Scheme 5.1 (acids are shown as anions) is called the shikimic acid or shikimate pathway [1, 2, 5]. It has its origins in carbohydrate metabolism and shows several interesting features, much of it known from detailed examination of the steps involved. The first step is a stereospecific aldol-type condensation between phosphoenolpyruvate (5.7) and D-erythrose-4-phosphate (5.2) to give 3-deoxy-D-arabinoheptulosonic acid 7-phosphate (5.5 DAHP), in which addition occurs to the jz-face of the double bond in (5.7) and the r -face of the carbonyl group in (5.2) and which has been rationalized in terms of the mechanism shown in Scheme 5.2... 

Anthranilic acid (or o-amino-benzoic acid) is an aromatic acid with the formula C H NO, which consists of a substituted benzene ring with two adjacent, or "ortho- functional groups, a carboxylic acid, and an amine (Fig. 14.1). Anthranilic acid is biosynthesized from shikimic acid (for shikimic acid biosynthesis, see Chapter 10) following the chorismic acid-mediated pathway [1]. Based on its biosynthetic mechanism, shikimate is transformed to shikimate 3-phosphate with the consumption of one molecule of ATP, catalyzed by shikimate kinase. 5-Enolpyruvylshikimate-3-phosphate (EPSP) synthase is then catalyze the addition of phosphoenolpyruvate to 3-phospho-shikimate followed by the elimination of phosphate, which leads to EPSP. EPSP is further transformed into chorismate by chorismate synthase. Chorismate reacts with glutamine to afford the final product anthranilate and glutamate pyruvate catalyzed by anthranilate synthase (Fig. 14.1). 

Aromatic compounds arise in several ways. The major mute utilized by autotrophic organisms for synthesis of the aromatic amino acids, quinones, and tocopherols is the shikimate pathway. As outlined here, it starts with the glycolysis intermediate phosphoenolpyruvate (PEP) and erythrose 4-phosphate, a metabolite from the pentose phosphate pathway. Phenylalanine, tyrosine, and tryptophan are not only used for protein synthesis but are converted into a broad range of hormones, chromophores, alkaloids, and structural materials. In plants phenylalanine is deaminated to cinnamate which yields hundreds of secondary products. In another pathway ribose 5-phosphate is converted to pyrimidine and purine nucleotides and also to flavins, folates, molybdopterin, and many other pterin derivatives. 

Pyocyanin (160) is derived from the shikimate pathway, and one protein, PhzC, is equivalent to enzymes that catalyze the first step in this pathway, converting erythrose 4-phosphate (162) and phosphoenolpyruvic acid (163) to 3-deoxy-D-arabinoheptulosonate 7-phosphate (164) (Fig. 28). The equivalent enzyme in the shikimate pathway is thought to be feedback regulated, and PhzC is likely to shunt intermediates toward the shikimate pathway in preparation for pyocyanin (160)... 

The benzene ring of the aromatic amino acids is formed by the shikimate pathway. The carbons in the benzene ring are derived from erythrose-4-phosphate and phosphoenolpyruvate. These two molecules condense to form 2-keto-3-deoxy-arabinoheptulosonate-7-phosphate, a molecule that is subsequently converted to chorismate in a series of reactions that are outlined in Figure 14.10. Choris-mate is the branch point in the syntheses of various aromatic compounds. 

Herbicides that inhibit enzymes important for amino acid synthesis account for 28% of the herbicide market. Just three enzymes are involved the enzyme that adds phosphoenolpyruvate to shikimate-3-phoshate in the pathway leading to aromatic compounds, the enzyme that makes glutamine from glutamate and ammonia, and the first common enzyme in the biosynthesis of the branched-chain amino acids. 

The 3-deoxy-D-ara6mo-2-heptulosonic acid 7-phosphate (DAHP) synthetase (EC 4.1.2.15) is an enzyme involved in the shikimic pathway of aromatic amino acids biosynthesis in bacteria and plants, where catalyzes the construction of 3-deoxy-D-ara6/ o-2-heptulosonic acid 7-phosphate from phosphoenolpyruvate and D-erythrose 4-phosphate [6]. Although 3-deoxy-D-ara6/H0-2-heptulosonic acid 7-phosphate (DAHP) synthetase has not been widely investigated it has been employed for the DAHP synthesis on preparative scale from D-fructose in multienzyme system [68], This one-pot synthesis was subsequently even more simplified by the results of further studies which indicated that it was more efficient and economical to use the whole cells containing a DAHP synthetase plasmid [69]. 

The shikimate pathway provides the precursors for benzoic acid derivatives and phenylpropa-noid compounds in plants (Fig. 15). Shikimate is biosynthesized from D-erythrose-4-phosphate and phosphoenolpyruvate, two metabolites derived from the pentose phosphate cycle and glycolysis, respectively. Shikimate is further converted to chorismate by addition of a unit... 

A condensation between phosphoenolpyruvate (8) and D-erythrose-4-phosphate (7) initiates the common part of the shikimate pathway. Nutritional studies with bacterial mutants failed initially to reveal any intermediates earlier in the pathway than the first cyclic compound 3-dehydroquinic acid (10) and elucidation of the first two... 

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