Sandbox Reserved 692
From Proteopedia
| This Sandbox is Reserved from 30/01/2013, through 30/12/2013 for use in the course "Biochemistry II" taught by Hannah Tims at the Messiah College. This reservation includes Sandbox Reserved 686 through Sandbox Reserved 700. |
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Quorum-sensing in Pseudomonas aeruginosa
Since their initial discovery when it was found that E. coli could inactivate penicillin, antibiotic-resistant bacteria have posed concerns to many. Recently, hospital acquired infections have increased with the increasingly common lactose-fermenting gram-negative bacteria, and this has resulted in increased attention among clinicians. One such pathogen, Pseudomonas aeruginosa, is a dangerous bacterium that is resistant to many classes of antibiotics. (Bonomo and Szabo 2006) This bacterium is the most significant pathogen that inhabits the lungs of patients with the disease cystic fibrosis (CF). Once P. aeruginosa has colonized the lungs of these patients, antibiotics have little efficacy in eradicating the pathogen, which frequently leads to eventual to lung damage, respiratory failure, and death. (Singh et al., 2000) One reason that colonization is so harmful to patients infected with the pathogen is due to the quorum-sensing systems las and rhl, which contribute to the negative health effects of infection by this bacterium. Quorum sensing in bacteria involves the production and detection of acyl homoserine lactones (AHLs). These molecules can freely diffuse across bacterial membranes, which means that the concentration of these quorum-sensing molecules is the same both inside the cell that produces them and in the extracellular medium of that cell. As these molecules are produced by an increasing number of bacterial cells, their extracellular concentrations increase accordingly, where they form a complex with a transcriptional activator. This complex induces gene expression, resulting in the bacterium’s response to the factors produced by other bacterial cells. (Davies and Bilton, 2009)
Las system introduction
One quorum-sensing system in P. aeruginosa is the las system. The AHL in this system is N-(3-oxododecanoyl) homoserine lactone (3OC12-HSL), which is produced by the synthase protein lasI. As concentration of 3OC12-HSL increases, it binds to and activates the transcriptional activator protein LasR. The activated LasR/3OC12-HSL complex then binds to the lux-box, which is a chromosomal DNA sequence upstream of various target genes, including lasI and perhaps lasR. (Anguige, King, Ward, 2006)
LasI
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The synthase uses 3-oxo-C12-acyl-carrier protein (acyl-ACP) and S-adenosyl-L-methionine to synthesize 3O-C12-HSL. The protein can be seen in pink with its ligands in lime green. The residues Arg23, Phe27, and Trp33 are presumed to form the , which can be seen here in dark blue. The residues Arg154 and Lys150 are thought to be the , seen here in light blue.
LasR
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The transcriptional activator LasR binds to 3O-C12-HSL and the complex then activates transcription. In solution the binding domain forms a , which can be seen here with one subunit in light blue, the other in light green, and the ligand 3O-C12-HSL in red. Each subunit consists of a 5-stranded antiparallel (shown here in yellow) with two sets of three (shown here in green) on either side of the sheets.
The loop (shown here in royal blue) covers the binding pocket of the binding domain and prevents it from being accessible to solvent. A number of including Tyr-56, Trp-60 , Asp-73, and Ser-129 (shown here in light blue) are involved in hydrogen-bonding with the polar head of the ligand.
