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

Research output: Contribution to journalArticle

45 Scopus citations

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 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
JournalStructure
Volume10
Issue number11
DOIs
StatePublished - Nov 1 2002

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Keywords

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

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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