Cocrystal structures of diaminopimelate decarboxylase: mechanism, evolution, and inhibition of an antibiotic resistance accessory factor

Structure. 2002 Nov;10(11):1499-508. doi: 10.1016/s0969-2126(02)00880-8.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins*
  • Binding Sites
  • Carboxy-Lyases / chemistry*
  • Crystallography, X-Ray
  • Dimerization
  • Drug Resistance
  • Kinetics
  • Methanococcus / enzymology
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Secondary
  • Sequence Homology, Amino Acid
  • Staphylococcus aureus / metabolism

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Carboxy-Lyases
  • LysA protein, Bacteria
  • diaminopimelic acid decarboxylase