Different bacteria respond to AI-2 in different ways. Some, notablyVibrio sp., detect the presence of AI-2 using specific two component signal transduction to initiate a phospho-relay [17–19]. Others, likeSalmonellaandEscherichia colipossess ABC transporter proteins which import and modify AI-2 [16,20–22]. In each of these scenarios, the precise chemical nature of AI-2 appears to differ since the binding protein components have been shown to interact with different, but structurally related molecules. The LuxP AI-2 binding protein ofV. harveyiwas co-crystallized with a furanosyl-borate diester (3A-methyl-5,6-dihydro-furo(2,3-D)(1,3,2)dioxaborole-2,2,6,6A-tetraol;S-THMF-borate) find more [23], whilst LsrB ofS. entericiaserovar

Typhimurium was found in complex with (2R, 4S)-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran (BIIB057 solubility dmso R-THMF) [24]. Other cyclisation derivatives of DPD such as 4-hydroxy-5-methyl-3(2H)-furanone (MHF) or a furanosyl carbonate

diester [25] have also been shown to possess AI-2 activity [14,26]. The LuxS enzyme is an established part of the activated methyl cycle (AMC) that KU55933 price generatesS-adenosyl-L-methionine (SAM) the methyl donor for methylation of RNA, DNA, proteins and certain metabolites. In this cycle, SAM is first converted toS-adenosyl-L-homocysteine (SAH) which is then detoxified by the Pfs enzyme to generate adenine andS-ribosyl-L-homocyteine (SRH), the substrate of the LuxS enzyme. In the conversion of SRH to homocysteine, DPD is produced as a byproduct and derivatives of this with AI-2 activity are found in culture supernatants [14,26]. The homocysteine moiety is then converted to methionine and subsequently, SAM. Using AI-2 induced bioluminescence ofV. harveyias a reporter system, numerous species of bacteria have been shown to produce AI-2 activity includingHelicobacter pylori[27],E. coli and Salmonella Vildagliptin entericaserovar Typhimurium [22,28,29],Neisseria meningitidis[30–32],Haemophilus influenza[33]Clostridium difficile[34] andC. jejuni[35]. Many of the AI-2 producing bacteria studied are pathogens, and currently numerous reports concluding that LuxS and AI-2 contribute to novel signalling systems

exist, although critical evaluation of this data suggests that further studies are required to verify these observations [10,26,36–38]. The potential importance of LuxS in recycling intermediates in the activated methyl cycle via the conversion of SRH to homocysteine and then methionine should not be overlooked. Indeed the disruption ofluxSitself could decrease the virulence of a pathogen through metabolic perturbations without any involvement of AI-2 in cell-to-cell signalling. Support for this hypothesis comes from two recent studies inNeisseria meningitidiswhere evidence for a proteomic or transcriptional response to AI-2 was lacking [31,32], but the mutant was significantly attenuatedin vivo[30,39]. Discrimination between the two roles of LuxS/AI-2 is somewhat hazardous.