On the biosynthesis of the antibiotic vancomycin

Hammond, Stephen J.; Williamson, Michael P.; Williams, Dudley H.; Boeck, L. D.; Marconi, Gary G.

doi:10.1039/c39820000344

Cited by 61 publications

(41 citation statements)

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“…It has been shown that the aromatic amino acids (2S,3R)-mchloro-␤-hydroxytyrosine and (R)-4-hydroxyphenylglycine in the aglycone of vancomycin group antibiotics are derived from tyrosine (10), and all enzymes in the biosynthesis of the latter amino acid were identified recently (11,12). The backbone of a third unusual amino acid in these antibiotics, (S)-3,5-dihydroxyphenylglycine, was shown to be derived from acetate, and a polyketide synthase (PKS) 1 reaction was proposed (10).…”

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confidence: 99%

“…The backbone of a third unusual amino acid in these antibiotics, (S)-3,5-dihydroxyphenylglycine, was shown to be derived from acetate, and a polyketide synthase (PKS) 1 reaction was proposed (10). Therefore, it was of considerable interest that the biosynthetic gene cluster of balhimycin does not contain genes for typical bacterial PKS (type I or II) but a gene for a protein related to the plant-specific polyketide synthases of the chalcone synthase family (reviewed in Ref.…”

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confidence: 99%

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A Polyketide Synthase in Glycopeptide Biosynthesis

Pfeifer¹,

Nicholson²,

Ries³

et al. 2001

Journal of Biological Chemistry

140

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Balhimycin, a vancomycin-type antibiotic from Amycolatopsis mediterranei, contains the unusual amino acid (S)-3,5-dihydroxyphenylglycine (Dpg), with an acetate-derived carbon backbone. After sequence analysis of the biosynthetic gene cluster, one gene, dpgA, for a predicted polyketide synthase (PKS) was identified, sharing 20 -30% identity with plant chalcone synthases. Inactivation of dpgA resulted in loss of balhimycin production, and restoration was achieved by supplementation with 3,5-dihydroxyphenylacetic acid, which is both a possible product of a PKS reaction and a likely precursor of Dpg. Enzyme assays with the protein expressed in Streptomyces lividans showed that this PKS uses only malonyl-CoA as substrate to synthesize 3,5-dihydroxyphenylacetic acid. The PKS gene is organized in an operon-like structure with three downstream genes that are similar to enoyl-CoA-hydratase genes and a dehydrogenase gene. The heterologous co-expression of all four genes led to accumulation of 3,5-dihydroxyphenylglyoxylic acid. Therefore, we now propose a reaction sequence. The final step in the pathway to Dpg is a transamination. A predicted transaminase gene was inactivated, resulting in abolished antibiotic production and accumulation of 3,5-dihydroxyphenylglyoxylic acid. Interestingly, restoration was only possible by simultaneous supplementation with (S)-3,5-dihydroxyphenylglycine and (S)-4-hydroxyphenylglycine, indicating that the transaminase is essential for the formation of both amino acids.

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confidence: 99%

A Polyketide Synthase in Glycopeptide Biosynthesis

Pfeifer¹,

Nicholson²,

Ries³

et al. 2001

Journal of Biological Chemistry

140

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“…To confirm that the precursors for A47934 were the same as other glycopeptides (6,8,9), the labeled substrates shown in Table 1 were fed to antibiotic production cultures of S. toyocaensis. As expected, these select substrates were efficiently incorporated into A47934.…”

Section: Methodsmentioning

confidence: 99%

“…1), produced by Streptomyces virginiae, differs from A47934 by the absence of a sulfate group on ring G of the antibiotic (4). Both antibiotics belong to the general class of glycopeptide antibiotics represented by vancomycin (9) and ristocetin (8). Structurally, these compounds are heptapeptides that contain unusual amino acids such as ,-hydroxy-3-chlorotyrosine, modified p-hydroxyphenylglycine (PHPG), and 3,4-dihydroxyphenylglycine (DHPG) units.…”

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Biosynthetic studies on antibiotic A47934

Zmijewski

Briggs

Logan

et al. 1987

Antimicrob Agents Chemother

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A47934, a peptide antibiotic produced by Streptomyces toyocaensis, belongs to the glycopeptide class of compounds which includes ristocetin and vancomycin. Incorporation studies with radioisotope-labeled substrates indicated that tyrosine, p-hydroxyphenylglycine, p-hydroxyphenylglyoxylate, acetate, and sulfate were efficiently incorporated into A47934. This is consistent with the reported biosynthesis of other glycopeptide antibiotics. Prototrophic mutants blocked in antibiotic biosynthesis were isolated at a low frequency (0.4%) after mutagenesis. Secretor-convertor pairings of the 36 mutants obtained demonstrated that they belonged to three classes: two groups of secretor-convertor pairs and a larger group of mutants that did not make antibiotic under any condition tested. Neither the secretor-convertor studies not supplementation of the cultures with putative biosynthetic intermediates was useful in identifying the location of the biosynthetic blocks. All studies to determine the timing of the sulfate addition step in the biosynthesis indicated that the sulfate is added prior to the formation of intermediates that possess antimicrobial activity.

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Die Vancomycin-Antibiotica und der Kampf gegen resistente Bakterien

Williams¹,

Bardsley²

1999

Angewandte Chemie

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104

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Die letzte Verteidigungslinie gegen „Superbakterien”︁ bilden die Antibiotica der Vancomycin‐Gruppe. Wie aus der umfassenden Aufklärung des Wirkungsmechanismus der Antibiotica und eines Resistenzmechanismus gegen diese Wirkstoffe hevorgeht, kann diese Form der Resistenz überwunden werden, ohne die Bindungsstelle des Antibioticums für die Zellwandvorstufen pathogener Bakterien direkt zu modifizieren.

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On the biosynthesis of the antibiotic vancomycin

Cited by 61 publications

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A Polyketide Synthase in Glycopeptide Biosynthesis

A Polyketide Synthase in Glycopeptide Biosynthesis

Biosynthetic studies on antibiotic A47934

Die Vancomycin-Antibiotica und der Kampf gegen resistente Bakterien

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