Penicillin-binding protein (PBP) serine-type D-Ala-D-Ala carboxypeptidase (PBP)

Serine-type D-Ala-D-Ala carboxypeptidases, frequently categorized as low-molecular-weight penicillin-binding proteins (LMW PBPs), are essential bacterial enzymes involved in the final stages of peptidoglycan synthesis and cell wall remodeling (Sauvage et al., 2008). These enzymes catalyze the removal of the terminal D-alanine residue from the pentapeptide side chains of peptidoglycan precursors, a process that regulates the extent of cross-linking and maintains the structural integrity and shape of the bacterial cell wall (Macheboeuf et al., 2006). By controlling the availability of peptide stems for transpeptidation, they ensure the proper mechanical strength of the cell envelope. Because these proteins are located on the outer surface of the cytoplasmic membrane, they are highly accessible to beta-lactam antibiotics (Bush & Bradford, 2016). These drugs function as substrate analogs, covalently binding to the active-site serine and irreversibly inhibiting the enzyme's activity. This inhibition leads to weakened cell walls, osmotic instability, and eventual bacterial lysis, making these proteins critical targets for treating a wide range of bacterial infections (StatPearls, 2023). Furthermore, these enzymes are often involved in the development of antibiotic resistance through mutations or the acquisition of alternative enzymes with lower drug affinity.

Other names

DD-carboxypeptidaseD-alanyl-D-alanine carboxypeptidaseLow-molecular-weight penicillin-binding proteinDD-peptidaseLMW PBPD-Ala-D-Ala carboxypeptidase

Beta-lactam antibiotics act as structural analogs of the D-Ala-D-Ala terminus of peptidoglycan precursors; they covalently bind to the active-site serine residue of the carboxypeptidase, forming a stable acyl-enzyme intermediate that inhibits the enzyme's ability to remodel the cell wall (Sauvage et al., 2008; Bush & Bradford, 2016).