♦ See referenced article, J. Biol. Chem. 2016, 291, 6610–6624
Pseudomonas aeruginosa is a common drug-resistant bacterium that causes a variety of illnesses, including pneumonia and sepsis. The bacterium produces an important signaling molecule called 2-heptyl-4(1H)-quinolone that is made by a condensation reaction. The reaction is catalyzed by an enzyme known as the β-ketoacyl-(acyl carrier protein) synthase III (FabH)-like enzyme, PqsBC. This enzyme is a target for drug development. However, the structure of PqsBC is known to be dissimilar to that of other members in the same family of FabH-like condensing enzymes; PqsBC is a heterodimer, whereas other family members are homodimers. Furthermore, PqsBC's mode of action is unclear. In this Paper of the Week, a team led by Susanne Fetzner at the University of Münster in Germany and Jonas Emsley at the University of Nottingham in the U.K. elucidated the catalytic mechanism and resolved the structure of PqsBC. They found that the heterodimeric subunits PqsB and PqsC had a structure unexpectedly similar to the homodimer of the canonical enzyme in this family. The investigators also demonstrated that 2-aminoacetophenone, a molecule also produced by P. aeruginosa, acted as a competitive inhibitor of PqsBC. The authors say, “Taken together, this work significantly increases our knowledge of the structure, enzyme mechanism, and inhibition of PqsBC, and in a broader dimension, the work has implications for the development of novel therapeutics which control P. aeruginosa infection by attenuating virulence gene expression.”
The PqsBCC129A heterodimer is shown with PqsC (cyan) and PqsB (red) covered with a transparent molecular surface illustrating the interface.