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Chemical Compound Review

AC1L18U1     [5-hydroxy-6-(hydroxymethyl)- 3-(3...

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Disease relevance of lipid X

  • In our work, this is best illustrated by the analysis of phosphatidylglycerol-deficient mutants of E. coli, which provided the clue (i.e. lipid X) that permitted the elucidation of lipid A biosynthesis [1].
  • Lipid X appears to have a novel mechanism of inhibiting LPS effect and may have efficacy in the treatment of gram-negative sepsis [2].
  • This inhibition was not due to cellular toxicity, the phospholipidlike nature of lipid X, interference with the PAI-2 assay, or monocyte production of a substance interfering with PAI-2 [3].
  • Lipid A synthase from Salmonella accepts not only lipid X but also the synthetic di-N-acyl-2,3-diamino-D-glucose analogue as substrate (Raetz, C.R.H., unpublished results) [4].
  • LBP was found to bind to a variety of LPS types from both rough and smooth strains of Gram-negative bacteria, to lipid A, and to the tetraacyl glucosamine disaccharide diphosphate precursor IVA, but bound very poorly to the diacyl glucosamine phosphate, lipid X [5].

Psychiatry related information on lipid X

  • Intracerebroventricular, but not intravenous, injections of lipid X induced small but significant increases in both slow-wave sleep and rapid-eye-movement sleep without affecting delta amplitudes or brain-colonic temperatures [6].

High impact information on lipid X

  • In contrast, MPLA, lipid X, and deacylated LPS failed to inhibit LPS-stimulated release of TNF [7].
  • Although lipid X inhibited thrombin-induced phosphorylation of P47 it did not suppress secretion of [14C]serotonin, indicating the role of protein kinase C-independent pathways in platelet stimulation by thrombin [8].
  • Inhibition of endotoxin-induced priming of human neutrophils by lipid X and 3-Aza-lipid X [2].
  • Although PagL is most likely active as a monomer, its active site architecture shows high resemblance to that of the dimeric 12-stranded outer membrane phospholipase A. Modeling of the substrate lipid X onto the active site reveals that the 3-O-acyl chain is accommodated in a hydrophobic groove perpendicular to the membrane plane [9].
  • If lipid X and lipid A induce by common mechanism(s) B-lymphocyte proliferation, then it follows from structural comparison that the reducing-end subunit of lipid A is the minimal structural requirement for this activity [10].

Chemical compound and disease context of lipid X

  • Previous studies from our laboratory have documented the presence in vivo of the precursors 2,3-diacylglucosamine 1-phosphate (2,3-diacyl-GlcN-1-P) (lipid X of E. coli) and UDP-2,3-diacylglucosamine (UDP-2,3-diacyl-GlcN) (Bulawa, C.E., and Raetz, C.R.H.J. Biol. Chem. 259, 4846-4851) [11].
  • Mitogenic and PBA activity of GLA-27 were stronger than those of lipid X, which corresponds to the reducing D-GlcN (GlcN-I) subunit of Escherichia coli lipid A and is a 1-O-phosphorylated GlcN derivative carrying N- and 3-O-linked C14OH groups [12].
  • The effects of lipid X and 3-aza-lipid X on in vitro neutrophil function were related to their ability to inhibit the toxicity of endotoxin in galactosamine-sensitized mice [13].
  • Pulmonary oxygen toxicity in rats: prevention by pyrogenic diphosphoryl lipid A and potentiation by nontoxic monophosphoryl lipid A and lipid X [14].

Biological context of lipid X

  • These results suggest that lipid X, a compound structurally related to lipid A, may block neutrophil priming by competing with LPS for cellular binding sites [2].
  • The lipid moieties of lipid X are heterogenous in that about 50% of headgroups remain bound to a lipid moiety after mild alkaline hydrolysis [15].
  • Elimination and tissue distribution of the monosaccharide lipid A precursor, lipid X, in mice and sheep [16].
  • The pharmacokinetics described here should greatly aid in the design and interpretation of animal studies investigating the therapeutic applications of lipid X in gram-negative septicemia [16].
  • However, like endotoxin, lipid X also produced a late phase (3-6 h later) of increased lung vascular permeability to fluid and protein as reflected by significant (P less than 0.05) increases in both lung-lymph flow and lung-lymph protein clearance in the presence of stable pulmonary vascular pressures at or below base-line levels [17].

Anatomical context of lipid X

  • Increasing concentrations of lipid X shifted the LPS dose response curve of neutrophils rightward but did not prevent maximum priming at higher LPS concentrations, a finding consistent with competitive inhibition [2].
  • We have examined the activity of lipid X (Mr = 711.9) and several related compounds as mitogens towards mouse lymphocytes [10].
  • Endotoxin-induced production of plasminogen activator inhibitor by human monocytes is autonomous and can be inhibited by lipid X [3].
  • Lipid X, on the other hand, was incapable of making macrophages hyporesponsive for TNF production [18].
  • A monosaccharide precursor of Escherichia coli lipid A, designated lipid X, which is a diacylglucosamine 1-phosphate with beta-hydroxymyristoyl groups at positions 2 and 3, was shown to have the ability to induce the production of tumor necrosis factor (TNF)-like tumor-cytotoxic factor by a murine macrophage-like cell line, J774 [19].

Associations of lipid X with other chemical compounds


Gene context of lipid X

  • Lipid X was an effective inhibitor of PAI-2 production even when added up to 30 minutes after LPS [3].
  • The monosaccharide lipid A precursor lipid X also blocked stimulation of neutrophils by LPS, although with a 100-fold reduction in potency [20].
  • Pretreatment of macrophages with IFN-gamma resulted in the release of higher amounts of TNF on subsequent induction with either LPS or lipid X [18].
  • These data suggest the involvement of a GTPase in LPS action, and indicate that lipid X may act to directly antagonize LPS at this level [24].
  • However, recent work shows that synthetic lipid X can be contaminated with small amounts of N,O-acylated disaccharide-1-phosphate (H. Aschauer, A. Grob, J. Hildebrandt, E. Schuetze, and P. Steutz, J. Biol. Chem. 265:9159-9164, 1990) [25].

Analytical, diagnostic and therapeutic context of lipid X


  1. Molecular genetics of membrane phospholipid synthesis. Raetz, C.R. Annu. Rev. Genet. (1986) [Pubmed]
  2. Inhibition of endotoxin-induced priming of human neutrophils by lipid X and 3-Aza-lipid X. Danner, R.L., Joiner, K.A., Parrillo, J.E. J. Clin. Invest. (1987) [Pubmed]
  3. Endotoxin-induced production of plasminogen activator inhibitor by human monocytes is autonomous and can be inhibited by lipid X. Schwartz, B.S., Monroe, M.C., Bradshaw, J.D. Blood (1989) [Pubmed]
  4. Different lipid A types in lipopolysaccharides of phototrophic and related non-phototrophic bacteria. Weckesser, J., Mayer, H. FEMS Microbiol. Rev. (1988) [Pubmed]
  5. Identification of a lipid A binding site in the acute phase reactant lipopolysaccharide binding protein. Tobias, P.S., Soldau, K., Ulevitch, R.J. J. Biol. Chem. (1989) [Pubmed]
  6. Somnogenic activities of synthetic lipid A. Cady, A.B., Kotani, S., Shiba, T., Kusumoto, S., Krueger, J.M. Infect. Immun. (1989) [Pubmed]
  7. Lipid IVA inhibits synthesis and release of tumor necrosis factor induced by lipopolysaccharide in human whole blood ex vivo. Kovach, N.L., Yee, E., Munford, R.S., Raetz, C.R., Harlan, J.M. J. Exp. Med. (1990) [Pubmed]
  8. Modulation of human platelet protein kinase C by endotoxic lipid A. Grabarek, J., Timmons, S., Hawiger, J. J. Clin. Invest. (1988) [Pubmed]
  9. Crystal structure and catalytic mechanism of the LPS 3-O-deacylase PagL from Pseudomonas aeruginosa. Rutten, L., Geurtsen, J., Lambert, W., Smolenaers, J.J., Bonvin, A.M., de Haan, A., van der Ley, P., Egmond, M.R., Gros, P., Tommassen, J. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. Molecular requirements for B-lymphocyte activation by Escherichia coli lipopolysaccharide. Raetz, C.R., Purcell, S., Takayama, K. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  11. The biosynthesis of gram-negative endotoxin. Formation of lipid A disaccharides from monosaccharide precursors in extracts of Escherichia coli. Ray, B.L., Painter, G., Raetz, C.R. J. Biol. Chem. (1984) [Pubmed]
  12. Structural requirements for inducing in vitro B lymphocyte activation by chemically synthesized derivatives related to the nonreducing D-glucosamine subunit of lipid A. Kumazawa, Y., Matsuura, M., Maruyama, T., Homma, J.Y., Kiso, M., Hasegawa, A. Eur. J. Immunol. (1986) [Pubmed]
  13. Protection of mice against lethal endotoxemia by lipid X is mediated through inhibition of neutrophil function. Lam, C., Schütze, E., Walzl, H., Basalka, E. Circ. Shock (1987) [Pubmed]
  14. Pulmonary oxygen toxicity in rats: prevention by pyrogenic diphosphoryl lipid A and potentiation by nontoxic monophosphoryl lipid A and lipid X. Smith, R.M. Res. Commun. Chem. Pathol. Pharmacol. (1988) [Pubmed]
  15. Characterization of glycophospholipid intermediate in the biosynthesis of glycophosphatidylinositol anchors accumulating in the Thy-1-negative lymphoma line SIA-b. Puoti, A., Desponds, C., Fankhauser, C., Conzelmann, A. J. Biol. Chem. (1991) [Pubmed]
  16. Elimination and tissue distribution of the monosaccharide lipid A precursor, lipid X, in mice and sheep. Golenbock, D.T., Ebert, S., Will, J.A., Proctor, R.A. Antimicrob. Agents Chemother. (1988) [Pubmed]
  17. Pulmonary pathophysiological changes in sheep caused by endotoxin precursor, lipid X. Burhop, K.E., Proctor, R.A., Helgerson, R.B., Raetz, C.H., Starling, J.R., Will, J.A. J. Appl. Physiol. (1985) [Pubmed]
  18. The production of tumor necrosis factor by mouse bone marrow-derived macrophages in response to bacterial lipopolysaccharide and a chemically synthesized monosaccharide precursor. Sayers, T.J., Macher, I., Chung, J., Kugler, E. J. Immunol. (1987) [Pubmed]
  19. A monosaccharide precursor of Escherichia coli lipid A has the ability to induce tumor-cytotoxic factor production by a murine macrophage-like cell line, J774.1. Amano, F., Nishijima, M., Akamatsu, Y. J. Immunol. (1986) [Pubmed]
  20. Lipopolysaccharide-induced stimulation of CD11b/CD18 expression on neutrophils. Evidence of specific receptor-based response and inhibition by lipid A-based antagonists. Lynn, W.A., Raetz, C.R., Qureshi, N., Golenbock, D.T. J. Immunol. (1991) [Pubmed]
  21. Regulation of the synthesis of the third component of complement and factor B in cord blood monocytes by lipopolysaccharide. Sutton, M.B., Strunk, R.C., Cole, F.S. J. Immunol. (1986) [Pubmed]
  22. CD14(+) cells are necessary for increased survival of eosinophils in response to lipopolysaccharide. Meerschaert, J., Busse, W.W., Bertics, P.J., Mosher, D.F. Am. J. Respir. Cell Mol. Biol. (2000) [Pubmed]
  23. Nature of glycosylphosphatidylinositols produced by mouse embryonic stem cells. Quinlan, L.R., Kane, M.T. Reproduction (2001) [Pubmed]
  24. Bacterial lipopolysaccharide-stimulated GTPase activity in RAW 264.7 macrophage membranes. Tanke, T., van de Loo, J.W., Rhim, H., Leventhal, P.S., Proctor, R.A., Bertics, P.J. Biochem. J. (1991) [Pubmed]
  25. Immunostimulatory, but not antiendotoxin, activity of lipid X is due to small amounts of contaminating N,O-acylated disaccharide-1-phosphate: in vitro and in vivo reevaluation of the biological activity of synthetic lipid X. Lam, C., Hildebrandt, J., Schütze, E., Rosenwirth, B., Proctor, R.A., Liehl, E., Stütz, P. Infect. Immun. (1991) [Pubmed]
  26. Lipid X protects mice against fatal Escherichia coli infection. Golenbock, D.T., Leggett, J.E., Rasmussen, P., Craig, W.A., Raetz, C.R., Proctor, R.A. Infect. Immun. (1988) [Pubmed]
  27. Lipid X ameliorates pulmonary hypertension and protects sheep from death due to endotoxin. Golenbock, D.T., Will, J.A., Raetz, C.R., Proctor, R.A. Infect. Immun. (1987) [Pubmed]
  28. A glycolipid precursor of bacterial lipopolysaccharide (lipid X) lacks activity against endothelial cells in vitro and is not toxic in vivo. Pohlman, T.H., Winn, R.K., Callahan, K.S., Maier, R.V., Harlan, J.M. J. Surg. Res. (1988) [Pubmed]
  29. Serum cortisol changes in heifers induced by lipid X: a monosaccharide precursor in the biosynthesis of Gram-negative endotoxin. Peter, A.T., Bosu, W.T., Perez, G.I., Loro-Kujjo, G., Gaines, J.D. Res. Vet. Sci. (1991) [Pubmed]
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