D-alanine—D-alanine ligase (Mycobacterium tuberculosis) (DdlA)

D-alanine—D-alanine ligase (Ddl) is an essential enzyme in Mycobacterium tuberculosis that catalyzes the ATP-dependent formation of the D-alanyl-D-alanine dipeptide [UniProt: P9WMT1]. This dipeptide is a fundamental building block for the peptidoglycan layer of the bacterial cell wall, specifically serving as a precursor for the pentapeptide side chain [PubMed: 22432239]. Since the D-alanine pathway is unique to bacteria and absent in humans, Ddl represents a highly selective target for antimicrobial therapy [PubMed: 25613164]. The drug D-cycloserine is a well-characterized inhibitor of this enzyme, acting as a structural analog of D-alanine to competitively block the active site [DrugBank: DB00260]. Inhibition of Ddl results in the depletion of cell wall precursors, leading to impaired cell wall synthesis and eventual bacterial lysis [PubMed: 18410156]. Despite its potential, the development of new Ddl inhibitors is challenging due to the need to overcome the neurotoxic side effects associated with existing drugs like cycloserine [PubMed: 23939614]. The enzyme's critical role in maintaining cell wall integrity makes it a focal point for research into multi-drug resistant tuberculosis treatments [PubMed: 21114351].

Other names

D-alanyl-D-alanine synthetaseD-alanine:D-alanine ligaseDdlD-Ala-D-Ala ligase

Competitive inhibition of the D-alanine binding site, preventing the formation of the D-alanyl-D-alanine dipeptide required for peptidoglycan synthesis.