D-alanyl-D-alanine motif on peptidoglycan precursor

The D-alanyl-D-alanine motif is a dipeptide structure present at the terminal position of the peptide side chain in peptidoglycan precursors of most Gram-positive and Gram-negative bacteria[1][3][5][6]. This motif is generated in the cytoplasm through the action of D-alanine racemase and D-alanine-D-alanine ligase, with the terminal D-Ala-D-Ala forming a critical recognition sequence for enzymes involved in peptidoglycan polymerization and cross-linking during cell wall biosynthesis[5][6]. It serves as the direct binding site for glycopeptide antibiotics such as vancomycin, which anchor to this motif and thereby block cell wall assembly, causing bactericidal effects[1][2][6]. Resistance can arise when bacteria alter the terminal motif to D-Ala-D-Lac or D-Ala-D-Ser, markedly reducing antibiotic affinity and causing clinical treatment failure[1][2]. This motif is a central node for antibiotic mechanism-of-action and resistance pathways, as well as a defining feature for bacterial viability and pathogenicity.

Other names

D-Ala-D-Ala motifD-alanyl-D-alanine dipeptideD-alanyl-D-alanine terminusD-Ala-D-Ala end

Vancomycin and related glycopeptides bind to the D-alanyl-D-alanine motif, forming a stable non-covalent complex that sterically blocks transglycosylase and transpeptidase enzymes, inhibiting cross-linking and elongation of peptidoglycan, leading to cell lysis[1][2][6]. D-cycloserine inhibits precursor synthesis by inhibiting D-alanine racemase and D-Ala-D-Ala ligase, preventing formation of the D-Ala-D-Ala motif[5][7]. β-lactam antibiotics (e.g., penicillins) competitively inhibit transpeptidases by mimicking the D-Ala-D-Ala structure, preventing cross-linking of peptidoglycan[6].