Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
Associated disease: infection due to Escherichia coli [ICD11:
XN6P4 
]
NCBI PubMed ID: 15654872Publication DOI: 10.1111/j.1742-4658.2004.04471.xJournal NLM ID: 101229646Publisher: Blackwell Publishing
Correspondence: useydel
fz-borstel.de
Institutions: Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften, D-23845 Borstel, Germany, Osaka University, Department of Chemistry, Osaka, Japan, European Molecular Biology Laboratory, c ⁄ o DESY, Hamburg, Germany
Lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria belongs to the most potent activators of the mammalian immune system. Its lipid moiety, lipid A, the 'endotoxic principle' of LPS, carries two negatively charged phosphate groups and six acyl chain residues in a defined asymmetric distribution (corresponding to synthetic compound 506). Tetraacyl lipid A (precursor IVa or synthetic 406), which lacks the two hydroxylated acyl chains, is agonistically completely inactive, but is a strong antagonist to bioactive LPS when administered to the cells before LPS addition. The two negative charges of lipid A, represented by the two phosphate groups, are essential for agonistic as well as for antagonistic activity and no highly active lipid A are known with negative charges other than phosphate groups. We hypothesized that the phosphate groups could be substituted by other negatively charged groups without changing the endotoxic properties of lipid A. To test this hypothesis, we synthesized carboxymethyl (CM) derivatives of hexaacyl lipid A (CM-506 and Bis-CM-506) and of tetraacyl lipid A (Bis-CM-406) and correlated their physicochemical with their endotoxic properties. We found that, similarly to compounds 506 and 406, also for their carboxymethyl derivatives a particular molecular ('endotoxic') conformation and with that, a particular aggregate structure is a prerequisite for high cytokine-inducing capacity and antagonistic activity, respectively. In other parameters such as acyl chain melting behaviour, antibody binding, activity in the Limulus lysate assay, and partially the binding of 3-deoxy-d-manno-oct-2-ulosonic acid transferase, strong deviations from the properties of the phosphorylated compounds were observed. These data allow a better understanding of endotoxic activity and its structural prerequisites.
Lipopolysaccharide, inflammation, endotoxic shock, signal transduction
Structure type: oligomer
Location inside paper: p.328, fig.1, tetraacyl lipid A (406)
Trivial name: lipid IV A, lipid IV(A)
Compound class: lipid A, glycolipid
Contained glycoepitopes: IEDB_135394,IEDB_135515,IEDB_141807,IEDB_151531
Methods: chemical synthesis, biological assays, FTIR, serological methods
Comments, role: synthetic lipid A
Related record ID(s): 10149
NCBI Taxonomy refs (TaxIDs): 562
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There is only one chemically distinct structure:
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