D-alanyl-D-alanine terminus of peptidoglycan pentapeptide (D-Ala-D-Ala)

The D-alanyl-D-alanine (D-Ala-D-Ala) terminus is a critical structural motif found at the end of the peptidoglycan pentapeptide chain in Gram-positive bacteria [1]. This terminus serves as the essential substrate for transpeptidase enzymes, also known as penicillin-binding proteins (PBPs), which facilitate the cross-linking of peptidoglycan layers to provide mechanical strength and osmotic stability to the bacterial cell wall [2]. It is the primary molecular target for glycopeptide antibiotics like vancomycin, which bind to the terminus with high affinity and sterically hinder the enzymes responsible for cell wall synthesis [1,3]. Because this specific D-amino acid configuration is unique to bacteria and absent in eukaryotic cells, it provides a high degree of selective toxicity for antimicrobial therapy [2]. However, bacterial resistance can emerge through the enzymatic modification of this terminus to D-alanyl-D-lactate or D-alanyl-D-serine, which drastically reduces the binding affinity of glycopeptides and renders the drugs ineffective [1,2].

Other names

D-alanyl-D-alaninePeptidoglycan pentapeptide terminusC-terminal D-Ala-D-AlaBacterial cell wall precursor terminusD-Ala-D-Ala dipeptide

Glycopeptide antibiotics bind to the D-Ala-D-Ala terminus of the peptidoglycan precursor via five hydrogen bonds, sterically inhibiting the transglycosylation and transpeptidation reactions required for cell wall assembly [1,2].