(6S)-6-fluoroshikimic acid, an antibacterial agent acting on the aromatic biosynthetic pathway

Davies, Gareth; Barrett‐Bee, Keith; Jude, David A.; Lehan, Malcolm; Nichols, Wright W.; Pinder, Philip; Thain, J L; Watkins, W. J.; Wilson, R. Geoffrey

doi:10.1128/aac.38.2.403

Cited by 99 publications

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References 14 publications

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“…The antimicrobial action of (6S)-6-fluoroshikimate is, however, unlikely to be mediated by the inhibition of chorismate synthase by (6S)-6-fluoro-EPSP. This is because the susceptibility of E. coli to the antimicrobial agent (6S)-6-fluoroshikimate is overcome by the addition of 4-aminobenzoate, a folate cofactor precursor, and not by the aromatic amino acids phenylalanine, tyrosine, and tryptophan (27). These observations suggest that (6S)-6-fluoro-EPSP is a substrate of E. coli chorismate synthase and that the product, 6-fluorochorismate, inhibits 4-aminobenzoate synthase.…”

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confidence: 63%

“…It is therefore clear that the antimicrobial activity of (6S)-6-fluoroshikimate is not mediated by the inhibition of chorismate synthase by (6S)-6-fluoro-EPSP. 6-Fluorochorismate most probably inhibits 4-aminobenzoic acid synthase as proposed by Davies et al (27). The PabA and PabB proteins of 4-aminobenzoic acid synthase are responsible for the conversion of chorismate to the 4-aminobenzoate precursor 4-amino-4-deoxychorismate (38).…”

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confidence: 99%

“…The product 6-fluorochorismate (0.5 ml) was prepared using the conditions described in the legend to Fig. 1 antimicrobial agent (6S)-6-fluoroshikimate was overcome by the addition of 4-aminobenzoic acid and not by aromatic amino acids (27). It is therefore clear that the antimicrobial activity of (6S)-6-fluoroshikimate is not mediated by the inhibition of chorismate synthase by (6S)-6-fluoro-EPSP.…”

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confidence: 99%

“…Chorismate synthase is a prime candidate because it has been identified as one of the rate-limiting enzymes of this pathway (26). The 6R-and 6S-isomers of 6-fluoroshikimate are antibacterial agents displaying minimum inhibitory concentrations of 64 and 0.5 g ml Ϫ1 against E. coli K12, respectively (27). Both isomers of 6-fluoroshikimate are converted in vitro to 6-fluoro-EPSP by E. coli shikimate kinase and EPSP synthase (28).…”

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Escherichia coli Chorismate Synthase Catalyzes the Conversion of (6S)-6-Fluoro-5-enolpyruvylshikimate-3-phosphate to 6-Fluorochorismate

Bornemann

Ramjee

Balasubramanian

et al. 1995

Journal of Biological Chemistry

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Chorismate synthase (EC 4.6.1.4) is the seventh enzyme of the shikimate pathway (1, 2) and catalyzes the conversion of 5-enolpyruvylshikimate-3-phosphate 1 (EPSP) 1 to chorismate 2 (Scheme 1). Chorismate is a common intermediate in the biosynthesis of aromatic metabolites such as aromatic amino acids and folate cofactors. The chorismate synthase reaction involves the 1,4-elimination of phosphate and the C-(6proR) hydrogen with overall anti-stereochemistry (3-5). A concerted elimination appears to be unlikely since studies with model systems (6, 7) and molecular orbital considerations (8, 9) suggest that concerted 1,4-eliminations with syn-stereochemistry are favored. For these reasons, several non-concerted mechanisms have been suggested for the chorismate synthase reaction (10). Proposed mechanisms include an X-group mechanism, involving the nucleophilic attack of the C-1 position of the substrate (5) (Scheme 2d), and a cationic mechanism, involving the step-wise loss of phosphate and a proton (11, 12) (Scheme 2a). An allylic rearrangement of phosphate followed by a 1,2-elimination (13) has been discounted because the intermediate iso-EPSP is a competitive inhibitor rather than a substrate of the Neurospora crassa enzyme (14).Reduced FMN is required for enzyme activity despite there being no overall reduction or oxidation in the conversion of EPSP to chorismate (15)(16)(17)(18)(19). The role of flavin is not yet clear but it appears to be directly involved in catalysis. A transient flavin intermediate has been characterized by uv/visible spectroscopy during single and multiple turnover experiments using the enzyme from Escherichia coli (20,21). It has been suggested that this spectrum is consistent with a charge transfer complex or a C-4a-flavin adduct (20). However, such a perturbation of the reduced flavin spectrum could, at least in part, be due to noncovalent interactions between the substrate and the flavin. The absence of detectable activity of the N. crassa (22) and E. coli (23) enzymes reconstituted with reduced 5-deaza-FMN provides additional evidence that reduced flavin is chemically, and not just structurally, involved in turnover. In the presence of the inhibitor (6R)-6-fluoro-EPSP the E. coli enzyme forms a protein-bound flavin semiquinone, suggesting the possibility of radical intermediates during normal turnover (24). A radical mechanism involving the initial abstraction of a hydrogen atom from the C-6 position of the substrate (11, 22, 25) seems unlikely since there are no obvious candidates for a catalytic center that can accept single electrons, such as transition metal ions (24), particularly given the requirement for fully reduced flavin for activity.

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confidence: 63%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Escherichia coli Chorismate Synthase Catalyzes the Conversion of (6S)-6-Fluoro-5-enolpyruvylshikimate-3-phosphate to 6-Fluorochorismate

Bornemann

Ramjee

Balasubramanian

et al. 1995

Journal of Biological Chemistry

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“…antibacterial properties have been reported for (6S)-6-fluoro-shikimic acid 3 ( Figure 1). 5 Although its effect is disputed, the drug oseltamivir (tamiflu ® ) 4 6 -a shikimic acid derivative -lately has become wellknown as a drug repressing the symptoms of the bird flu (avian influenza). 7 Furthermore, the 4-epi-shikimic acid skeleton 8 is present in numerous natural products with interesting biological properties -one example is the (6S)-6-chloro derivative (5, pericosine A), an antitumour agent from Periconia byssoid.…”

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Synthesis of (6S)-6-hydroxy-4-epi-shikimic acid

Griesbeck¹,

Miara²,

Neudörfl³

2006

Arkivoc

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The synthesis of the 6-hydroxylated epimer 7 of shikimic acid from natural shikimic acid 1 is conducted by a sequence of protecting steps, dehydration to the 1,3-cyclohexadiene 4 and photosensitized singlet oxygen cycloaddition reaction. The target molecule is then obtained from the endoperoxide 9 by reduction and deprotection. A new hydroxyl group is thereby inserted into position 6 of shikimic acid whereas the configuration at position 4 is formally inverted.

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The kinetic model of the shikimate pathway as a tool to optimize enzyme assays for high-throughput screening

Noble

Sinha

Kolupaev

et al. 2006

Biotechnol. Bioeng.

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Four-enzyme section of the shikimate pathway (Aro B, D, E, and K) of Streptococcus pneumoniae has been studied. Kinetic properties of the individual enzymes and three- and four-enzyme linked reactions have been characterized in vitro. On the basis of the data measured in spectrophotometric and LC-MS experiments, kinetic mechanisms of the enzymes have been suggested and all kinetic parameters have been identified. Kinetic models for these three- and four-enzyme sections of the shikimate pathway have been constructed and validated. The model of the four-enzyme section of shikimate pathway has been employed to design an inhibition-sensitive reconstituted pathway for a high-throughput screening effort on the shikimate pathway. It was demonstrated that using the model it was possible to optimize this reconstituted pathway in such a way to provide equal sensitivity of the enzymes to inhibition.

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(6S)-6-fluoroshikimic acid, an antibacterial agent acting on the aromatic biosynthetic pathway

Cited by 99 publications

References 14 publications

Escherichia coli Chorismate Synthase Catalyzes the Conversion of (6S)-6-Fluoro-5-enolpyruvylshikimate-3-phosphate to 6-Fluorochorismate

Escherichia coli Chorismate Synthase Catalyzes the Conversion of (6S)-6-Fluoro-5-enolpyruvylshikimate-3-phosphate to 6-Fluorochorismate

Synthesis of (6S)-6-hydroxy-4-epi-shikimic acid

The kinetic model of the shikimate pathway as a tool to optimize enzyme assays for high-throughput screening

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