O-Carbamyl-L-serine, an Inhibitory Analog of L-Glutamine

Skinner, Charles G.; McCord, Tommy J.; Ravel, Joanne M.; Shive, William

doi:10.1021/ja01592a019

Cited by 25 publications

(8 citation statements)

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“…The determination of primary site of action was based on the observed accumulation of UDP-NAcmuramyl-L-ala-D-glu-L-lys and on the absence of D-ala-Ocarbamyl-D-serine accumulation. It was also observed that D-isomer 1 had no effect on the strains Streptococcus lactis, Lactobacillus arabinosus, and E. coli at 200 mg mL À1 (GI 50 ¼ 1.3 Â 10 À3 M) and these results were also in agreement with those reported earlier 42 .…”

Section: Inhibitors Of Alanine Racemasesupporting

confidence: 92%

Inhibitors of alanine racemase enzyme: a review

Azam

Jayaram

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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Alanine racemase is a fold type III PLP-dependent amino acid racemase enzyme catalysing the conversion of l-alanine to d-alanine utilised by bacterial cell wall for peptidoglycan synthesis. As there are no known homologs in humans, it is considered as an excellent antibacterial drug target. The standard inhibitors of this enzyme include O-carbamyl-d-serine, d-cycloserine, chlorovinyl glycine, alaphosphin, etc. d-Cycloserine is indicated for pulmonary and extra pulmonary tuberculosis but therapeutic use of drug is limited due to its severe toxic effects. Toxic effects due to off-target affinities of cycloserine and other substrate analogs have prompted new research efforts to identify alanine racemase inhibitors that are not substrate analogs. In this review, an updated status of known inhibitors of alanine racemase enzyme has been provided which will serve as a rich source of structural information and will be helpful in generating selective and potent inhibitor of alanine racemase.

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Section: Inhibitors Of Alanine Racemasesupporting

confidence: 92%

Inhibitors of alanine racemase enzyme: a review

Azam

Jayaram

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Since 5 X 10-3M was required for growth inhibition, these results were also in agreement with those reported by Skinner et al (21). In addition, the medium used by Skinner et al (21) contained a significant concentration of D-alanine (2.3 X 10-4 M), which would reverse the effect of O-carbamyl-D-serine. These results also confirmed that growth in the presence of the antibiotic caused the accumulation of N-acylamino sugar (30).…”

Section: Discussionsupporting

confidence: 89%

“…The studies with S. faecalis R confirmed the observations made by Tanaka et al (30) that growth in the presence of the antibiotic resulted in lysis and that its action was reversed by D-alanine. Skinner et al (21) reported that the D-isomer had no effect on S. lactis, Lactobacillus arabinosus, and Escherichia coli at 200 Ag/ml (1.3 X 10-M). Since 5 X 10-3M was required for growth inhibition, these results were also in agreement with those reported by Skinner et al (21).…”

Section: Discussionmentioning

confidence: 99%

“…Skinner et al (21) reported that the D-isomer had no effect on S. lactis, Lactobacillus arabinosus, and Escherichia coli at 200 Ag/ml (1.3 X 10-M). Since 5 X 10-3M was required for growth inhibition, these results were also in agreement with those reported by Skinner et al (21). In addition, the medium used by Skinner et al (21) contained a significant concentration of D-alanine (2.3 X 10-4 M), which would reverse the effect of O-carbamyl-D-serine.…”

Section: Discussionmentioning

confidence: 99%

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On the Mechanism of Action of the Antibiotic O -Carbamyl- d -Serine in Streptococcus faecalis

Lynch

Neuhaus

1966

J Bacteriol

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LYNCH, JUDITH L. (Northwestern University, Evanston, Ill.), AND FRANCIS C. NEUHAUS. On the mechanism of action of the antibiotic O-carbamyl-D-serine in Streptococcus faecalis. J. Bacteriol. 91:449-460. 1966.-The antibiotic O-carbamyl-Dserine, an analogue of D-alanine, is an inhibitor of bacterial cell-wall biosynthesis. Growth of Streptococcus faecalis R in the presence of O-carbamyl-D-serine resulted in the accumulation of the cell-wall precursor uridine diphosphate-NAc-muramyl-L-alanyl-D-glutamyl-L-lysine (UDP-NAc-muramyl-L-ala-D-glu-L-lys). The incorporation of D-alanine from L-alanine into peptidoglycan is catalyzed by the sequential action of the following enzymes: (i) alanine racemase; (ii) D-alanine: D-alanine ligase [adenosine diphosphate (ADP)]; (iii) UDP-NAc-muramyl-L-ala-D-glu-Llys: D-ala-D-ala ligase (ADP); (iv) phospho-NAc-muramyl-pentapeptide translocase [uridine monophosphate (UMP)]. O-carbamyl-D-serine is an effective inhibitor of the alanine racemase (Ki= 4.8 X 10-4M, K. of L-alanine = 6.8 X 10-3M). In addition, D-ala-O-carbamyl-D-ser was formed when D-alanine and O-carbamyl-Dserine were incubated with D-alanine: D-alanine ligase (ADP). This dipeptide was utilized by the UDP-NAc-muramyl-L-ala-D-glu-L-lys: D-ala-D-ala ligase (ADP) with the formation of UDP-NAc-muramyl-L-ala-D-glu-L-lys-D-ala-O-carbamyl-Dser. From a consideration of the following results, i.e., (i) accumulation of UDP-NAc-muramyl-L-ala-D-glu-L-lys; (ii) absence of D-ala-O-carbamyl-D-ser accumulation in bacterial cultures grown in the presence of O-carbamyl-D-serine; and (iii) effective inhibition of the racemase, it was concluded that the first enzyme, the racemase, is the primary site of antibiotic action.

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“…Properties 0-Carbamyl-n-serine has three titratible groups: pKa, = 2.25, and two between 8.00 and 9.10 1 . The following decomposition points were observed: 212-215°C (SKINNER et at., 1955);226-234°C (HAGE-MANN et at., 1955);198°C (TANAKA et al, 1963). The following specific rotations for 0-carbamyl-n-serine were found: .6° (c = 2 in 1 N HCl) and +2° (c = 2 in water) HAGEMANN et al, 1955); .1° (c = 2 in 1 N HCl) (SKINNER et at., 1955); [0(~] = +7.6° (c = 2.5 in water) and -19.6° (c = 2 in 1 N HCl) .…”

Section: Other Effectsmentioning

confidence: 99%

Antibiotics

1967

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AII rights, especially that of tnmslation into foreign languages, reserved. It is also forbidden to reproduce this book, either whole DedicationFor most areas of scientific pursuit, there is usually that rare investigator who has the imagination to conceive ideas, who has faith in his visions, and who has the ability to critically test his concepts in the laboratory. Almost invariably, this scientist also inspires younger men to enthusiastically enter into his research program. To him should go the accolades and the recognitions of the esteem in which he is held. As only a small part of this esteem, we wish to dedicate these books to Professor SELMAN A. W AKSMAN in appreciation of his leadership and contributions in all facets of antibiotic research. PrefaceThe idea for publishing these books on the mechanism of action and on the biosynthesis of antibiotics was born of frustration in our attempts to keep abreast of the literature. Gone were the years when we were able to keep a bibliography on antibiotics and feel confident that we could find everything that was being published on this subject. These fields of investigation were moving forward so rapidly and were encompassing so wide a range of specialized areas in microbiology and chemistry that it was almost impossible to keep abreast of developments. In our naivete and enthusiasm, however, we were unaware that we were toying with an idea that might enmesh us, that we were creating an entity with a life of its own, that we were letting loose a Golom who instead of being our servant would be our master.That we set up ideals for these books is obvious; they would be current guides to developments and information in the areas of mechanism of action and biosynthesis of antibiotics. For almost every subject, we wished to enlist the aid of an investigator who himself had played a part in determining the nature of the phenomena that were being discussed. One concept for the books was that they include only antibiotics for which a definitive, well-documented mechanism of action or biosynthetic pathway was known. Yet, such an approach would not entirely serve the purpose we projected, for it would not encompass all of the information available in these fields of antibiotic investigations and blind searches for the original literature would still have to be made. We therefore chose to include any and all antibiotics about which some pertinent information had been published. It was obvious even at the start that such a compilation, integration, and analysis of information could never be complete unless scientific investigations ceased at the moment the last manuscript was submitted-an end that was neither desirable nor possible. An addendum was therefore included at the end of the volume and left open for the addition of new information until the last pages of the regular articles had been printed.The original concept has also been further expanded as the authors of several papers found it advisable to elaborate on their subject. Some of the articles included discussions...

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O-Carbamyl-L-serine, an Inhibitory Analog of L-Glutamine

Cited by 25 publications

References 1 publication

Inhibitors of alanine racemase enzyme: a review

Inhibitors of alanine racemase enzyme: a review

On the Mechanism of Action of the Antibiotic O -Carbamyl- d -Serine in Streptococcus faecalis

Antibiotics

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