title: Synthetic tripeptides as alternate substrates of murein peptide ligase (Mpl).
abstract: Murein peptide ligase (Mpl) is an enzyme found in Gram-negative bacteria. It catalyses the addition of tripeptide L-Ala-γ-D-Glu-meso-diaminopimelate to nucleotide precursor UDP-N-acetylmuramic acid during the recycling of peptidoglycan. Although not essential, this enzyme represents an interesting target for antibacterial compounds through the synthesis of alternate substrates whose incorporation into peptidoglycan might be deleterious for the bacterial cell. Therefore, we have synthesised 10 tripeptides L-Ala-γ-D-Glu-Xaa in which Xaa represents amino acids different from diaminopimelic acid. Tripeptide with Xaa = ε-D-Lys proved to be an excellent substrate of Escherichia coli Mpl in vitro. Tripeptides with Xaa = p-amino- or p-nitro-L-phenylalanine were poor substrates, while tripeptides with Xaa = D- or L-2-aminopimelate, DL-2-aminoheptanoic acid, L-Glu, L-norleucine, L-norvaline, L-2-aminobutyric acid or L-Ala were not substrates at all. Although a good Mpl substrate, the D-Lys-containing tripeptide was devoid of antibacterial activity against E. coli, presumably owing to poor uptake.
authors.affiliation: Univ Paris-Sud, Laboratoire des Enveloppes Bactériennes et Antibiotiques, Institut de Biochimie et Biophysique Moléculaire et Cellulaire, UMR 8619, F-91405 Orsay, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Hervé
authors.forename: Andreja
authors.initials: A
authors.lastname: Kovač
authors.forename: Cécile
authors.initials: C
authors.lastname: Cardoso
authors.forename: Delphine
authors.initials: D
authors.lastname: Patin
authors.forename: Boris
authors.initials: B
authors.lastname: Brus
authors.forename: Hélène
authors.initials: H
authors.lastname: Barreteau
authors.forename: Dominique
authors.initials: D
authors.lastname: Mengin-Lecreulx
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.forename: Didier
authors.initials: D
authors.lastname: Blanot
mesh_terms: D002851:Chromatography, High Pressure Liquid; D029968:Escherichia coli Proteins / Q000378:metabolism*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D010453:Peptide Synthases / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D029968:Escherichia coli Proteins; D009842:Oligopeptides; D010453:Peptide Synthases; C049145:UDP-N-acetylmuramoylalanyl-D-glutamate-2,6-diaminopimelate ligase