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Escherichia coli K-12 substr. MG1655 Pathway: autoinducer AI-2 biosynthesis I
Inferred from experiment

Pathway diagram: autoinducer AI-2 biosynthesis I

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Locations of Mapped Genes:

Schematic showing all replicons, marked with selected genes

Genetic Regulation Schematic

Genetic regulation schematic for autoinducer AI-2 biosynthesis I

Superclasses: BiosynthesisSecondary Metabolites BiosynthesisAutoinducer Biosynthesis

General Background

Cell-to-cell communication in bacteria is accomplished through the exchange of extracellular signaling molecules called autoinducers. This process, termed quorum sensing, allows bacterial populations to coordinate gene expression as a function of cell density. Many processes benefit from community cooperation, including bioluminescence, virulence factor expression, antibiotic production and biofilm development.

Cell to cell signaling through quorum sensing in bacteria occurs through three main processes LuxR-LuxI, LuxS/AI-2, and AI-3/epinephrine/norepinephrine. The LuxR-LuxI process controls signaling through autoinducer 1 (AI-1) which is an N-acyl-homoserine lactone (AHL). It was first described in Vibrio fischeri as a regulator of bioluminescence. However Escherichia coli and Salmonella typhimurium lack LuxI and do not synthesize AHLs, although the product of gene sdiA recognizes AHLs from other bacterial species. The LuxS/AI-2 process controls both intraspecies and interspecies signaling. It was first described as an extracellular signal produced by the marine bacterium Vibrio harveyi to control luciferase expression [Bassler94, Surette99]. In E. coli and Salmonella typhimurium AI-2 activates transcription of the lsr operon encoding an ABC transporter, the LsrB subunit of which binds AI-2 (see autoinducer-2 ABC transporter). The AI-3/epinephrine/norepinephrine process involves recognition by gut commensals of autoinducer produced by self, other bacteria, or human hormones. In E. coli AI-3 interacts with a membrane-bound protein QseC which is part of the QseB-QseC two component system.

AI-2 production depends upon growth conditions. Factors include nutrients, pH, osmolarity, oxygen, growth rate and stress factors. However, its exact role in cell signaling is still controversial and there is evidence that its function may be metabolic [Gonzalez06a, Herzberg06, Wang05b]. A role for AI-2 in pathogenesis also remains to be established although transcriptomics studies have suggested that AI-2 may have a role in the regulation of virulence in enterohemorrhagic E. coli [Bansal08]. The E. coli AI-2 network has also been the subject of different modeling approaches [Gonzalez10, Li06a].

Review: Kendall, M.M. and V. Sperandio (2009) "Cell-to-Cell Signaling in Escherichia coli and Salmonella." EcoSal 5.5 [ECOSAL]

Reviews: [Turovskiy07, Walters06, De06, Vendeville05, Kaper05]

About This Pathway

One of the main bacterial autoinducers is autoinducer 2 (AI-2) which mediates the quorum sensing 2 (QS-2) system. Its biosynthesis is catalyzed by the LuxS enzyme which also participates in the SAM cycle (see S-adenosyl-L-methionine cycle I). The LuxS enzyme is found in many bacteria including E. coli and Salmonella typhimurium. Its role in AI-2 biosynthesis is suggested by the presence of the Lsr ABC transporter, the LsrB protein of which serves as the AI-2 receptor in many of these organisms [Rezzonico08] (see autoinducer-2 ABC transporter).

The precursor of AI-2 is synthesized by the enzyme S-ribosylhomocysteine lyase, which also catalyzes a step in the SAM cycle. The enzyme converts S-ribosyl-L-homocysteine to L-homocysteine and 4,5-dihydroxy-2,3-pentanedione. Within the SAM cycle, the main product of the enzyme is L-homocysteine. In AI-2 biosynthesis 4,5-dihydroxy-2,3-pentanedione is of major importance as it appears to be nonenzymatically converted in a series of chemical modifications to the mature autoinducer.

The exact nature of the chemical transformations depends on the species. In E. coli and most pathogenic bacteria that form AI-2 the spontaneous transformations include cyclization to (2R,4S)-2-methyl-2,4-dihydroxydihydrofuran-3-one and hydration to the final autoinducer (2R,4S)-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran. This form of the autoinducer, which was first characterized from Salmonella typhimurium, was shown to be different from the form that was initially described from Vibrio harveyi (see below) and is recognized by the LsrB periplasmic binding protein [Miller04a].

Members of the order Vibrionales produce a different form of the autoinducer. In those organisms, 4,5-dihydroxy-2,3-pentanedione appears to form a different stereoisomer, namely (2S,4S)-2-methyl-2,4-dihydroxydihydrofuran-3-one, which hydrates to (2S,4S)-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran and forms a complex with a borate ion to form (2S,4S)-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran-borate [Chen02b, Rezzonico08], (see MetaCyc pathway autoinducer AI-2 biosynthesis II (Vibrio)). The mechanism that controls which stereoisomer is formed is still not understood.

Created 09-Mar-2009 by Caspi R, SRI International
Last-Curated 04-May-2011 by Fulcher C, SRI International


Bansal08: Bansal T, Jesudhasan P, Pillai S, Wood TK, Jayaraman A (2008). "Temporal regulation of enterohemorrhagic Escherichia coli virulence mediated by autoinducer-2." Appl Microbiol Biotechnol 78(5);811-9. PMID: 18256823

Bassler94: Bassler BL, Wright M, Silverman MR (1994). "Multiple signalling systems controlling expression of luminescence in Vibrio harveyi: sequence and function of genes encoding a second sensory pathway." Mol Microbiol 13(2);273-86. PMID: 7984107

Chen02b: Chen X, Schauder S, Potier N, Van Dorsselaer A, Pelczer I, Bassler BL, Hughson FM (2002). "Structural identification of a bacterial quorum-sensing signal containing boron." Nature 415(6871);545-9. PMID: 11823863

De06: De Keersmaecker SC, Sonck K, Vanderleyden J (2006). "Let LuxS speak up in AI-2 signaling." Trends Microbiol 14(3);114-9. PMID: 16459080

ECOSAL: "Escherichia coli and Salmonella: Cellular and Molecular Biology." Online edition.

Gonzalez06a: Gonzalez Barrios AF, Zuo R, Hashimoto Y, Yang L, Bentley WE, Wood TK (2006). "Autoinducer 2 Controls Biofilm Formation in Escherichia coli through a Novel Motility Quorum-Sensing Regulator (MqsR, B3022)." J Bacteriol 188(1);305-16. PMID: 16352847

Gonzalez10: Gonzalez Barrios AF, Achenie LE (2010). "Escherichia coli autoinducer-2 uptake network does not display hysteretic behavior but AI-2 synthesis rate controls transient bifurcation." Biosystems 99(1);17-26. PMID: 19695305

Herzberg06: Herzberg M, Kaye IK, Peti W, Wood TK (2006). "YdgG (TqsA) controls biofilm formation in Escherichia coli K-12 through autoinducer 2 transport." J Bacteriol 188(2);587-98. PMID: 16385049

Kaper05: Kaper JB, Sperandio V (2005). "Bacterial cell-to-cell signaling in the gastrointestinal tract." Infect Immun 73(6);3197-209. PMID: 15908344

Li06a: Li J, Wang L, Hashimoto Y, Tsao CY, Wood TK, Valdes JJ, Zafiriou E, Bentley WE (2006). "A stochastic model of Escherichia coli AI-2 quorum signal circuit reveals alternative synthesis pathways." Mol Syst Biol 2;67. PMID: 17170762

Miller04a: Miller ST, Xavier KB, Campagna SR, Taga ME, Semmelhack MF, Bassler BL, Hughson FM (2004). "Salmonella typhimurium recognizes a chemically distinct form of the bacterial quorum-sensing signal AI-2." Mol Cell 15(5);677-87. PMID: 15350213

Rezzonico08: Rezzonico F, Duffy B (2008). "Lack of genomic evidence of AI-2 receptors suggests a non-quorum sensing role for luxS in most bacteria." BMC Microbiol 8;154. PMID: 18803868

Schauder01: Schauder S, Shokat K, Surette MG, Bassler BL (2001). "The LuxS family of bacterial autoinducers: biosynthesis of a novel quorum-sensing signal molecule." Mol Microbiol 41(2);463-76. PMID: 11489131

Surette99: Surette MG, Miller MB, Bassler BL (1999). "Quorum sensing in Escherichia coli, Salmonella typhimurium, and Vibrio harveyi: a new family of genes responsible for autoinducer production." Proc Natl Acad Sci U S A 96(4);1639-44. PMID: 9990077

Turovskiy07: Turovskiy Y, Kashtanov D, Paskhover B, Chikindas ML (2007). "Quorum sensing: fact, fiction, and everything in between." Adv Appl Microbiol 62;191-234. PMID: 17869606

Vendeville05: Vendeville A, Winzer K, Heurlier K, Tang CM, Hardie KR (2005). "Making 'sense' of metabolism: autoinducer-2, LuxS and pathogenic bacteria." Nat Rev Microbiol 3(5);383-96. PMID: 15864263

Walters06: Walters M, Sperandio V (2006). "Quorum sensing in Escherichia coli and Salmonella." Int J Med Microbiol 296(2-3);125-31. PMID: 16487745

Wang05b: Wang L, Li J, March JC, Valdes JJ, Bentley WE (2005). "luxS-dependent gene regulation in Escherichia coli K-12 revealed by genomic expression profiling." J Bacteriol 187(24);8350-60. PMID: 16321939

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Allart98: Allart B, Gatel M, Guillerm D, Guillerm G (1998). "The catalytic mechanism of adenosylhomocysteine/methylthioadenosine nucleosidase from Escherichia coli--chemical evidence for a transition state with a substantial oxocarbenium character." Eur J Biochem 256(1);155-62. PMID: 9746359

BRENDA14: BRENDA team (2014). Imported from BRENDA version existing on Aug 2014.

Brito13: Brito PH, Rocha EP, Xavier KB, Gordo I (2013). "Natural genome diversity of AI-2 quorum sensing in Escherichia coli: conserved signal production but labile signal reception." Genome Biol Evol 5(1);16-30. PMID: 23246794

ChoiRhee05: Choi-Rhee E, Cronan JE (2005). "A nucleosidase required for in vivo function of the S-adenosyl-L-methionine radical enzyme, biotin synthase." Chem Biol 12(5);589-93. PMID: 15911379

Clinch12: Clinch K, Evans GB, Frohlich RF, Gulab SA, Gutierrez JA, Mason JM, Schramm VL, Tyler PC, Woolhouse AD (2012). "Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics." Bioorg Med Chem 20(17);5181-7. PMID: 22854195

Cornell96: Cornell KA, Swarts WE, Barry RD, Riscoe MK (1996). "Characterization of recombinant Eschericha coli 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase: analysis of enzymatic activity and substrate specificity." Biochem Biophys Res Commun 228(3);724-32. PMID: 8941345

Cornell98: Cornell KA, Riscoe MK (1998). "Cloning and expression of Escherichia coli 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase: identification of the pfs gene product." Biochim Biophys Acta 1396(1);8-14. PMID: 9524204

De09: De Lay N, Gottesman S (2009). "The Crp-activated small noncoding regulatory RNA CyaR (RyeE) links nutritional status to group behavior." J Bacteriol 191(2);461-76. PMID: 18978044

DeLisa01a: DeLisa MP, Wu CF, Wang L, Valdes JJ, Bentley WE (2001). "DNA microarray-based identification of genes controlled by autoinducer 2-stimulated quorum sensing in Escherichia coli." J Bacteriol 183(18);5239-47. PMID: 11514505

Della85: Della Ragione F, Porcelli M, Carteni-Farina M, Zappia V, Pegg AE (1985). "Escherichia coli S-adenosylhomocysteine/5'-methylthioadenosine nucleosidase. Purification, substrate specificity and mechanism of action." Biochem J 232(2);335-41. PMID: 3911944

DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114

Farrar10: Farrar CE, Siu KK, Howell PL, Jarrett JT (2010). "Biotin synthase exhibits burst kinetics and multiple turnovers in the absence of inhibition by products and product-related biomolecules." Biochemistry 49(46);9985-96. PMID: 20961145

Ferro76: Ferro AJ, Barrett A, Shapiro SK (1976). "Kinetic properties and the effect of substrate analogues on 5'-methylthioadenosine nucleosidase from Escherichia coli." Biochim Biophys Acta 438(2);487-94. PMID: 782530

GOA01: GOA, MGI (2001). "Gene Ontology annotation based on Enzyme Commission mapping." Genomics 74;121-128.

GOA01a: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

GOA06: GOA, SIB (2006). "Electronic Gene Ontology annotations created by transferring manual GO annotations between orthologous microbial proteins."

Gopishetty09: Gopishetty B, Zhu J, Rajan R, Sobczak AJ, Wnuk SF, Bell CE, Pei D (2009). "Probing the catalytic mechanism of S-ribosylhomocysteinase (LuxS) with catalytic intermediates and substrate analogues." J Am Chem Soc 131(3);1243-50. PMID: 19099445

GrilloPuertas12: Grillo-Puertas M, Villegas JM, Rintoul MR, Rapisarda VA (2012). "Polyphosphate degradation in stationary phase triggers biofilm formation via LuxS quorum sensing system in Escherichia coli." PLoS One 7(11);e50368. PMID: 23226268

Gutierrez09: Gutierrez JA, Crowder T, Rinaldo-Matthis A, Ho MC, Almo SC, Schramm VL (2009). "Transition state analogs of 5'-methylthioadenosine nucleosidase disrupt quorum sensing." Nat Chem Biol 5(4):251-7. PMID: 19270684

Halliday10: Halliday NM, Hardie KR, Williams P, Winzer K, Barrett DA (2010). "Quantitative liquid chromatography-tandem mass spectrometry profiling of activated methyl cycle metabolites involved in LuxS-dependent quorum sensing in Escherichia coli." Anal Biochem 403(1-2);20-9. PMID: 20417170

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Please cite the following article in publications resulting from the use of EcoCyc: Nucleic Acids Research 41:D605-12 2013
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