Peptidoglycan precursor stem peptide of Lipid II (Lipid II stem peptide)

The peptidoglycan precursor stem peptide of Lipid II is a fundamental component of the bacterial cell wall biosynthetic pathway (Breukink & de Kruijff, 2006, Nature Reviews Drug Discovery). Lipid II consists of a C55 undecaprenyl lipid carrier linked to a disaccharide (N-acetylglucosamine and N-acetylmuramic acid) which bears a pentapeptide side chain, typically ending in a D-alanyl-D-alanine (D-Ala-D-Ala) dipeptide (Schneider & Sahl, 2010, Current Opinion in Investigational Drugs). This stem peptide is essential for the cross-linking of peptidoglycan strands, a process catalyzed by transpeptidases to provide mechanical strength to the bacterial cell wall. It is the primary molecular target for several classes of potent antibiotics, most notably glycopeptides like vancomycin, which bind to the D-Ala-D-Ala terminus to sterically hinder cell wall assembly (PubMed: 16485011). Disruption of this target leads to cell wall defects, osmotic instability, and eventual bacterial cell death. Resistance mechanisms, such as those found in Vancomycin-Resistant Enterococci (VRE), involve the modification of the stem peptide terminus to D-alanyl-D-lactate, which prevents antibiotic binding while maintaining cell wall integrity (Nature: 10.1038/nature14098).

Other names

Lipid II pentapeptideD-alanyl-D-alanine terminusPeptidoglycan stem peptideLipid II stem peptideUndecaprenyl-pyrophosphoryl-MurNAc-pentapeptide-GlcNAc stem peptide

Binding to the D-alanyl-D-alanine C-terminus of the stem peptide via hydrogen bonding, which sterically blocks the transglycosylase and transpeptidase enzymes from incorporating the precursor into the peptidoglycan layer (Schneider & Sahl, 2010).