The presence of palmitate in a minor fraction of lipid A has been known since the chemical structure of lipid A was first elucidated, but the functional importance in bacterial pathogenesis of regulated lipid A palmitoylation has become clear only recently. A palmitate chain from a phospholipid is incorporated into lipid A by an outer membrane enzyme PagP. The isolation of pagP mutants from pathogenic Gram-negative bacteria has revealed that palmitoylated lipid A can both protect the bacterium from certain host immune defenses and attenuate the ability of lipid A to activate those same defenses through the TLR4 signal transduction pathway. The mechanisms by which bacteria regulate the incorporation of palmitate into lipid A strikingly reflect the corresponding organism's pathogenic lifestyle. Variations on these themes can be illustrated with the known pagP homologs from Gram-negative bacteria, which include pathogens of humans and other mammals in addition to pathogens of insects and plants. The PagP enzyme is now lending itself both as a target for the development of anti-infective agents, and as a tool for the synthesis of lipid A-based vaccine adjuvants and endotoxin antagonists.
Raetz CR, Whitfield C.Lipopolysaccharide endotoxins. Annu Rev Biochem2002; 71: 635—700.
2.
Loppnow H., Brade L., Brade H. et al. Induction of human interleukin 1 by bacterial and synthetic lipid A. Eur J Immunol1986; 16: 1263—1267.
3.
Feist W., Ulmer AJ, Musehold J. et al. Induction of tumor necrosis factor-alpha release by lipopolysaccharide and defined lipopolysaccharide partial structures. Immunobiology1989; 179: 293—307.
4.
Tanamoto K., Azumi S.Salmonella-type heptaacylated lipid A is inactive and acts as an antagonist of lipopolysaccharide action on human line cells. J Immunol2000; 164: 3149—3156.
5.
Muroi M., Ohnishi T., Tanamoto K.MD-2, a novel accessory molecule, is involved in species-specific actions of Salmonella lipid A. Infect Immun2002; 70: 3546—3550.
6.
Janusch H., Brecker L., Lindner B. et al. Structural and biological characterization of highly purified hepta-acyl lipid A present in the lipopolysaccharide of the Salmonella enterica sv. Minnesota Re deep rough mutant strain R595. J Endotoxin Res2002; 8: 343—356.
7.
Kawasaki K., Ernst RK, Miller SI3-O-Deacylation of lipid A by PagL, a PhoP/PhoQ-regulated deacylase of Salmonella typhimurium, modulates signaling through Toll-like receptor 4. J Biol Chem2004; 279: 20044—20048.
8.
Bishop RE, Gibbons HS, Guina T. et al. Transfer of palmitate from phospholipids to lipid A in outer membranes of Gram-negative bacteria. EMBO J2000; 19: 5071—5080.
9.
Hwang PM, Choy WY, Lo EI et al. Solution structure and dynamics of the outer membrane enzyme PagP by NMR. Proc Natl Acad Sci USA2002; 99: 13560—13565.
10.
Ahn VE, Lo EI, Engel CK et al. A hydrocarbon ruler measures palmitate in the enzymatic acylation of endotoxin. EMBO J2004; 23: 2931—2941.
11.
Hwang PM, Bishop RE, Kay LEThe integral membrane enzyme PagP alternates between two dynamically distinct states. Proc Natl Acad Sci USA2004; 101: 9618—9623.
12.
Jia W., El Zoeiby A., Petruzziello TN et al. Lipid trafficking controls endotoxin acylation in outer membranes of Escherichia coli. J Biol Chem2004; 279: 44966—44975.
13.
Guo L., Lim KB, Poduje CM et al. Lipid A acylation and bacterial resistance against vertebrate antimicrobial peptides. Cell1998; 95: 189—198.
14.
Guina T., Yi EC, Wang H. et al. A PhoP-regulated outer membrane protease of Salmonella enterica serovar typhimurium promotes resistance to alpha-helical antimicrobial peptides . J Bacteriol2000; 182: 4077—4086.
15.
Hancock RE, Falla T., Brown M.Cationic bactericidal peptides. Adv MicrobPhysiol1995; 37: 135—175.
16.
Guo L., Lim KB, Gunn JS et al. Regulation of lipid A modifications by Salmonella typhimurium virulence genes phoP-phoQ. Science1997; 276: 250—253.
17.
Garcia-Vescovi E., Soncini FC, Groisman EAMg2+ as an extracellular signal: environmental regulation of Salmonella virulence. Cell1996 ; 84: 165—174.
18.
Forbes JR, Gros P.Divalent-metal transport by NRAMP proteins at the interface of host-pathogen interactions. Trends Microbiol2001; 9: 397—403.
19.
Belden WJ, Miller SIFurther characterization of the PhoP regulon: identification of new PhoP-activated virulence loci. Infect Immun1994; 62: 5095—5101.
20.
Gibbons HS, Kalb SR, Cotter RJ, Raetz CRRole of Mg2+ and pH in the modification of Salmonella lipid A after endocytosis by macrophage tumour cells. Mol Microbiol2005; 55: 425—440.
21.
Robey M., O'Connell W., Cianciotto NPIdentification of Legionella pneumophila rcp, a pagP-like gene that confers resistance to cationic antimicrobial peptides and promotes intracellular infection . Infect Immun2001; 69: 4276—4286.
22.
Zahringer U. , Knirel YA, Lindner B. et al. The lipopolysaccharide of Legionella pneumophila serogroup 1 (strain Philadelphia 1): chemical structure and biological significance. Prog Clin Biol Res1995; 392: 113—139.
23.
Preston A., Maxim E., Toland E. et al. Bordetella bronchiseptica PagP is a Bvg-regulated lipid A palmitoyl transferase that is required for persistent colonization of the mouse respiratory tract. Mol Microbiol2003; 48: 725—736.
24.
Pilione MR, Pishko EJ, Preston A. et al. pagP is required for resistance to antibody-mediated complement lysis during Bordetella bronchiseptica respiratory infection. Infect Immun2004; 72: 2837—2842.
25.
Preston A., Parkhill J., Maskell DJThe bordetellae: lessons from genomics. Nat Rev Microbiol2004; 2: 379—390.
26.
Chain PS, Carniel E., Larimer FW et al. Insights into the evolution of Yersinia pestis through whole-genome comparison with Yersinia pseudotuberculosis. Proc Natl Acad Sci USA2004; 101: 13826—13831.
27.
Rebeil R., Ernst RK, Gowen BB et al. Variation in lipid A structure in the pathogenic yersiniae. Mol Microbiol2004; 52: 1363—1373.
28.
Wren BWThe yersiniae — a model genus to study the rapid evolution of bacterial pathogens. Nat Rev Microbiol2003; 1: 55—64.
29.
Alba BM, Gross CARegulation of the Escherichia coli sigma E-dependent envelope stress response . Mol Microbiol2004; 52: 613—619.
30.
Tam C., Missiakas D.Changes in lipopolysaccharide structure induce the sigma E-dependent response of Escherichia coli. Mol Microbiol2005; In press.
31.
Fukuoka S., Brandenburg K., Muller M., Lindner B., Koch MH, Seydel U.Physico-chemical analysis of lipid A fractions of lipopolysaccharide from Erwinia carotovora in relation to bioactivity. Biochim Biophys Acta2001; 1510: 185—197.
32.
Derzelle S. , Turlin E., Duchaud E. et al. The PhoP-PhoQ two-component regulatory system of Photorhabdus luminescens is essential for virulence in insects. J Bacteriol2004; 186: 1270—1279.
33.
Eguchi Y., Okada T., Minagawa S. et al. Signal transduction cascade between EvgA/EvgS and PhoP/PhoQ two-component systems of Escherichia coli. J Bacteriol2004; 186: 3006—3014.
34.
Winfield MD , Groisman EAPhenotypic differences between Salmonella and Escherichia coli resulting from disparate regulation of homologous genes . Proc Natl Acad Sci USA2004; 101: 17162—17167.
35.
Ernst RK, Yi EC, Guo L. et al. Specific lipopolysaccharide found in cystic fibrosis airway Pseudomonas aeruginosa. Science1999; 286: 1561—1565.
36.
Stover CK, Pham XQ, Erwin AL et al. Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature2000; 406: 959—964.
37.
Hawkins LD, Christ WJ, Rossignol DPInhibition of endotoxin response by synthetic TLR4 antagonists. Curr Top Med Chem2004; 4: 1147—1171.
38.
Persing DH, Coler RN, Lacy MJ et al. Taking toll: lipid A mimetics as adjuvants and immunomodulators . Trends Microbiol2002; 10: S32—S37.
39.
Stöver AG, Da Silva Correia J., Evans JT et al. Structure—activity relationship of synthetic Toll-like receptor 4 agonists. J Biol Chem2004; 279: 4440—4449.
40.
Tefsen B., Geurtsen J., Beckers F. et al. Lipopolysaccharide transport to the bacterial outer membrane in spheroplasts. J Biol Chem2005; 280: 4504—4509.
41.
Bishop RE, Lo EI, Khan MA et al. Enzymology of lipid A palmitoylation in bacterial outer membranes . J Endotoxin Res2004; 10: 107—112.
42.
Nielsen H., Engelbrecht J., Brunak S. et al. Identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Protein Eng1997; 10, 1—6.
