Structural Superimposition

Abstact

Glutamate decarboxylase (GadB) is a pyridoxal phosphate (PLP)-dependent enzyme that contributes to intracellular pH homeostasis and supports the survival of Mycobacterium tuberculosis (Mtb) in lung tissue, granulomas, and within host macrophages. Here, we demonstrate that glutamate decarboxylase from Mycobacterium tuberculosis (MtbGadB) is a multimeric enzyme exhibiting maximal activity under acidic conditions. MtbGadB is inhibited by the clinical antibiotic d-cycloserine as well as l-cycloserine in vitro. Both cycloserine enantiomers break the internal aldimine bond between PLP and the conserved Lys277 residue, forming a previously unrecognised PLP-oxime product and subsequently inhibiting catalysis. Given that PLP-dependent enzymes are promising drug targets, understanding the chemical behaviour of PLP is essential for developing selective inhibitors.