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Eur J Biochem. 1985 Nov 15;153(1):81-7.

Specificity of the uridine-diphosphate-N-acetylmuramyl-L-alanyl-D-glutamate: meso-2,6-diaminopimelate synthetase from Escherichia coli.


To investigate the specificity of the uridine-diphosphate-N-acetylmuramyl-L-alanyl-D-glutamate: meso-2,6-diaminopimelate synthetase, various compounds mimicking more or less different parts of the UDP-MurNAc-L-Ala-D-Glu substrate were prepared. Their size ranged from that of uridine or L-Ala-D-Glu to that of the whole nucleotide substrate. Chemical synthesis led to N alpha-acyl-dipeptides, in which the acyl group mimicked the MurNAc moiety, and to glycopeptides MurNAc(alpha or beta-Me)-L-Ala-D-Glu, in which the anomeric function is blocked. Partial degradation or chemical modification of the substrate UDP-MurNAc-L-Ala-D-Glu afforded: MurOHNAc-L-Ala-D-Glu, P1-MurNAc-L-Ala-D-Glu, and DDP-MurNAc-L-Ala-D-Glu (DDP = dihydrouridine-diphosphate). All these compounds were tested as substrates or (and) inhibitors of the reaction catalyzed by the A2pm-adding enzyme, which, after partial purification, was obtained in two active forms. Among the compounds tested as substrates, only DDP-MurNAc-L-Ala-D-Glu was a good one. The Km for this compound was 97 microM versus 55 microM for the natural substrate. Among the various compounds tested as inhibitors, only P1-MurNAc-L-Ala-D-Glu and MurNAc(alpha or beta-Me)-L-Ala-D-Glu had a significant inhibitory effect at 1mM. Apparently, no particular portion of the molecule is predominantly responsible for its recognition by the enzyme. In other words, multiple sites located over the whole molecule are required for a proper recognition and determine the high specificity of this activity. Therefore, to obtain efficient competitive inhibitors it is necessary to synthesize molecules very similar in size and structure to the natural substrate.

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