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A peptide inhibitor of MurA UDP-N-acetylglucosamine enolpyruvyl transferase: the first committed step in peptidoglycan biosynthesis
Authors:Molina-López José  Sanschagrin François  Levesque Roger C
Institution:

aDepartamento de Salud Pública, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico

bCentre de Recherche sur la Fonction, Structure et Ingénierie des Protéines, Pav. C.-E. Marchand, Faculté de Médicine, Université Laval, Sainte-Foy, Québec, Canada G1K 7P4

Abstract:The MurA enzyme from Pseudomonas aeruginosa was purified to homogeneity and found to be biologically active as a UDP-N-acetylglucosamine (UNAG) enolpyruvyl transferase in a coupled enzyme assay where ATPase activity was measured by the release of inorganic phosphate. A microtiter plate assay coupled to competitive biopanning using the UDP-N-acetylglucosamine was used to screen 109 C-7-C and 12-mers peptides from phage display libraries. From 60 phage-encoded peptides identified after the fourth round of biopanning, deduced amino acid sequences were aligned and two peptides were synthesized and tested for inhibition of the MurA-catalyzed reaction. The PEP 1354 peptide inhibited the ATPase activity of MurA with an IC50 value of 200 μM and was found to be a competitive inhibitor of UNAG. The pre-incubation of MurA with inhibitor indicated a time-independent inhibition. This time-dependent inhibition is the first report of peptide inhibitors of MurA, which represent the scaffold for the synthesis of inhibitory peptidomimetic molecules.
Keywords:MurA  Phage display  UDP-N-acetylglucosamine  Peptide inhibitors
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