Hybrid Potential Simulation of the Acylation of Enterococcus faecium l,d-Transpeptidase by Carbapenems.

Abstract : The l,d-transpeptidases, Ldts, catalyze peptidoglycan cross-linking in β-lactam-resistant mutant strains of several bacteria, including Enterococcus faecium and Mycobacterium tuberculosis. Although unrelated to the essential d,d-transpeptidases, which are inactivated by the β-lactam antibiotics, they are nevertheless inhibited by the carbapenem antibiotics, making them potentially useful targets in the treatment of some important diseases. In this work, we have investigated the acylation mechanism of the Ldt from E. faecium by the carbapenem, ertapenem, using computational techniques. We have employed molecular dynamics simulations in conjunction with QC/MM hybrid potential calculations to map out possible reaction paths. We have focused on determining the following: (i) the protonation state of the nucleophilic cysteine of the enzyme when it attacks; (ii) whether nucleophilic attack and β-lactam ring-opening are concerted or stepwise, the latter occurring via an oxyanion intermediate; and (iii) the identities of the proton acceptors at the beginning and end of the reaction. Overall, we note that there is considerable plasticity in the mechanisms, owing to the significant flexibility of the enzyme, but find that the preferred pathways are ones in which nucleophilic attack of cysteine thiolate is concerted with β-lactam ring-opening.
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Journal of Physical Chemistry B, American Chemical Society, 2016, 120 (21), pp.4767-81. 〈10.1021/acs.jpcb.6b02836〉
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Soumis le : mercredi 27 juillet 2016 - 08:40:46
Dernière modification le : jeudi 11 janvier 2018 - 06:15:24

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Nicholus Bhattacharjee, Martin J Field, Jean-Pierre Simorre, Michel Arthur, Catherine M Bougault. Hybrid Potential Simulation of the Acylation of Enterococcus faecium l,d-Transpeptidase by Carbapenems.. Journal of Physical Chemistry B, American Chemical Society, 2016, 120 (21), pp.4767-81. 〈10.1021/acs.jpcb.6b02836〉. 〈hal-01349215〉

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