title: Cocrystal structures of diaminopimelate decarboxylase: mechanism, evolution, and inhibition of an antibiotic resistance accessory factor.
abstract: 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 A and 2.0 A, respectively. This PLP-dependent enzyme is responsible for the final step of L-lysine biosynthesis in bacteria and plays a role in beta-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 (K(i)) for azelaic acid (89 microM) 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.
authors.affiliation: Laboratory of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
authors.forename: Soumya S
authors.initials: SS
authors.lastname: Ray
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Bonanno
authors.forename: K R
authors.initials: KR
authors.lastname: Rajashankar
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Pinho
authors.forename: Guoshun
authors.initials: G
authors.lastname: He
authors.forename: Herminia
authors.initials: H
authors.lastname: De Lencastre
authors.forename: Alexander
authors.initials: A
authors.lastname: Tomasz
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Burley
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins; D001665:Binding Sites; D002262:Carboxy-Lyases / Q000737:chemistry*; D018360:Crystallography, X-Ray; D019281:Dimerization; D004351:Drug Resistance; D007700:Kinetics; D017017:Methanococcus / Q000201:enzymology; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D013211:Staphylococcus aureus / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002262:Carboxy-Lyases; C079912:LysA protein, Bacteria; C020031:diaminopimelic acid decarboxylase