Mycobacterium smegmatis D-alanine:D-alanine ligase and alanine racemase (Ddl / Alr)

Mycobacterium smegmatis D-alanine:D-alanine ligase (Ddl) and alanine racemase (Alr) are two essential enzymes that work in tandem within the peptidoglycan biosynthesis pathway [1][3]. Alanine racemase (Alr) catalyzes the conversion of L-alanine to D-alanine, providing the necessary substrate for the subsequent step [1]. D-alanine:D-alanine ligase (Ddl) then facilitates the ATP-dependent ligation of two D-alanine molecules to form the D-alanyl-D-alanine dipeptide, a critical component of the bacterial cell wall [2][3]. These enzymes are the primary therapeutic targets of the antibiotic D-cycloserine, which acts as a structural analog of D-alanine to competitively inhibit both proteins [3][4]. Inhibition of these targets leads to a depletion of the D-alanyl-D-alanine dipeptide, resulting in the arrest of peptidoglycan synthesis and eventual bacterial cell death [3]. While Mycobacterium smegmatis is a non-pathogenic species, it is frequently used as a surrogate model for studying these targets due to their high conservation in the human pathogen Mycobacterium tuberculosis [2]. Understanding the structural biology of these enzymes in M. smegmatis has been pivotal for the design of novel antitubercular agents [2]. [1] UniProt (A0A0D6H5B1); [2] Peter et al. (2012) PMID: 22431634; [3] Feng and Barletta (2003) PMID: 12501311; [4] PubChem (CID 6247).

Other names

D-alanyl-D-alanine synthetaseD-alanine--D-alanine ligaseAlrDdlDdlAAlanine racemase

Competitive inhibition of alanine racemase and D-alanine:D-alanine ligase by acting as a structural analog of D-alanine