Synthesis and incorporation of (2S,3S)-valine-4 13C into .beta.-lactam antibiotics

Kluender, Harold C.; Bradley, C. H.; Sih, Charles J.; Fawcett, Patricia; Abraham, E. P.

doi:10.1021/ja00799a070

Cited by 69 publications

(20 citation statements)

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“…Alternatively, the 8-methylene hydroxy penam (5) has also been proposed as a feasible intermediate for the bioconversion (Abraham, 1977;Baldwin et al, 1978), a transformation for which there is also a synthetic precedent (Stork & Cheung, 1965). The postulated intermediates are in stereochemical accord with the observation that the 3,-methyl group of penicillin N (1) is incorporated into the dihydrothiazine moiety of DAOC (2) (Kluender et al, 1973;Neuss et al, 1973; Scheme 1.…”

Section: Introductionmentioning

confidence: 92%

Purification and initial characterization of an enzyme with deacetoxycephalosporin C synthetase and hydroxylase activities

Baldwin

Adlington

Coates

et al. 1987

Biochemical Journal

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Deacetoxycephalosporin C synthetase (expandase) from Cephalosporium acremonium (Acremonium chrysogenum) was purified to near homogeneity as judged by SDS/polyacrylamide-gel electrophoresis. The enzyme (Mr about 40,000) exhibited a pH optimum around 7.5. It required 2-oxoglutarate (Km 0.04 mM), Fe2+ and O2 as cofactors, and ascorbate and dithiothreitol were necessary for maximum activity. It was stable for over 4 weeks at -70 degrees C in the presence of 1 mM-dithiothreitol. Activity was inhibited by the thiol-quenching reagent N-ethylmaleimide, the metal-ion-chelating reagent bathophenanthroline, and NH4HCO3. The highly purified enzyme also showed deacetoxycephalosporin C hydroxylase (deacetylcephalosporin C synthetase) activity, indicating that both expandase and hydroxylase activities are properties of a single protein. These activities could not be separated by ion-exchange, dye-ligand, gel-filtration or hydrophobic chromatography. A beta-sulphoxide and a 3 beta-methylene hydroxy analogue of penicillin N were synthesized to test as potential intermediates in the ring-expansion reaction, Neither compound was a substrate for the enzyme. A synthetic analogue in which the 3 beta-methyl group and the 2-hydrogen atom of penicillin N were replaced by a cyclopropane ring was not a substrate but was a reversible inhibitor of the enzyme.

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Section: Introductionmentioning

confidence: 92%

Purification and initial characterization of an enzyme with deacetoxycephalosporin C synthetase and hydroxylase activities

Baldwin

Adlington

Coates

et al. 1987

Biochemical Journal

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“…It has been shown that the carboxy group of penicillin corresponds to the carboxy grouR of valine (12) and, using "3C-labeled chiral valine, a correlation between the methyl groups of valine and penicillin could be made (8,10). Evidence has also been given that the intact carbon chain of valine is used for penicillin biosynthesis (1 Culture conditions.…”

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confidence: 99%

“…This would explain the loss of isotope on C2 and C3 of valine and the change of configuration at C3 of penicillin. The stereotopic labeling of either the a or ,B methyl group of penicillin after feeding 13C-labeled chiral valines (8,10) can be an indication of such a mechanism. However, since it was discovered that the tripeptide in Cephalosporium (9) and also in Penicillium …”

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confidence: 99%

Incorporation of Double-Labeled l -Cystine and dl -Valine in Penicillin

Adriaens

Vanderhaeghe

Meesschaert

et al. 1975

Antimicrob Agents Chemother

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L- [3,3'-3H ]cystine was incorporated into penicillin with retention of one.tritium. This result can be explained by ,l-lactam formation through ring closure between C3 of cysteine and NH of valine. No radioactivity of DL-[2,3-3H]valine was incorporated into penicillin. The loss of isotope at C2 occurs during the inversion of configuration. The loss of label at C3 is discussed in terms of possible intermediates for the formation of the thiazolidine ring of penicillin.

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“…Further, by use of chi rally labelled CD3 valines and mass spectrometric analysis it was shown that all three deuterium atoms of each methyl group of valine were incorporated into penicillin N (KLUENDER et al, 1974). Similarly, the 13C of(2S, 3S)-[4-13C]valine was incorporated exclusively into the exocyclic methylene of cephalosporin C at C-17 and that of (2 RS, 3 R)-[4-13 C]valine into the C-2 of cephalosporins (KLUENDER et al, 1973). Similarly, the 13C of(2S, 3S)-[4-13C]valine was incorporated exclusively into the exocyclic methylene of cephalosporin C at C-17 and that of (2 RS, 3 R)-[4-13 C]valine into the C-2 of cephalosporins (KLUENDER et al, 1973).…”

Section: B Valinementioning

confidence: 99%

Biosynthesis

1981

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Synthesis and incorporation of (2S,3S)-valine-4 13C into .beta.-lactam antibiotics

Cited by 69 publications

References 0 publications

Purification and initial characterization of an enzyme with deacetoxycephalosporin C synthetase and hydroxylase activities

Purification and initial characterization of an enzyme with deacetoxycephalosporin C synthetase and hydroxylase activities

Incorporation of Double-Labeled l -Cystine and dl -Valine in Penicillin

Biosynthesis

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