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Specificity of L,D-transpeptidases from gram-positive bacteria producing different peptidoglycan chemotypes.

Abstract : We report here the first direct assessment of the specificity of a class of peptidoglycan cross-linking enzymes, the L,D-transpeptidases, for the highly diverse structure of peptidoglycan precursors of Gram-positive bacteria. The lone functionally characterized member of this new family of active site cysteine peptidases, Ldt(fm) from Enterococcus faecium, was previously shown to bypass the D,D-transpeptidase activity of the classical penicillin-binding proteins leading to high level cross-resistance to glycopeptide and beta-lactam antibiotics. Ldt(fm) homologues from Bacillus subtilis (Ldt(Bs)) and E. faecalis (Ldt(fs)) were found here to cross-link their cognate disaccharide-peptide subunits containing meso-diaminopimelic acid (mesoDAP(3)) and L-Lys(3)-L-Ala-L-Ala at the third position of the stem peptide, respectively, instead of L-Lys(3)-d-iAsn in E. faecium. Ldt(fs) differed from Ldt(fm) and Ldt(Bs) by its capacity to hydrolyze the L-Lys(3)-D-Ala(4) bond of tetrapeptide (L,D-carboxypeptidase activity) and pentapeptide (L,D-endopeptidase activity) stems, in addition to the common cross-linking activity. The three enzymes were specific for their cognate acyl acceptors in the cross-linking reaction. In contrast to Ldt(fs), which was also specific for its cognate acyl donor, Ldt(fm) tolerated substitution of L-Lys(3)-D-iAsn by L-Lys(3)-L-Ala-L-Ala. Likewise, Ldt(Bs) tolerated substitution of mesoDAP(3) by L-Lys(3)-D-iAsn and L-Lys(3)-L-Ala-L-Ala in the acyl donor. Thus, diversification of the structure of peptidoglycan precursors associated with speciation has led to a parallel evolution of the substrate specificity of the L,D-transpeptidases affecting mainly the recognition of the acyl acceptor. Blocking the assembly of the side chain could therefore be used to combat antibiotic resistance involving L,D-transpeptidases.
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https://www.hal.inserm.fr/inserm-00185684
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Submitted on : Tuesday, November 6, 2007 - 4:48:25 PM
Last modification on : Wednesday, August 19, 2020 - 11:18:05 AM
Long-term archiving on: : Monday, April 12, 2010 - 1:32:00 AM

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Sophie Magnet, Ana Arbeloa, Jean-Luc Mainardi, Jean-Emmanuel Hugonnet, Martine Fourgeaud, et al.. Specificity of L,D-transpeptidases from gram-positive bacteria producing different peptidoglycan chemotypes.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2007, 282 (18), pp.13151-9. ⟨10.1074/jbc.M610911200⟩. ⟨inserm-00185684⟩

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