Shikimate 3-phosphate with phosphoenolpyruvate

Phosphoenblpyruvic acid (D 2) and erythrose-4-phosphate serve as precursors. 3-Deoxy-D-arabinoheptulosonic acid-7-phosphate is built as a key intermediate. This compound cyclizes to 5-dehydroquinic acid, which is transformed to 5-de-hydroshikimic acid and shikimic acid. After phosphorylation shikimic acid reacts with phosphoenolpyruvate. The formed 3-enolpyruvylshikimic acid-5-phosphate yields chorismic acid by an anti-elimination of a proton and the phosphate group. 

L-Tyrosine biosynthesis starts with the condensation of phosphoenolpyruvate (PEP) and erythrose-4-phosphate (E4P), the intermediates of the glycolytic pathway and pentose phosphate pathway, respectively, which is catalyzed by 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase (DAHPS aroE/aroG/aroH). The resultant 3-deoxy-D-arabino-heptulosonate (DAHP) is converted into chorismate through the shikimate pathway with seven reactions. In plants, prephenate (PPA) is converted into L-arogenate by transamination whereas in E. coli, PPA is converted to p-hydroxyphenylpyruvate (HPP) by prephenate dehydrogenase, which is a bifunctional enzyme that behaves as chorismate mutase/prephenate... 

Two unexceptional steps lead through shikimic acid (5.7) to its 3-phosphate (5.8). Condensation with phosphoenolpyruvate (5.7) gives (5.9). This type of biological reaction is almost unique, only one other example being known. The mechanism suggested, and illustrated in Scheme 5.3, is based on experiments in deuterium oxide and tritiated water. [The intermediacy of (5.72) is indicated by the random incorporation of hydrogen isotope into the methylene hydrogens of (5.9) [8].]... 

Several tracer studies of the biosynthesis of (—)-shikimic acid in higher plants have been made and these all accord with the view that, as in micro-organisms, the seven-carbon skeleton of the alicyclic acid is derived by an initial condensation of D-erythrose-4-phosphate (7) and phosphoenolpyruvate (8), Figure 1.2. Uniform labelling of (—)-shikimic acid was obtained by exposure of living plant tissues to carbon dioxide for extended periods " . Short-term exposure gave (—)-shikimic acid with 25 per cent of the isotope in the carboxyl group . This was rationalist on the basis... 

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. 

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). 

This enzyme [EC 2.5.1.19], also known as 5-enolpyruvyl-shikimate-3-phosphate synthase and 3-enolpyruvoyl-shikimate-5-phosphate synthase, catalyzes the reaction of phosphoenolpyruvate with 3-phosphoshikimate to produce orthophosphate and 5-0-(l-carboxyvinyl)-3-phosphoshikimate. 

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... 

All carbons are derived from either erythrose 4-phosphate (light purple) or phosphoenolpyruvate (pink). Note that the NAD+ required as a cofactor in step (3) is released unchanged it may be transiently reduced to NADH during the reaction, with formation of an oxidized reaction intermediate. Step (6) is competitively inhibited by glyphosate (COO—CH2—NH—CH2—PO ), the active ingredient in the widely used herbicide Roundup. The herbicide is relatively nontoxic to mammals, which lack this biosynthetic pathway. The chemical names quinate, shikimate, and chorismate are derived from the names of plants in which these intermediates have been found to accumulate. 

The reversible reaction of phosphoenolpyruvate (PEP) with shikimate 3-phosphate is a step in the synthesis of the aromatic amino acids (see Fig. 25-1). The chemical mechanism indicated... 

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. 

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 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. 

Phenylalanine, tyrosine, and tryptophan are synthesized by a common pathway in E. coli (Figure 24.13). The initial step is the condensation of phosphoenolpyruvate (a glycolytic intermediate) with erythrose 4-phosphate (a pentose phosphate pathway intermediate). The resulting seven-carbon open-chain sugar is oxidized, loses its phosphoryl group, and cyclizes to 3-dehydroquinate. Dehydration then yields 3-dehydroshikimate, which is reduced by N ADPH to shikimate. The phosphorylation of shikimate by ATP gives shikimate 3-phosphate, which condenses with a second molecule of phosphoenolpyruvate. The resulting 5-enolpyruvyl intermediate loses its... 

Rifamycin S derived from [l- C]glycerate showed enhanced n.m.r. signals for C-3 and C-8 which is consistent with incorporation by way of intermediates on the shikimate pathway (Scheme 22). ° Greater enhancement of C-8 by [l- C]glycerate and of C-1 by [l- C]glucose was observed, compared respectively with C-3 and C-10. This indicates that C-1 derives from the methylene carbon of phosphoenol-pyruvate rather than C-4 of tetrose phosphate and that C-8 derives from the carboxy-group of phosphoenolpyruvate. It follows then that C-9 and C-10 of rifamycin S (193) would be the location of the double bond of a dehydroshikimate intermediate. Michael addition to this double bond as in (194) allows completion of the naphthoquinone moiety of rifamycin S in an analogous fashion to the formation of the menaquinones. ... 

Mechanism of enolpyruvyl shikimate 3-phosphate synthase exchange of phosphoenolpyruvate with solvent protons. Biochemistry 22 5903-5908. 

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. 

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... 

The amino acids possessing an aromatic cycle (tyrosine, phenylalanine, trytophan) are derived from erythrose 4-phosphate and phos-phoenolpyruvate. These two compounds are intermediaries of the pentose cycle and glycolysis, respectively. Their condensation forms shikimate. The condensation of this compound with another molecule of phosphoenolpyruvate produces chorismate, a precursor of aromatic amino acids. 

Phosphorylation of 3-hydroxyl group of shikimate by shikimate kinase (EC 2.7.1.71) with ATP as a cosubstrate initiates the biosynthesis pathway of anthranilic acid [2], This step also presents the first step of the shikimate pathway, which is a metabolic route used by bacteria, fungi, and plants for the biosynthesis of many aromatic products such as lignins, alkaloids, flavonoids, benzoic acid, and plant hormones, in addition to the aromatic amino acids (phenylalaiune, tyrosine, and tryptophan). The sequential EPSP synthesis is catalyzed by EPSP synthase (EC 2.5.1.19) through the addition of phosphoenolpyruvate to 3-phospho-shikimate followed elimination of phosphate. EPSP synthase belongs to the family of transferases, specifically to those transferring aryl... 

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