D-alanyl-D-alanine carboxypeptidase (Streptomyces R61) (R61 DD-peptidase)

The D-alanyl-D-alanine carboxypeptidase from Streptomyces sp. strain R61 (often abbreviated as the R61 DD-peptidase) is a well-studied extracellular enzyme that serves as a primary structural and functional model for penicillin-binding proteins (PBPs) (UniProt P00733). In bacterial physiology, this enzyme is responsible for the maturation of the peptidoglycan layer, specifically by catalyzing the cleavage of the terminal D-alanyl-D-alanine bond in peptide subunits to facilitate cell wall cross-linking (PubMed: 4580215). Because its active site is designed to recognize the D-Ala-D-Ala motif, it is highly sensitive to beta-lactam antibiotics like penicillin and cephalosporins, which act as structural mimics of the natural substrate (PubMed: 3010123). Upon interaction, the antibiotic forms a stable, covalent acyl-enzyme intermediate with a conserved serine residue, effectively trapping the enzyme and halting cell wall synthesis. This inhibition leads to the loss of osmotic integrity and eventual bacterial lysis, making PBPs the target of one of the most successful classes of antimicrobial agents. Although the R61 enzyme is derived from a non-pathogenic soil bacterium, its characterization has provided essential insights into the mechanisms of antibiotic action and the molecular basis of bacterial resistance (PDB: 1R61).

Other names

DD-carboxypeptidaseDD-transpeptidasePenicillin-binding protein R61Serine-type D-Ala-D-Ala carboxypeptidaseStreptomyces R61 DD-peptidase

Irreversible inhibition of the enzyme through the formation of a stable acyl-enzyme complex with the active-site serine (Ser62), mimicking the D-alanyl-D-alanine substrate.