Meso-diaminopimelate D-dehydrogenase (DAPDH) (DAPDH)

Meso-diaminopimelate D-dehydrogenase (DAPDH) is an enzyme that catalyzes the reversible oxidative deamination of meso-2,6-diaminopimelate to L-2-amino-6-oxopimelate using NADP+ as a cofactor (UniProt: EC 1.4.1.16). This enzyme provides an alternative single-step route for L-lysine biosynthesis in several bacterial species, bypassing the more common multi-step succinylase or acetylase pathways (PubMed: 22493450). Because the diaminopimelate pathway is essential for the synthesis of both L-lysine and the peptidoglycan cross-linking agent meso-diaminopimelate, it is vital for bacterial survival and cell wall integrity (PubMed: 25611112). Importantly, this metabolic pathway is entirely absent in humans, who must obtain lysine through their diet, making DAPDH an attractive target for the development of selective antibacterial agents (PubMed: 28841015). Inhibition of DAPDH leads to lysine starvation and weakened cell walls, particularly in pathogens like Mycobacterium tuberculosis and Bacteroides species. Current drug discovery efforts focus on identifying small-molecule inhibitors that can effectively penetrate bacterial membranes and provide a novel mechanism to combat multi-drug resistant infections. Research has identified various substrate analogs and sulfonamide-based compounds as potential lead candidates for therapeutic development. The high specificity of the enzyme for its substrate and the lack of a human homolog minimize the risk of off-target toxicity in the host.

Other names

meso-alpha,epsilon-diaminopimelate dehydrogenasemeso-diaminopimelate dehydrogenaseD-diaminopimelate dehydrogenaseDDHmeso-DAPDH

Inhibition of the enzyme prevents the conversion of meso-2,6-diaminopimelate to L-2-amino-6-oxopimelate, disrupting the biosynthesis of L-lysine and peptidoglycan components.