Biapenem inactivation by B2 metallo β-lactamases: energy landscape of the hydrolysis reaction.

ABSTRACT:

Background

A general mechanism has been proposed for metallo β-lactamases (MβLs), in which deprotonation of a water molecule near the Zn ion(s) results in the formation of a hydroxide ion that attacks the carbonyl oxygen of the β-lactam ring. However, because of the absence of X-ray structures that show the exact position of the antibiotic in the reactant state (RS) it has been difficult to obtain a definitive validation of this mechanism.

Methodology/principal findings

We have employed a strategy to identify the RS, which does not rely on substrate docking and/or molecular dynamics. Starting from the X-ray structure of the enzyme:product complex (the product state, PS), a QM/MM scan was used to drive the reaction uphill from product back to reactant. Since in this process a

SUBMITTER: Ackerman SH 

PROVIDER: S-EPMC3556986 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature