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

Mycobacterium tuberculosis alanine racemase (Alr) and D-alanyl-D-alanine synthetase (Ddl) are two distinct enzymes that function sequentially in the biosynthesis of peptidoglycan, a critical component of the bacterial cell wall (UniProt: P9WIP9, P9WIP7). Alr is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the racemization of L-alanine to D-alanine, while Ddl is an ATP-dependent ligase that joins two D-alanine molecules to form the D-alanyl-D-alanine dipeptide (PubMed: 22432239). This dipeptide is essential for the formation of the pentapeptide side chains that cross-link the peptidoglycan polymer, providing structural integrity to the mycobacterium. Because these enzymes are vital for bacterial survival and lack human homologs, they are significant targets for antitubercular drug development. The antibiotic D-cycloserine acts as a structural analog of D-alanine and functions as a competitive inhibitor of both Alr and Ddl, leading to cell wall instability and bacterial death (DrugBank: DB00260). Clinical use of drugs targeting these enzymes is primarily reserved for multi-drug-resistant tuberculosis (MDR-TB) due to the risk of severe central nervous system side effects, including seizures and psychosis (PubMed: 24101688).

Other names

AlrDdlDdlAAlanine racemaseD-alanine--D-alanine ligaseD-alanyl-D-alanine ligaseM. tuberculosis Alr/Ddl

Competitive inhibition of alanine racemase and D-alanyl-D-alanine synthetase, which prevents the synthesis of D-alanyl-D-alanine and disrupts the assembly of the peptidoglycan layer in the bacterial cell wall (PubMed: 22432239, 25157100).