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

43 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Carboxy-Lyases
R Factors
Microbial Drug Resistance
Lysine
Staphylococcus aureus
Methanocaldococcus
Lactams
Enzyme Assays
Substrate Specificity
Anti-Infective Agents
Bacteria
Enzymes
Pharmaceutical Preparations
azelaic acid

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Cocrystal structures of diaminopimelate decarboxylase : Mechanism, evolution, and inhibition of an antibiotic resistance accessory factor. / Ray, Soumya S.; Bonanno, Jeffrey B.; Rajashankar, K. R.; Pinho, Mariana G.; He, Guoshun; De Lencastre, Herminia; Tomasz, Alexander; Burley, Stephen K.

In: Structure, Vol. 10, No. 11, 01.11.2002, p. 1499-1508.

Research output: Contribution to journalArticle

Ray, Soumya S. ; Bonanno, Jeffrey B. ; Rajashankar, K. R. ; Pinho, Mariana G. ; He, Guoshun ; De Lencastre, Herminia ; Tomasz, Alexander ; Burley, Stephen K. / Cocrystal structures of diaminopimelate decarboxylase : Mechanism, evolution, and inhibition of an antibiotic resistance accessory factor. In: Structure. 2002 ; Vol. 10, No. 11. pp. 1499-1508.
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