Cocrystal structures of Methanococcus jannaschii diaminopimelate decarboxylase (DAPDC) bound to a substrate analog, azelaic acid, and its L-lysine product have been determined at 2.6 Å and 2.0 Å, respectively. This PLP-dependent enzyme is responsible for the final step of L-lysine biosynthesis in bacteria and plays a role in β-lactam antibiotic resistance in Staphylococcus aureus. Substrate specificity derives from recognition of the L-chiral center of diaminopimelate and a system of ionic “molecular rulers” that dictate substrate length. A coupled-enzyme assay system permitted measurement of kinetic parameters for recombinant DAPDCs and inhibition constants (Ki) for azelaic acid (89 μM) and other substrate analogs. Implications for rational design of broad-spectrum antimicrobial agents targeted against DAPDCs of drug-resistant strains of bacterial pathogens, such as Staphylococcus aureus, are discussed.
Ray, S. S., Bonanno, J. B., Rajashankar, K. R., Pinho, M. G., He, G., De Lencastre, H., … Burley, S. K. (2002). Cocrystal Structures of Diaminopimelate Decarboxylase. Structure, 10(11), 1499–1508. https://doi.org/10.1016/s0969-2126(02)00880-8