Cocrystal structures of diaminopimelate decarboxylase: mechanism, evolution, and inhibition of an antibiotic resistance accessory factor.
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.
Ray
Soumya S
SS
Laboratory of Molecular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Bonanno
Jeffrey B
JB
Rajashankar
K R
KR
Pinho
Mariana G
MG
He
Guoshun
G
De Lencastre
Herminia
H
Tomasz
Alexander
A
Burley
Stephen K
SK
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
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002262:Carboxy-Lyases; C079912:LysA protein, Bacteria; C020031:diaminopimelic acid decarboxylase