D-alanine—D-alanine ligase (Ddl (also: D-Ala:D-Ala ligase))

D-alanine—D-alanine ligase is a bacterial enzyme (EC 6.3.2.4) that catalyzes the ATP-dependent formation of the D-alanyl–D-alanine dipeptide, a critical precursor in peptidoglycan biosynthesis, which is a major component of bacterial cell walls. The enzyme binds two molecules of D-alanine and ATP, producing D-alanyl–D-alanine, ADP, and phosphate. It is a member of the ATP-grasp ligase family and is essential for bacterial cell viability. Because inhibition of this enzyme disrupts peptidoglycan formation, it is a validated antibacterial drug target, notably for drugs such as D-cycloserine. Resistance to antibiotics targeting this enzyme can arise through expression of alternative ligase enzymes (such as VanA) that alter the cell wall precursor so it is not bound by antibiotics like vancomycin.

Other names

D-alanylalanine synthetaseAlanine:alanine ligase (ADP-forming)D-Ala-D-Ala synthetaseD-alanyl-D-alanine synthetase

Inhibition of D-alanine—D-alanine ligase leads to disruption of peptidoglycan crosslinking, compromising bacterial cell wall synthesis and resulting in bacterial cell death. D-cycloserine acts as a competitive inhibitor at the D-alanine binding site. Some drugs (e.g., phosphinate and phosphonate analogs) act as reversible inhibitors by mimicking reaction intermediates.