Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.184 (LasR)
 897 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Quorum sensing is a widespread form of bacterial communication in which individual cells produce and respond to specific N-acyl homoserine lactone signal metabolites. The different autoinducer synthases that generate these signals and the receptor/activator proteins that mediate the cell's response to them constitute evolutionarily conserved families of regulatory proteins known as the LuxI and LuxR families, respectively. We have performed a phylogenetic analysis of 76 individual LuxI and LuxR homologues present in diverse members of the Gram-negative Proteobacteria. The results were consistent with an early origin for these regulators during the evolution of the Proteobacteria, with functional pairs of luxI and luxR genes possibly coevolving as regulatory cassettes. In many cases, specific LuxI and LuxR family members appeared to have been inherited horizontally. In particular, those species containing multiple LuxI and/or LuxR homologues usually appeared to have obtained each individual homologue or functional pair of homologues from an independent source. Because multiple homologues interact to form regulatory cascades, this finding suggests that hierarchical signalling pathways can potentially evolve by the sequential integration of pre-existing regulatory circuits acquired from diverse sources.
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PMID:The evolution of bacterial LuxI and LuxR quorum sensing regulators. 1149 14

Intrinsic and acquired antibiotic resistance of the nosocomial pathogen Pseudomonas aeruginosa is mediated mainly by the expression of several efflux pumps of broad substrate specificity. Here we report that nfxC type mutants, overexpressing the MexEF-OprN efflux system, produce lower levels of extracellular virulence factors than the susceptible wild type. These include pyocyanin, elastase, and rhamnolipids, three factors controlled by the las and rhl quorum-sensing systems of P. aeruginosa. In agreement with these observations are the decreased transcription of the elastase gene lasB and the rhamnosyltransferase genes rhlAB measured in nfxC type mutants. Expression of the lasR and rhlR regulator genes was not affected in the nfxC type mutant. In contrast, transcription of the C4-homoserine lactone (C4-HSL) autoinducer synthase gene rhlI was reduced by 50% in the nfxC type mutant relative to that in the wild type. This correlates with a similar decrease in C4-HSL levels detected in supernatants of the nfxC type mutant. Transcription of an rhlAB-lacZ fusion could be partially restored by the addition of synthetic C4-HSL and Pseudomonas quinolone signal (PQS). It is proposed that the MexEF-OprN efflux pump affects intracellular PQS levels.
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PMID:Overexpression of the MexEF-OprN multidrug efflux system affects cell-to-cell signaling in Pseudomonas aeruginosa. 1151 2

During nutrient starvation, Escherichia coli elicits a stringent response involving the ribosome-associated protein RelA. Activation of RelA results in a global change in the cellular metabolism including enhanced expression of the stationary-phase sigma factor RpoS. In the human pathogen Pseudomonas aeruginosa, a complex quorum-sensing circuitry, linked to RpoS expression, is required for cell density-dependent production of many secreted virulence factors, including LasB elastase. Quorum sensing relies on the activation of specific transcriptional regulators (LasR and RhlR) by their corresponding autoinducers (3-oxo-C(12)-homoserine lactone [HSL] and C(4)-HSL), which function as intercellular signals. We found that overexpression of relA activated the expression of rpoS in P. aeruginosa and led to premature, cell density-independent LasB elastase production. We therefore investigated the effects of the stringent response on quorum sensing. Both lasR and rhlR gene expression and autoinducer synthesis were prematurely activated during the stringent response induced by overexpression of relA. Premature expression of lasR and rhlR was also observed when relA was overexpressed in a PAO1 rpoS mutant. The stringent response induced by the amino acid analogue serine hydroxamate (SHX) also led to premature production of the 3-oxo-C(12)-HSL autoinducer. This response to SHX was absent in a PAO1 relA mutant. These findings suggest that the stringent response can activate the two quorum-sensing systems of P. aeruginosa independently of cell density.
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PMID:Stringent response activates quorum sensing and modulates cell density-dependent gene expression in Pseudomonas aeruginosa. 1151 23

Rhizobium etli CNPAF512 produces an autoinducer that inhibits growth of Rhizobium leguminosarum bv. viciae 248 and activates the Agrobacterium tumefaciens tra reporter system. Production of this compound in R. etli is dependent on two genes, named cinR and cinI, postulated to code for a transcriptional regulator and an autoinducer synthase, respectively. NMR analysis of the purified molecule indicates that the R. etli autoinducer produced by CinI is a saturated long chain 3-hydroxy-acyl-homoserine lactone, abbreviated as 3OH-(slc)-HSL. Using cin-gusA fusions, expression of cinI and cinR was shown to be growth phase-dependent. Deletion analysis of the cinI promoter region indicates that a regulatory element negatively controls cinI expression. Mutational analysis revealed that expression of the cinI gene is positively regulated by the CinR/3OH-(slc)-HSL complex. Besides 3OH-(slc)-HSL, R. etli produces at least six other autoinducer molecules, for which the structures have not yet been revealed, and of which the synthesis requires the previously identified raiI and raiR genes. At least three different autoinducers, including a compound co-migrating with 3OH-(slc)-HSL, are produced in R. etli bacteroids isolated from bean nodules. This is further substantiated by the observation that cinI and cinR are both expressed under symbiotic conditions. Acetylene reduction activity of nodules induced by the cin mutants was reduced with 60-70% compared with wild-type nodules, indicating that the R. etli 3OH-(slc)-HSL is involved in the symbiotic process. This was further confirmed by transmission electron microscopy of nodules induced by the wild type and the cinI mutant. Symbiosomes carrying cinI mutant bacteroids did not fully differentiate compared with wild-type symbiosomes. Finally, it was observed that the cinR gene and raiR control growth of R. etli.
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PMID:The cin quorum sensing locus of Rhizobium etli CNPAF512 affects growth and symbiotic nitrogen fixation. 1167 32

Acyl-homoserine-L-lactones (AHLs) are diffusible chemical signals that are required for virulence of many Gram-negative bacteria. AHLs are produced by AHL synthases from two substrates, S-adenosyl-L-methionine and acyl-acyl carrier protein. The AHL synthase EsaI, which is homologous to the AHL synthases from other pathogenic bacterial species, has been crystallized in the primitive tetragonal space group P4(3), with unit-cell parameters a = b = 66.40, c = 47.33 A. The structure was solved by multiple-wavelength anomalous diffraction with a novel use of the rhenium anomalous signal. The rhenium-containing structure has been refined to a resolution of 2.5 A and the perrhenate ion binding sites and liganding residues have been identified.
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PMID:Crystallization and rhenium MAD phasing of the acyl-homoserinelactone synthase EsaI. 1171 25

Novel molecular tools have been constructed which allow for in situ detection of N-acyl homoserine lactone (AHL)-mediated quorum sensing in Pseudomonas aeruginosa biofilms. The reporter responds to AHL activation of LasR by expression of an unstable version of the green-fluorescent protein (Gfp). Gfp-based reporter technology has been applied for non-destructive, single-cell-level detection of quorum sensing in laboratory-based P. aeruginosa biofilms. It is reported that a synthetic halogenated furanone compound, which is a derivative of the secondary metabolites produced by the Australian macroalga Delisea pulchra, is capable of interfering with AHL-mediated quorum sensing in P. aeruginosa. It is demonstrated that the furanone compound specifically represses expression of a PlasB-gfp reporter fusion without affecting growth or protein synthesis. In addition, it reduces the production of important virulence factors, indicating a general effect on target genes of the las quorum sensing circuit. The furanone was applied to P. aeruginosa biofilms established in biofilm flow chambers. The Gfp-based analysis reveals that the compound penetrates microcolonies and blocks cell signalling and quorum sensing in most biofilm cells. The compound did not affect initial attachment to the abiotic substratum. It does, however, affect the architecture of the biofilm and enhances the process of bacterial detachment, leading to a loss of bacterial biomass from the substratum.
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PMID:Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. 1178 2

Pseudomonas aeruginosa has two well-characterized quorum-sensing systems, Las and Rhl. These systems are composed of LuxR-type proteins, LasR and RhlR, and two acyl homoserine lactone (AHL) synthases, LasI and RhlI. LasI catalyzes the synthesis of N-(3-oxododecanoyl)homoserine lactone (3O-C12-HSL), whereas RhlI catalyzes the synthesis of N-butyryl-homoserine lactone. There is little known about the importance of AHLs in vivo and what effects these molecules have on eukaryotic cells. In order to understand the role of AHLs in vivo, we first tested the effects that deletions of the synthase genes in P. aeruginosa had on colonization of the lung. We demonstrate that in an adult mouse acute-pneumonia model, deletion of the lasI gene or both the lasI and rhlI genes greatly diminished the ability of P. aeruginosa to colonize the lung. To determine whether AHLs have a direct effect on the host, we examined the effects of 3O-C12-HSL injected into the skin of mice. In this model, 3O-C(12)-HSL stimulated a significant induction of mRNAs for the cytokines interleukin-1alpha (IL-1alpha) and IL-6 and the chemokines macrophage inflammatory protein 2 (MIP-2), monocyte chemotactic protein 1, MIP-1beta, inducible protein 10, and T-cell activation gene 3. Additionally, dermal injections of 3O-C12-HSL also induced cyclooxygenase 2 (Cox-2) expression. The Cox-2 enzyme is important for the conversion of arachidonic acid to prostaglandins and is associated with edema, inflammatory infiltrate, fever, and pain. We also demonstrate that 3O-C12-HSL activates T cells to produce the inflammatory cytokine gamma interferon and therefore potentially promotes a Th1 environment. Induction of these inflammatory mediators in vivo is potentially responsible for the significant influx of white blood cells and subsequent tissue destruction associated with 3O-C12-HSL dermal injections. Therefore, the quorum-sensing systems of P. aeruginosa contribute to its pathogenesis both by regulating expression of virulence factors (exoenzymes and toxins) and by inducing inflammation.
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PMID:The Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)homoserine lactone contributes to virulence and induces inflammation in vivo. 1180 74

Burkholderia multivorans ATCC 17616 ordinarily produces insufficient amounts of N-acyl homoserine lactones (AHLs) to promote AHL-dependent formation of the pigment violacein by the reporter strain Chromobacterium violaceum CV026. We have isolated AHL-overproducing mutants of strain 17616 by screening for variants which do cross-feed AHLs to strain CV026. Nucleotide-sequence analysis of the bmuIR locus which specifies AHL synthase (BmuI) and AHL-binding transcriptional activator protein (BmuR) indicated that the increased capacity to produce AHLs was not a consequence of changes upstream or internal to the bmuI or bmuR genes. We conclude that the mutations leading to AHL overproduction lie outside the bmuI/bmuR locus.
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PMID:Characterization of N-acyl homoserine lactone overproducing mutants of Burkholderia multivorans ATCC 17616. 1181 64

The quorum sensing mechanism in Gram-negative bacteria uses small intercellular signal molecules, N-acyl-homoserine lactones (AHLs), to control transcription of specific genes in relation to population density. In this communication, we describe the parallel synthesis of new AHL analogues, in which substituents have been introduced into the 3- and 4-positions of the lactone ring. These analogues have been screened for their ability to activate and inhibit a Vibrio fischeri LuxI/LuxR-derived quorum sensing reporter system.
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PMID:Synthesis of new 3- and 4-substituted analogues of acyl homoserine lactone quorum sensing autoinducers. 1181 88

Individuals with cystic fibrosis (CF) are commonly colonized with Pseudomonas aeruginosa. The chronic infections caused by P. aeruginosa are punctuated by acute exacerbations of the lung disease, which lead to significant morbidity and mortality. As regulators of virulence determinants, P. aeruginosa quorum-sensing systems may be active in the chronic lung infections associated with CF. We have examined the levels of autoinducer molecules and transcript accumulation from the bacterial populations found in the lungs of patients with CF. We detected biologically active levels of N-(3-oxododecanoyl)-L-homoserine (3-oxo-C12-HSL) and N-butyryl-L-homoserine lactone (C4-HSL) in sputum from CF patients. Interestingly, it appears that C4-HSL is less frequently detected than 3-oxo-C12-HSL in the lungs of patients with CF. We also examined the transcription of the autoinducer synthase gene lasI and showed that it is frequently expressed in the lungs of patients with CF. We observed a significant correlation between the expression of lasI and four target genes of the Las quorum-sensing system. Taken together, our results indicate that quorum-sensing systems are active and may control virulence factor expression in the lungs of patients with CF.
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PMID:Pseudomonas aeruginosa quorum-sensing systems may control virulence factor expression in the lungs of patients with cystic fibrosis. 1189 39


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