Shikimate pathway scheme

This enzyme produces 3-deoxy-D-arabino-heptulsonic acid 7-phosphate (32 DAHP) from D-erythrose 4-phosphate (31). The enzyme was used by Frost ° ° to synthesize DAHP as an intermediate in the chemical synthesis of its phosphonate analog, 3-deoxy-D-arab/no-heptulsonic acid 7-phosphonate (DAH phosphonate), a potential inhibitor of the shikimate pathway (Scheme 10). 

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. ... 

The Shikimate pathway is responsible for biosynthesis of aromatic amino acids in bacteria, fungi and plants [28], and the absence of this pathway in mammals makes it an interesting target for designing novel antibiotics, fungicides and herbicides. After the production of chorismate the pathway branches and, via specific internal pathways, the chorismate intermediate is converted to the three aromatic amino acids, in addition to a number of other aromatic compounds [29], The enzyme chorismate mutase (CM) is a key enzyme responsible for the Claisen rearrangement of chorismate to prephenate (Scheme 1-1), the first step in the branch that ultimately leads to production of tyrosine and phenylalanine. 

Aryl side chain containing L-a-amino acids, such as phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp), are derived through the shikimate pathway. The enzymatic transformation of phosphoenolpyr-uvate (PEP) and erythro-4-phosphate, through a series of reactions, yields shikimate (Scheme 2). Although shikimate is an important biosynthetic intermediate for a number of secondary metabolites, this chapter only describes the conversion of shikimate to amino acids containing aryl side chains. In the second part of the biosynthesis, shikimate is converted into chorismate by the addition of PEP to the hydroxyl group at the C5 position. Chorismate is then transformed into prephenate by the enzyme chorismate mutase (Scheme 3). 

The route of formation of the carbazole nucleus is still far from understood, and has been variously considered to arise from 3-prenylquinolone via a pathway involving shikimic acid (394) and mevalonic acid (MVA) (400) (Scheme 3.1) (1,112,362-366), anthranilic acid (397) and prephenic acid (404) via a pathway involving shikimic acid (394) (Scheme 3.2) (367), and also tryptophan (408) involving the mevalonate (400) pathway (Scheme 3.3) (133). All of these pathways lack experimental proof. However, based on the occurrence of the diverse carbazole alkaloids derived from anthranilic acid (397) in the family Rutaceae, the pathway... 

Chorismate is formally the last metabolite of the shikimate pathway and serves as a branch point towards different biosynthetic byways (Scheme 6.4.2) [2], From an evolutionary standpoint chorismate was evolved not as a metabolite with a distinct cell function, but rather as a highly flexible building block. Because of the special character of 1,3-cyclohexadiene systems, with only a small energy barrier to aromatization, chorismate and its constitutional isomer isochorismate, which... 

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. 

The shikimate pathway is utilized by plants to form aromatic amino acids.107 109 In this bioprocess, shown in Scheme 1.4.8, D-erythrose-4-phosphate is combined with phosphophenylpyruvate giving 3-deoxy-D-arabino-heptulosonic acid-7-phosphate (DAHP). The next step utilizes DHQ synthase to convert DAHP to dehydroquinate (DHQ). 

The biologically active monosaccharide 3-deoxy-D-ura6//io-heptulosonic acid 7-phosphate (8 DAMP) is an important intermediate in the biosynthesis of aromatic amino acids in plants (the shikimate pathway). As shown in Scheme 2, this compound has been produced in a combined chemical and enzymatic synthesis from racemic V-acetylaspartate 3-semialdehyde (4) and DHAP (1). The four-step synthesis proceeds in an overall yield of 13% (37% for the aldolase reaction). The enzymatic step generates the required, enantiomerically pure, syn aldol adduct compound (5). In view of the broad range of substrates tolerated by FDP aldolase, this method may be applicable to the production of analogs of DAMP. 

Fig. (5). Biosynthesis of anthraquinones by the shikimate pathway based on the scheme proposed by Wijnsma and Verpoorte [4]...

The studies of the origin of GHB in A. bisporus demonstrated the involvement of the shikimate-chorismate pathway (Scheme 102). Labeling experiments showed an efficient incorporation of H- and C-labeled shikimic acid 439,440) and C-labeled chorismic acid 441) into the 4-hydroxyaniline moiety of GHB. It was also demonstrated that in the biochemical shikimate-4-hydroxyaniline conversion in the mushroom, amination occurred at the 4 position of one of the carboxylic acid intermediates [initially assumed to be shikimic acid 439)]. Additionally, the p-aminobenzoic acid, which proved to be 441) the precursor of 4-hydroxyaniline, underwent a decarboxylative hydroxylation catalyzed by a FAD-dependent monooxygenase 4-aminobenzoate hydroxylase in the presence of NAD(P)H and O2. This enzyme from A. bisporus was recently purified to homogeneity by Tsuji et al. 442). 

The aromatic amino acids, including phenylalanine, tyrosine, and tryptophan are biosynthesized via the shikimate pathway as shown in Scheme 60 [93]. 

In this chapter, the discussion will concentrate on two inhibitors with a reasonable claim to selective action on enz3ones related to the shikimate pathway glyphosate, which inhibits 5-enolpyruvylshikimate 3-phosphate (EPSP) synthase and L-a-aminooxy-3 phenylpropionic acid (L-AOPP), an inhibitor of phenylalanine ammonia-lyase (PAL) (Fig. 2). In addition to introducing a novel inhibitor of PAL, (R)-(l-amino-2-phenylethyl)phosphonic acid (APEP), previous and current efforts to design inhibitors of other shikimate pathway enzymes will be described. The treatment presented here will show that the deductions and predictions made on the basis of the abstract scheme in Figure 1 can be, and have been, tested on the basis of the real pathway presented in Figure 2. 

Fig. 1. A generalized scheme showing the kinds of secondary products that arise from the aromatic amino acids in higher plants. Several similarities are found in fungi and bacteria some fungi produce alkaloids ftom tryptophan and lignin-like materials from phenylalanine. Plant pathogenic fungi produce cinnamate and para and meta hydroxy phenyl-acetate from phenylalanine. Certain bacteria produce antibiotics and fluorescent pigments from metabolites in the shikimate pathway. Microorganisms are not known to produce coumarin, substituted coumarins, flavonoids and isoflavonoids.

Simple benzoic acids are synthesized in plants via the shikimate pathway, which is derived from shikimic acid, which is itself derived from quinic acid via 3-dehydroquinic and 3-dehydroshikimic acids (Scheme 68.1). In fact, shikimic, but not quinic, acid has been described in the leaves and stems of this species [14]. The simplest benzoic acids are protocatechuic acid (3,4-dihydroxybenzoic acid) and gallic acid (3,4,5-trihydroxybenzoic acid). The latter proved to be present in the tissues of C. roseus, in addition to vanillic acid (4-hydroxy-3-methoxybenzoic acid) [15]. The quantitative composition of C. roseus in benzoic acids can be seen in Table 68.1, and the structures of these compounds are represented in Fig. 68.1. 

Scheme 68.2 Combination of acetate and shikimate pathways in flavonoids biosynthesis...

Phenolic compounds or polyphenols constitute one of the most abtmdant and widely distributed groups of substances in the plant kingdom with more than 8,000 phenolic structures currently known. They are products of the secondary metabolism of plants and arise biogenetically from two main primary synthetic pathways the shikimate pathway and the acetate pathway. Both acetic acid and shikimic acid are derived from glucose metabohsm [15] (Scheme 74.1). 

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... 

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