The origin of the β-lactam carbons of clavulanic acid

Thirkettle, Jan E.; Baldwin, Jack E.; Edwards, Jeff; Griffin, John P.; Schofield, Christopher J.

doi:10.1039/a701934c

Cited by 16 publications

(7 citation statements)

References 15 publications

(18 reference statements)

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“…27A)those leading to (3S,5S)-clavaminic acid, which are reasonably well established, and those involved in the conversion of clavaminic acid to CA, which are much less well understood. A combination of labeling, [382][383][384][385][386][387][388] in vitro enzyme assays and genetic studies 388,389 established the six steps leading to clavaminic acid. Fig.…”

Section: Clavulanic Acid Biosynthesismentioning

confidence: 99%

The enzymes of β-lactam biosynthesis

et al. 2013

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The β-lactam antibiotics and related β-lactamase inhibitors are amongst the most important small molecules in clinical use. Most, but not all, β-lactams including penicillins, cephalosporins, and clavulanic acid are produced via fermentation or via modification of fermented intermediates, with important exceptions being the carbapenems and aztreonam. The desire for more efficient routes to existing antibiotics and for access to new and synthetically challenging ones stimulates continued interest in β-lactam biosynthesis. We review knowledge of the pathways leading to β-lactam antibiotics focusing on the mechanisms, structures and biocatalytic applications of the enzymes involved.

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Section: Clavulanic Acid Biosynthesismentioning

confidence: 99%

The enzymes of β-lactam biosynthesis

et al. 2013

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“…The conversion of 38 to 39 takes place without loss of the bridgehead hydrogen. 63 Speculative precursors of the C 3 -carboxyethyl substituent of 33 include inter alia glycerol, glycerate, acrylate, malonic semialdehyde, -lactate, β-hydroxypropionate and pyruvate, 64-70 of which Thirkettle et al 70 consider pyruvate to be the most likely primary metabolic source. The participation of an acrylate derivative as originally proposed by Elson et al, 62,69 is also implicit in Townsend's conclusions based on an investigation of key genes and encoded enzymes which appear to catalyse a thiamine pyrophosphate-mediated conversion of -glyceraldehyde-3-phosphate and -arginine to N 2 -(2-carboxyethyl)arginine.…”

Section: Clavulanic Acid and Carbapenemsmentioning

confidence: 99%

Biogenetic speculation and biosynthetic advances

Thomas

2004

Nat. Prod. Rep.

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“…Clavulanic acid biosynthesis is thought to begin with the joining of arginine to a three-carbon glycolytic intermediate, likely pyruvate (25,31,34). The product of this condensation, N 2 -(2-carboxyethyl)-arginine, is then cyclized via ␤-lactam synthetase to form the monocyclic ␤-lactam product, deoxyguanidinoproclavaminic acid (2,21).…”

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Genes Specific for the Biosynthesis of Clavam Metabolites Antipodal to Clavulanic Acid Are Clustered with the Gene for Clavaminate Synthase 1 in Streptomyces clavuligerus

Mosher

Paradkar

Anders

et al. 1999

Antimicrob Agents Chemother

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Portions of the Streptomyces clavuligerus chromosome flanking cas1, which encodes the clavaminate synthase 1 isoenzyme (CAS1), have been cloned and sequenced. Mutants of S. clavuligerus disrupted in cvm1, the open reading frame located immediately upstream of cas1, were constructed by a gene replacement procedure. Similar techniques were used to generate S. clavuligerus mutants carrying a deletion that encompassed portions of the two open reading frames,cvm4 and cvm5, located directly downstream ofcas1. Both classes of mutants still produced clavulanic acid and cephamycin C but lost the ability to synthesize the antipodal clavam metabolites clavam-2-carboxylate, 2-hydroxymethyl-clavam, and 2-alanylclavam. These results suggested that cas1 is clustered with genes essential and specific for clavam metabolite biosynthesis. When a cas1 mutant of S. clavuligerus was constructed by gene replacement, it produced lower levels of both clavulanic acid and most of the antipodal clavams except for 2-alanylclavam. However, a double mutant of S. clavuligerus disrupted in both cas1 andcas2 produced neither clavulanic acid nor any of the antipodal clavams, including 2-alanylclavam. This outcome was consistent with the contribution of both CAS1 and CAS2 to a common pool of clavaminic acid that is shunted toward clavulanic acid and clavam metabolite biosynthesis.

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The origin of the β-lactam carbons of clavulanic acid

Cited by 16 publications

References 15 publications

The enzymes of β-lactam biosynthesis

The enzymes of β-lactam biosynthesis

Biogenetic speculation and biosynthetic advances

Genes Specific for the Biosynthesis of Clavam Metabolites Antipodal to Clavulanic Acid Are Clustered with the Gene for Clavaminate Synthase 1 in Streptomyces clavuligerus

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