D-alanine–D-alanine ligase (Ddl)

D-alanine–D-alanine ligase (Ddl) is a bacterial enzyme essential for catalyzing the ATP-dependent formation of the D-alanyl–D-alanine dipeptide, a critical precursor for peptidoglycan biosynthesis in the bacterial cell wall. Its central role makes it a highly attractive drug target for antibiotic development, notably in tuberculosis therapy. As an ATP-grasp enzyme, Ddl forms a homodimer composed of three domains, with crucial active site loops facilitating substrate binding and catalysis. Inhibition of Ddl disrupts cell wall formation, leading to bacterial death.

Other names

Alanine:alanine ligase (ADP-forming)Alanylalanine synthetaseD-Ala-D-Ala synthetaseD-alanylalanine synthetase

Drugs such as d-cycloserine act as enzyme inhibitors by mimicking the substrate and binding to the active site, blocking formation of D-alanyl–D-alanine and thus preventing peptidoglycan synthesis. Inhibition can involve preferential binding to one of two substrate binding sites, each with different affinity, and is modulated by ATP presence.