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

Soumya S. Ray, Jeffrey B. Bonanno, K. R. Rajashankar, Mariana G. Pinho, Guoshun He, Herminia De Lencastre, Alexander Tomasz, Stephen K. Burley

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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.

Original languageEnglish (US)
Pages (from-to)1499-1508
Number of pages10
Issue number11
StatePublished - Nov 1 2002



  • Antibiotic resistance
  • Diaminopimalate decarboxylase
  • Lysine biosynthesis
  • Structural genomics
  • X-ray crystallography

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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