Physicochemical and biological analysis of synthetic bacterial lipopeptides: validity of the concept of endotoxic conformation
| Autor: | Schromm, A. B., Howe, J., Ulmer, A. J., Wiesmüller, K. H., Seyberth, T., Jung, G., Rössle, M., Koch, M. H. J., Gutsmann, T., Brandenburg, K. |
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| Rok vydání: | 2007 |
| Předmět: |
Lipopolysaccharides
antagonists & inhibitors [Toll-Like Receptor 2] Chemical Phenomena metabolism [Toll-Like Receptor 2] Protein Conformation Lipoproteins chemical synthesis [Lipoproteins] toxicity [Lipoproteins] biosynthesis [Tumor Necrosis Factor-alpha] enzymology [Macrophages] ddc:570 chemistry [Lipoproteins] drug effects [Macrophage Activation] metabolism [Peptide Fragments] Humans Cells Cultured Polymyxin B drug effects [Macrophages] Molecular Structure Chemistry Physical Tumor Necrosis Factor-alpha Macrophages Cell Membrane toxicity [Peptide Fragments] Physicochemical Phenomena Macrophage Activation Peptide Fragments Toll-Like Receptor 2 pharmacology [Polymyxin B] pharmacology [Lipopolysaccharides] chemistry [Peptide Fragments] drug effects [Cell Membrane] metabolism [Macrophages] lipids (amino acids peptides and proteins) chemical synthesis [Peptide Fragments] metabolism [Lipoproteins] Protein Binding |
| Zdroj: | The journal of biological chemistry 282, 11030-11037 (2007). doi:10.1074/jbc.M700287200 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.M700287200 |
| Popis: | The importance of the biological function and activity of lipoproteins from the outer or cytoplasmic membranes of Gram-positive and Gram-negative bacteria is being increasingly recognized. It is well established that they are like the endotoxins (lipopolysaccharide (LPS)), which are the main amphiphilic components of the outer membrane of Gram-negative bacteria, potent stimulants of the human innate immune system, and elicit a variety of proinflammatory immune responses. Investigations of synthetic lipopeptides corresponding to N-terminal partial structures of bacterial lipoproteins defined the chemical prerequisites for their biological activity and in particular the number and length of acyl chains and sequence of the peptide part. Here we present experimental data on the biophysical mechanisms underlying lipopeptide bioactivity. Investigation of selected synthetic diacylated and triacylated lipopeptides revealed that the geometry of these molecules (i.e. the molecular conformations and supramolecular aggregate structures) and the preference for membrane intercalation provide an explanation for the biological activities of the different lipopeptides. This refers in particular to the agonistic or antagonistic activity (i.e. their ability to induce cytokines in mononuclear cells or to block this activity, respectively). Biological activity of lipopeptides was hardly affected by the LPS-neutralizing antibiotic polymyxin B, and the biophysical interaction characteristics were found to be in sharp contrast to that of LPS with polymyxin B. The analytical data show that our concept of "endotoxic conformation," originally developed for LPS, can be applied also to the investigated lipopeptide and suggest that the molecular mechanisms of cell activation by amphiphilic molecules are governed by a general principle. |
| Databáze: | OpenAIRE |
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