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

Enterohaemorrhagic Escherichia coli O157:H7 causes a characteristic histopathology in intestinal cells known as attaching and effacing lesion. The genes for the lesion are encoded by the Locus of Enterocyte Effacement (LEE) pathogenicity island, that encodes a type III secretion system, the intimin intestinal colonization factor, and the translocated intimin receptor protein that is translocated from the bacterium to the host epithelial cells. Expression of the operons encoded within LEE is complex, but recent studies have demonstrated that quorum sensing influences transcription from four of the LEE operon promoters. A transcriptional regulator (LuxR homologue), signal synthase (LuxI homologue), and autoinducer (acylhomoserine lactone) are indispensable for this system in most gram-negative bacteria. Vibrio harveyi, a gram-negative bioluminescent marine bacterium, regulates light production in response to two autoinducers (AI-1 and AI-2). AI-1 is a homoserine lactone produced by most gram-negative bacteria. The structure of AI-2 is not known, but many species of gram positive and gram-negative bacteria, including E. coli and more specifically O157:H7, have been shown to produce AI-2 depending on the function encoded by the luxS gene. The LuxS acts as an AI-2 synthase and the AI-2 is produced from S-adenosylmethionine in three enzymatic steps. The substrate for LuxS is S-ribosylhomocysteine, which is cleaved to form two products, one of which is homocysteine, and the other is AI-2. The biosynthetic pathways and the biochemical intermediates in AI-2 biosynthesis have been observed to be identical in several gram-negative bacteria, such as E. coli, Salmonella typhimurium, V. harveyi, Vibrio cholerae, and Enterococcus faecalis. Thus, unlike quorum sensing via the family of related homoserine autoinducers, AI-2 is a universal signal, which may be used by a variety of bacteria for communication among and between species and may be responsible for regulation of virulence genes in E. coli O157:H7.
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PMID:Quorum sensing and expression of virulence in Escherichia coli O157:H7. 1281 Feb 66

The RhlR quorum sensing (QS) receptor in the pathogen Pseudomonas aeruginosa plays a prominent role in infection, and both antagonism and agonism of RhlR have been shown to negatively regulate important virulence phenotypes. Non-native lactone ligands are known to modulate RhlR activity, but their utility as chemical probes is relatively limited due to hydrolytic instability. Herein, we report our design and biological evaluation of a suite of hybrid AHL analogs with structures merging (1) features of reported lead RhlR ligands and (2) head groups with improved hydrolytic stabilities. The most promising compounds identified were N-acyl l-homocysteine thiolactones, which displayed enhanced stabilities relative to lactones. Moreover, they were highly selective for RhlR over another key QS receptor in P. aeruginosa, LasR. These compounds are among the most potent RhlR modulators known and represent robust chemical tools to dissect the complex roles of RhlR in the P. aeruginosa QS circuitry.
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PMID:N-Acyl l-Homocysteine Thiolactones Are Potent and Stable Synthetic Modulators of the RhlR Quorum Sensing Receptor in Pseudomonas aeruginosa. 3239 93

Virulence in the Gram-negative pathogen Pseudomonas aeruginosa relies in part on the efficient functioning of two LuxI/R dependent quorum sensing (QS) cascades, namely, the LasI/R and RhlI/R systems that generate and respond to N-(3-oxo)-dodecanoyl-l-homoserine lactone and N-butyryl-l-homoserine lactone, respectively. The two acyl homoserine lactone (AHL) synthases, LasI and RhlI, use 3-oxododecanoyl-ACP and butyryl-ACP, respectively, as the acyl-substrates to generate the corresponding autoinducer signals for the bacterium. Although AHL synthases represent excellent targets for developing QS modulators in P. aeruginosa, and in other related bacteria, the identification of potent and signal synthase specific inhibitors has represented a significant technical challenge. In the current study, we sought to test the utility of AHL analogs as potential modulators of an AHL synthase and selected RhlI in P. aeruginosa as an initial target. We systematically varied the chemical functionalities of the AHL headgroup, acyl chain tail, and head-to-tail linkage to construct a small library of signal analogs and evaluated them for RhlI modulatory activity. Although the native N-butyryl-l-homoserine lactone did not inhibit RhlI, we discovered that several of our long-chain, unsubstituted acyl-d-homoserine lactones and acyl-d-homocysteine thiolactones inhibited while a few of the 3-oxoacyl-chain counterparts activated the enzyme. Additional mechanistic investigations with acyl-substrate analogs and docking experiments with AHL analogs revealed two distinct inhibitor and activator binding pockets in the enzyme. This study provides the first evidence of the yet untapped potential of AHL analogs as signal synthase modulators of QS pathways.
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PMID:N-Acyl Homoserine Lactone Analog Modulators of the Pseudomonas aeruginosa Rhll Quorum Sensing Signal Synthase. 3154 95