Catalysis by Chimeric Proteins: Conversion of a β-lactamase to a D,D-Carboxypeptidase

Abstract

The β-lactam antibiotics are the substrates of two large groups of bacterial enzymes. The first group, the penicillin binding proteins (PBPs), function as the D,D-carboxypeptidases (Cpase) and transpeptidases (Tpase) involved in the crosslinking of peptidoglycan in the final stage of cell wall biosynthesis (1). By catalyzing the hydrolysis of a C-terminal D-Ala-D-Ala dipeptide followed by transfer of the free amino terminus to another peptide chain, these enzymes stabilize the bacterial cell wall against hypotonic lysis (Figure 1). The PBPs are also able to bind the β-lactam antibiotics as structural analogues to the D-Ala-D-Ala dipeptide, however opening of the lactam bond by these enzymes leads to a stable acyl-enzyme complex. This slow reversible binding of the antibiotics prevents the crosslinking that is catalyzed by the PBPs and that is necessary for cell viability.