Mycobacterium tuberculosis alanine racemase and D-alanyl-D-alanine ligase (Alr/Ddl)

Alanine racemase (Alr) and D-alanyl-D-alanine ligase (Ddl) are essential enzymes in the peptidoglycan biosynthesis pathway of Mycobacterium tuberculosis (Mtb) [UniProt: P9WIP9, P9WIG5]. Alr is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the reversible conversion of L-alanine to D-alanine, while Ddl facilitates the ATP-dependent ligation of two D-alanine molecules to form the D-alanyl-D-alanine dipeptide [PubMed: 22435719]. These enzymes are critical for maintaining the structural integrity of the mycobacterial cell wall, and their absence in human cells makes them attractive targets for selective toxicity [PubMed: 25613164]. The antibiotic D-cycloserine, a structural analog of D-alanine, acts as a potent competitive inhibitor of both Alr and Ddl [PubChem: CID 6247]. By blocking these steps, D-cycloserine prevents the formation of the peptidoglycan precursor, leading to bacterial cell wall instability and lysis. This dual-targeting mechanism is particularly effective against multi-drug-resistant strains of Mtb, although its clinical application is often complicated by significant central nervous system side effects [StatPearls: NBK555954].

Other names

AlrDdlAlanine racemaseD-alanyl-D-alanine ligaseAlrADdlAD-alanine--D-alanine ligase

Competitive inhibition of alanine racemase and D-alanyl-D-alanine ligase, preventing the synthesis of D-alanine and the D-alanyl-D-alanine dipeptide required for peptidoglycan cross-linking.