TY - JOUR
T1 - The Vibrio cholerae quorum-sensing autoinducer CAI-1
T2 - Analysis of the biosynthetic enzyme CqsA
AU - Kelly, Robert C.
AU - Bolitho, Megan E.
AU - Higgins, Douglas A.
AU - Lu, Wenyun
AU - Ng, Wai Leung
AU - Jeffrey, Philip D.
AU - Rabinowitz, Joshua D.
AU - Semmelhack, Martin F.
AU - Hughson, Frederick McLaury
AU - Bassler, Bonnie Lynn
N1 - Funding Information:
We thank the staff of the National Synchrotron Light Source beamline X29 for assistance with X-ray data collection; N. Ruiz and A. Arnaudo (Princeton University) for strains; and J. Kirsch for insightful discussions. This work was supported by the Howard Hughes Medical Institute; US National Institutes of Health grants AI054442, GM065859 and AI069326; US National Science Foundation grant MCB-0639855; and a Dr. Horst Witzel Fellowship from Cephalon Corporation (to M.E.B.).
PY - 2009/12
Y1 - 2009/12
N2 - Vibrio cholerae, the bacterium that causes the disease cholera, controls virulence factor production and biofilm development in response to two extracellular quorum-sensing molecules, called autoinducers. The strongest autoinducer, called CAI-1 (for cholera autoinducer-1), was previously identified as (S)-3-hydroxytridecan-4-one. Biosynthesis of CAI-1 requires the enzyme CqsA. Here, we determine the CqsA reaction mechanism, identify the CqsA substrates as (S)-2-aminobutyrate and decanoyl coenzyme A, and demonstrate that the product of the reaction is 3-aminotridecan-4-one, dubbed amino-CAI-1. CqsA produces amino-CAI-1 by a pyridoxal phosphateg-dependent acyl-CoA transferase reaction. Amino-CAI-1 is converted to CAI-1 in a subsequent step via a CqsA-independent mechanism. Consistent with this, we find cells release ≥100 times more CAI-1 than amino-CAI-1. Nonetheless, V. cholerae responds to amino-CAI-1 as well as CAI-1, whereas other CAI-1 variants do not elicit a quorum-sensing response. Thus, both CAI-1 and amino-CAI-1 have potential as lead molecules in the development of an anticholera treatment.
AB - Vibrio cholerae, the bacterium that causes the disease cholera, controls virulence factor production and biofilm development in response to two extracellular quorum-sensing molecules, called autoinducers. The strongest autoinducer, called CAI-1 (for cholera autoinducer-1), was previously identified as (S)-3-hydroxytridecan-4-one. Biosynthesis of CAI-1 requires the enzyme CqsA. Here, we determine the CqsA reaction mechanism, identify the CqsA substrates as (S)-2-aminobutyrate and decanoyl coenzyme A, and demonstrate that the product of the reaction is 3-aminotridecan-4-one, dubbed amino-CAI-1. CqsA produces amino-CAI-1 by a pyridoxal phosphateg-dependent acyl-CoA transferase reaction. Amino-CAI-1 is converted to CAI-1 in a subsequent step via a CqsA-independent mechanism. Consistent with this, we find cells release ≥100 times more CAI-1 than amino-CAI-1. Nonetheless, V. cholerae responds to amino-CAI-1 as well as CAI-1, whereas other CAI-1 variants do not elicit a quorum-sensing response. Thus, both CAI-1 and amino-CAI-1 have potential as lead molecules in the development of an anticholera treatment.
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U2 - 10.1038/nchembio.237
DO - 10.1038/nchembio.237
M3 - Article
C2 - 19838203
AN - SCOPUS:73549097782
SN - 1552-4450
VL - 5
SP - 891
EP - 895
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 12
ER -