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Chem Biol. 2013 Dec 19;20(12):1481-91. doi: 10.1016/j.chembiol.2013.09.021. Epub 2013 Nov 14.

The end of an old hypothesis: the pseudomonas signaling molecules 4-hydroxy-2-alkylquinolines derive from fatty acids, not 3-ketofatty acids.

Author information

1
INRS-Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada.
2
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, MA 02114, USA.
3
INRS-Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada. Electronic address: francois.lepine@iaf.inrs.ca.
4
INRS-Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada. Electronic address: eric.deziel@iaf.inrs.ca.

Abstract

Groups of pathogenic bacteria use diffusible signals to regulate their virulence in a concerted manner. Pseudomonas aeruginosa uses 4-hydroxy-2-alkylquinolines (HAQs), including 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS), as unique signals. We demonstrate that octanoic acid is directly incorporated into HHQ. This finding rules out the long-standing hypothesis that 3-ketofatty acids are the precursors of HAQs. We found that HAQ biosynthesis, which requires the PqsABCD enzymes, proceeds by a two-step pathway: (1) PqsD mediates the synthesis of 2-aminobenzoylacetate (2-ABA) from anthraniloyl-coenzyme A (CoA) and malonyl-CoA, then (2) the decarboxylating coupling of 2-ABA to an octanoate group linked to PqsC produces HHQ, the direct precursor of PQS. PqsB is tightly associated with PqsC and required for the second step. This finding uncovers promising targets for the development of specific antivirulence drugs to combat this opportunistic pathogen.

PMID:
24239007
PMCID:
PMC3877684
DOI:
10.1016/j.chembiol.2013.09.021
[Indexed for MEDLINE]
Free PMC Article

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