Premium
Structures of the N‐Terminal Domain of PqsA in Complex with Anthraniloyl‐ and 6‐Fluoroanthraniloyl‐AMP: Substrate Activation in Pseudomonas Quinolone Signal (PQS) Biosynthesis
Author(s) -
Witzgall Florian,
Ewert Wiebke,
Blankenfeldt Wulf
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700374
Subject(s) - substrate (aquarium) , biosynthesis , chemistry , pseudomonas aeruginosa , terminal (telecommunication) , pseudomonas , quinolone , stereochemistry , domain (mathematical analysis) , combinatorial chemistry , biochemistry , bacteria , enzyme , biology , antibiotics , computer science , mathematics , genetics , ecology , telecommunications , mathematical analysis
Pseudomonas aeruginosa, a prevalent pathogen in nosocomial infections and a major burden in cystic fibrosis, uses three interconnected quorum‐sensing systems to coordinate virulence processes. At variance with other Gram‐negative bacteria, one of these systems relies on 2‐alkyl‐4(1 H )‐quinolones ( Pseudomonas quinolone signal, PQS) and might hence be an attractive target for new anti‐infective agents. Here we report crystal structures of the N‐terminal domain of anthranilate‐CoA ligase PqsA, the first enzyme of PQS biosynthesis, in complex with anthraniloyl‐AMP and with 6‐fluoroanthraniloyl‐AMP (6FABA‐AMP) at 1.4 and 1.7 Å resolution. We find that PqsA belongs to an unrecognized subfamily of anthranilate‐CoA ligases that recognize the amino group of anthranilate through a water‐mediated hydrogen bond. The complex with 6FABA‐AMP explains why 6FABA, an inhibitor of PQS biosynthesis, is a good substrate of PqsA. Together, our data might pave a way to new pathoblockers in P. aeruginosa infections.