Cocrystal structures of diaminopimelate decarboxylase: mechanism, evolution, and inhibition of an antibiotic resistance accessory factor. Academic Article uri icon

Overview

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 date

  • November 1, 2002

Research

keywords

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Carboxy-Lyases

Identity

Scopus Document Identifier

  • 0036848911

Digital Object Identifier (DOI)

  • 10.1016/s0969-2126(02)00880-8

PubMed ID

  • 12429091

Additional Document Info

volume

  • 10

issue

  • 11