D-alanine:D-alanine ligase (Ddl) (Ddl)

D-alanine:D-alanine ligase (Ddl) is an essential bacterial enzyme that catalyzes the ATP-dependent formation of the D-alanyl-D-alanine dipeptide [1, 6]. This dipeptide is a critical building block for the pentapeptide side chain of peptidoglycan, which provides structural integrity to the bacterial cell wall [14, 16]. Ddl belongs to the ATP-grasp superfamily of ligases and is found in both Gram-positive and Gram-negative bacteria [9, 10]. Because the enzyme is absent in eukaryotes, it serves as a highly selective target for the development of antibacterial agents [13]. Inhibition of Ddl leads to the depletion of cell wall precursors, resulting in weakened cell walls and eventual bacterial cell lysis [14, 16]. The most well-known clinical inhibitor is D-cycloserine, which is used as a second-line treatment for multi-drug-resistant tuberculosis [16, 17]. D-cycloserine acts as a competitive analogue of D-alanine, binding to the enzyme's active site and halting peptidoglycan synthesis [14, 17]. However, the clinical utility of Ddl inhibitors is often limited by significant neurotoxic side effects, such as convulsions and psychosis, due to off-target activity in the host [14, 17]. Additionally, bacteria can develop resistance through mutations that allow the enzyme to utilize alternative substrates like D-lactate or D-serine [7, 13].

Other names

D-alanyl-D-alanine synthetaseD-alanine—D-alanine ligase (ADP-forming)Alanylalanine synthetaseDdlADdlB

Competitive inhibition of the D-alanine binding site, mimicking the natural substrate to prevent the formation of the D-alanyl-D-alanine dipeptide.