Incorporation of β-hydroxypropionate into the β-lactam residue of clavulanic acid

Gutman, Arie L.; Ribon, Vered; Boltanski, Aviv

doi:10.1039/c39850001627

Cited by 15 publications

(10 citation statements)

References 2 publications

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“…The biosynthesis of clavulanic acid has been investigated by feeding labeled precursors to the fermentation (3,4). The three carbon atoms (C-5, C-6, and C-7) of the ,-lactam ring are derived from glycerol apparently via a P-hydroxypropionate intermediate (6,19). Elson and co-workers (3,4) provided evidence that carbons 2 and 8 of the molecule originated from glutamic acid.…”

mentioning

confidence: 99%

Utilization of ornithine and arginine as specific precursors of clavulanic acid

Romero‐García¹,

Liras²,

Martı́n³

1986

Appl Environ Microbiol

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Ornithine and arginine (5 to 20 mM), but not glutamic acid or proline, exerted a concentration-dependent stimulatory effect on the biosynthesis of clavulanic acid in both resting-cell cultures and long-term fermentations of Streptomyces clavuligerus. Ornithine strongly inhibited cephamycin biosynthesis in the same strain. [1-14C]-, [5-14C]-, or [U-14 C] ornithine was efficiently incorporated into clavulanic acid, whereas the incorporation of uniformly labeled glutamic acid was very poor. [U-14C] citrulline were not incorporated at all. Mutant nca-1, a strain that is blocked in clavulanic acid biosynthesis, did not incorporate arginine into clavulanic acid. S. clavuligerus showed arginase activity, converting arginine into ornithine, but not amidinotransferase activity. Both arginase activity and clavulanic acid formation were enhanced simultaneously by supplementing the production medium with 10 mM arginine.

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mentioning

confidence: 99%

Utilization of ornithine and arginine as specific precursors of clavulanic acid

Romero‐García¹,

Liras²,

Martı́n³

1986

Appl Environ Microbiol

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“…This result explains some of the previous confusion about the incorporation of C3 precursors into clavulanic acid. Incorporation of glycerol (9, 28), propionate (9), ␤-hydroxypropionate (12), pyruvate (23,28), and D-and L-glycerate (28) has been reported. The reported incorporation of labelled precursors must have been dependent on the biosynthetic route for the C3 unit used in each growth medium.…”

Section: Discussionmentioning

confidence: 99%

“…Incorporation of labelled pyruvate or glycerate into clavulanic acid has been reported (9,28), but the nature of the intermediate substrate that binds to the amino group of arginine remains uncertain. Gutman et al (12) proposed an intact incorporation of ␤-hydroxypropionate into the C3 unit based on the unchanged 3 H/ 14 C ratio in clavulanic acid following incorporation of double-labelled [2-3 H, 2-14 C]hydroxypropionate, which suggests that no tritium is lost from the C-2 methylene group during incorporation of the C3 unit. The oxidation levels of the carbon atoms of ␤-hydroxypropionate are the same as those in clavulanic acid.…”

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confidence: 99%

“…Townsend and Ho showed that glycerate is a precursor of the C3 unit (28), but the use of glycerate as the intermediate precursor of the C3 unit would require removal of the hydroxyl group at carbon 2 of the glycerate, which is not present in the ␤-lactam ring of clavulanic acid. Feeding experiments using racemic [1,[2][3][4][5][6][7][8][9][10][11][12][13] C, 2,3,3,-2 H] glycerate showed that no incorporation of the hydrogen at C-2 of glycerate into the C-6 of clavulanic acid occurred (23).…”

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confidence: 99%

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Deletion of the pyc Gene Blocks Clavulanic Acid Biosynthesis Except in Glycerol-Containing Medium: Evidence for Two Different Genes in Formation of the C3 Unit

et al. 1999

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The β-lactamase inhibitor clavulanic acid is formed by condensation of a pyruvate-derived C3 unit with a molecule of arginine. A gene (pyc, for pyruvate converting) located upstream of the bls gene in the clavulanic acid gene cluster ofStreptomyces clavuligerus encodes a 582-amino-acid protein with domains recognizing pyruvate and thiamine pyrophosphate that shows 29.9% identity to acetohydroxyacid synthases. Amplification of thepyc gene resulted in an earlier onset and higher production of clavulanic acid. Replacement of the pyc gene with theaph gene did not cause isoleucine-valine auxotrophy in the mutant. The pyc replacement mutant did not produce clavulanic acid in starch-asparagine (SA) or in Trypticase soy broth (TSB) complex medium, suggesting that the pyc gene product is involved in the conversion of pyruvate into the C3 unit of clavulanic acid. However, the β-lactamase inhibitor was still formed at the same level as in the wild-type strain in defined medium containing d-glycerol, glutamic acid, and proline (GSPG medium) as confirmed by high-pressure liquid chromatography and paper chromatography. The production of clavulanic acid by the replacement mutant was dependent on addition of glycerol to the medium, and glycerol-free GSPG medium did not support clavulanic acid biosynthesis, suggesting that an alternative gene product catalyzes the incorporation of glycerol into clavulanic acid in the absence of the Pyc protein. Thepyc replacement mutant overproduces cephamycin.

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“…where the Clar number Cl is the maximal number of aromatic rings that can appear in S [21,25] and ck is the number of possible Clar covers of order k. To illustrate these concepts, we show in Figure 2 all Clar covers of a single zigzag chain [26] of length four (abbreviated as N (4)), grouped by their respective order, together with the resulting ZZ polynomial of N (4). The computation of ZZ polynomials is a straightforward process owing to the existing recursive decomposition algorithms.…”

Section: Preliminariesmentioning

confidence: 99%

Connectivity Graphs for Single Zigzag Chains and their Application for Computing ZZ Polynomials

Langner¹,

Witek²

2017

Croat. Chem. Acta

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We present a graph-theoretical interpretation of the recently developed interface theory of single zigzag chains N(n) in form of connectivity graphs. A remarkable property of the connectivity graphs is the possibility of constructing the full set of Clar covers of N(n) as the complete set of walks on these graphs. Connectivity graphs can be constructed in a direct form, in which the number of vertices is growing linearly with the length n of N(n), and in a reduced form, in which the number of vertices is independent of the actual length of the chain. The presented results can be immediately used for the determination of the Zhang-Zhang (ZZ) polynomials of N(n) in an easy and natural manner. Two techniques for computing the ZZ polynomial are proposed, one based on direct recursive computations and the other based on a general solution to a set of recurrence relations. Generalization of the interface theory to arbitrary benzenoid structures, the construction of associated connectivity graphs, and techniques for the computation of the associated ZZ polynomials will be presented in the near future.

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Incorporation of β-hydroxypropionate into the β-lactam residue of clavulanic acid

Abstract: P-Hydroxypropionate is shown by radiochemical techniques to be incorporated specifically into the C-3 residue of the p-lactam portion of clavulanic acid.

Cited by 15 publications

References 2 publications

Utilization of ornithine and arginine as specific precursors of clavulanic acid

Utilization of ornithine and arginine as specific precursors of clavulanic acid

Deletion of the pyc Gene Blocks Clavulanic Acid Biosynthesis Except in Glycerol-Containing Medium: Evidence for Two Different Genes in Formation of the C3 Unit

Connectivity Graphs for Single Zigzag Chains and their Application for Computing ZZ Polynomials

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