Structure of the Pseudomonas aeruginosa acyl-homoserinelactone synthase LasI

Mol Microbiol. 2004 Aug;53(4):1135-46. doi: 10.1111/j.1365-2958.2004.04211.x.


The LasI/LasR quorum-sensing system plays a pivotal role in virulence gene regulation of the opportunistic human pathogen, Pseudomonas aeruginosa. Here we report the crystal structure of the acyl-homoserine lactone (AHL) synthase LasI that produces 3-oxo-C12-AHL from the substrates 3-oxo-C12-acyl-carrier protein (acyl-ACP) and S-adenosyl-L-methionine. The LasI six-stranded beta sheet platform, buttressed by three alpha helices, forms a V-shaped substrate-binding cleft that leads to a tunnel passing through the enzyme that can accommodate the acyl-chain of acyl-ACP. This tunnel places no apparent restriction on acyl-chain length, in contrast to a restrictive hydrophobic pocket seen in the AHL-synthase EsaI. Interactions of essential conserved N-terminal residues, Arg23, Phe27 and Trp33, suggest that the N-terminus forms an enclosed substrate-binding pocket for S-adenosyl-L-methionine. Analysis of AHL-synthase surface residues identified a binding site for acyl-ACP, a role that was supported by in vivo reporter assay analysis of the mutated residues, including Arg154 and Lys150. This structure and the novel explanation of AHL-synthase acyl-chain-length selectivity promise to guide the design of Pseudomonas aeruginosa-specific quorum-sensing inhibitors as antibacterial agents.

Publication types

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

MeSH terms

  • Acyl Carrier Protein / chemistry
  • Acyl Carrier Protein / metabolism
  • Amino Acid Sequence
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Crystallization
  • Gene Expression Regulation, Bacterial
  • Humans
  • Ligases / chemistry*
  • Ligases / genetics
  • Ligases / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Pseudomonas aeruginosa / enzymology*
  • Substrate Specificity
  • Virulence


  • Acyl Carrier Protein
  • Bacterial Proteins
  • LasI protein, Pseudomonas aeruginosa
  • Ligases
  • N-acylhomoserine lactone synthase