Making 'sense' of metabolism: autoinducer-2, LUXS and pathogenic bacteria

Abstract

Bacteria can act in a concerted manner by coordinating the gene expression of populations above a certain cell density through the production and sensing of small diffusible signalling molecules called autoinducers, in a process referred to as quorum sensing. LuxS produces the precursor of autoinducer-2 (AI-2), 4,5,-dihydroxy-2,3-pentanedione (DPD), whilst converting S-ribosylhomocysteine to homocysteine. These and subsequent chemical transformations plus molecular mechanisms of this reaction are described in this review. The realization that more than one active chemical structure ((2R,4S)-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran, 3A-methyl-5,6-dihydro-furo(2,3-D)(1,3,2)dioxaborole-2,2,6,6A-tetraol, and 4-hydroxy-5-methyl-3(2H)-furanone names) can result from cyclization of DPD has led to the use of AI-2 as a collective term. Many bacteria use LuxS and the enzyme Pfs to close the activated methyl cycle that is necessary to recycle the metabolite methionine, whilst others achieve this in a single step, using the enzyme S-adenosylhomocysteine hydrolase. The distribution of these alternative pathways is presented, and correlated with phylogeny. Two pathways responding to AI-2 have been described, one in Vibrio spp. involving two component signal regulators, and one in Salmonella enterica serovar Typhimurium, using an ABC transporter. These are described alongside their possible evolutionary origins and alternative functions. Many pathogens inhabiting different niches possess LuxS. The phenotypic effects of LuxS/AI-2 are discussed in relation to the disparate environments of their hosts (oral cavity, gastrointestinal tract, bloodstream, blood–brain barrier, cutaneous and soft tissue), and correlated with current knowledge to deduce their influence on pathogenesis. Throughout the review, reference is made to the likely contribution of LuxS to either quorum sensing or central metabolism as the basis of observed phenotypic changes.