Publication Abstract from PubMed
beta-lactams inhibit peptidoglycan polymerization by acting as suicide substrates of essential d,d-transpeptidases. Bypass of these enzymes by unrelated l,d-transpeptidases results in beta-lactam resistance, although carbapenems remain unexpectedly active. To gain insight into carbapenem specificity of l,d-transpeptidases (Ldts), we solved the nuclear magnetic resonance (NMR) structures of apo and imipenem-acylated Bacillus subtilis Ldt and show that the cysteine nucleophile is present as a neutral imidazole-sulfhydryl pair in the substrate-free enzyme. NMR relaxation dispersion does not reveal any preexisting conformational exchange in the apoenzyme, and change in flexibility is not observed upon noncovalent binding of beta-lactams (K(D) > 37.5 mM). In contrast, covalent modification of active cysteine by both carbapenems and 2-nitro-5-thiobenzoate induces backbone flexibility that does not result from disruption of the imidazole-sulfhydryl proton interaction or steric hindrance. The chemical step of the reaction determines enzyme specificity since no differences in drug affinity were observed.
Dynamics Induced by beta-Lactam Antibiotics in the Active Site of Bacillus subtilisl,d-Transpeptidase.,Lecoq L, Bougault C, Hugonnet JE, Veckerle C, Pessey O, Arthur M, Simorre JP Structure. 2012 May 9;20(5):850-61. PMID:22579252[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
