Synthesis of inhibitors of the meso-diaminopimelate-adding enzyme from Escherichia coli.
In order to obtain inhibitors of the meso-diaminopimelate-adding enzyme, which participates in the biosynthesis of bacterial peptidoglycan, several N alpha-propionyl-dipeptides of the general formula Pr-L-Ala-ambo-Xaa-OH were synthesized. Xaa represented methionine S,S-dioxide, methionine S-oxide, methionine sulfoximine, and 2-amino-4-phosphonobutyric acid, i.e. transition state analogs of glutamine synthetase and gamma-glutamyl-cysteine synthetase, which catalyze the same type of reaction as our target enzyme. After synthesis, the diastereoisomers were separated by preparative HPLC or t.l.c.; those containing methionine derivatives could be identified thanks to previously synthesized reference compounds. After preincubation with the meso-diaminopimelate-adding activity from Escherichia coli, the LD diastereoisomers displayed moderate inhibitory effects, whereas the LL ones were inefficient. The best inhibition was obtained with one diastereoisomer of Pr-L-Ala-zeta-2-amino-4-phosphonobutyrate, presumably the LD one. A chloromethylketone derivative Pr-L-Ala-D-Glu(CH2Cl)-OH, potential affinity labeler of the meso-diaminopimelate-adding enzyme, was also synthesized. In the assay with preincubation, this compound behaved as the best inhibitor.
Abo-Ghalia
M
M
Unit of Molecular and Cellular Biochemistry, CNRS, University of Paris-South, Orsay, France.
Flegel
M
M
Blanot
D
D
Van Heijenoort
J
J
D000345:Affinity Labels / Q000138:chemical synthesis; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D008025:Ligases / Q000037:antagonists & inhibitors*; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
D000345:Affinity Labels; D004151:Dipeptides; D008025:Ligases; D010453:Peptide Synthases; C049145:UDP-N-acetylmuramoylalanyl-D-glutamate-2,6-diaminopimelate ligase