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Synthesis of a peptide form of N-delta-(phosphonoacetyl)-L-ornithine. Its antibacterial effect through the specific inhibition of Escherichia coli L-ornithine carbamoyltransferase.

par Penninckx, Michel ;Gigot, Daniel
Référence The Journal of biological chemistry, 254, 14, page (6392-6396)
Publication Publié, 1979-07

Article révisé par les pairs

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Résumé :

N-delta-(Phosphonoacetyl)-L-ornithine is a potent inhibitor of the Escherichia coli L-ornithine carbamoyltransferase (Ki = 0.77 microM, pH 8.0, 37 degrees C). Nevertheless, the analog does not cross the bacterial membrane. Therefore we have designed a tripeptide, glycylglycyl-N-delta-(phosphonoacetyl)-L-ornithine, to take advantage of the broad specificity of the oligopeptide permease system of the bacterium. A lag effect, related to the tripeptide concentration, was observed in the growth of the wild type P4X strain. At high concentration (greater than or equal to 0.75 mM) the peptide appears to be bacteriostatic and the cells which escape this action were characterized gentically as mutants devoid of the oligopeptide transport system. It was shown that the in vivo cellular target of the toxic tripeptide is solely restricted to L-ornithine carbamoyl-transferase and that the tripeptide is probably split in the cell to permit an effective inhibition by N-delta-(phosphonoacetyl)-L-ornithine. Resistance of the wild type cells to moderate levels (less than 0.75 mM) of the phosphonic analog is accompanied by a derepression of the L-ornithine carbamoyltransferase activity. The P4XB2 strain, which is an arg R regulatory mutant, has a reduced lag effect in the presence of the tripeptide and appears to react to the intoxication by a further adjustment of the L-ornithine carbamoyltransferase cellular level.