title: Structure of Enterococcus faeciuml,d-transpeptidase acylated by ertapenem provides insight into the inactivation mechanism.
abstract: The maintenance of bacterial cell shape and integrity is largely attributed to peptidoglycan, a biopolymer highly cross-linked through d,d-transpeptidation. Peptidoglycan cross-linking is catalyzed by penicillin-binding proteins (PBPs) that are the essential target of β-lactam antibiotics. PBPs are functionally replaced by l,d-transpeptidases (Ldts) in ampicillin-resistant mutants of Enterococcus faecium and in wild-type Mycobacterium tuberculosis. Ldts are inhibited in vivo by a single class of β-lactams, the carbapenems, which act as a suicide substrate. We present here the first structure of a carbapenem-acylated l,d-transpeptidase, E. faecium Ldtfm acylated by ertapenem, which revealed key contacts between the carbapenem core and residues of the catalytic cavity of the enzyme. Significant reorganization of the antibiotic conformation occurs upon enzyme acylation. These results, together with the analysis of protein-to-carbapenem proton transfers, provide new insights into the mechanism of Ldt acylation by carbapenems.
authors.affiliation: CEA, Institut de Biologie Structurale Jean-Pierre Ebel , UMR 5075, Grenoble, France.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Lecoq
authors.forename: Vincent
authors.initials: V
authors.lastname: Dubée
authors.forename: Sébastien
authors.initials: S
authors.lastname: Triboulet
authors.forename: Catherine
authors.initials: C
authors.lastname: Bougault
authors.forename: Jean-Emmanuel
authors.initials: JE
authors.lastname: Hugonnet
authors.forename: Michel
authors.initials: M
authors.lastname: Arthur
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Simorre
mesh_terms: D000107:Acetylation; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016984:Enterococcus faecium / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D000077727:Ertapenem; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D006801:Humans; D008958:Models, Molecular; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation / Q000187:drug effects*; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D010458:Peptidyl Transferases; D000077727:Ertapenem