| Physicochemical and biological analysis of synthetic bacterial lipopeptides: validity of the concept of endotoxic conformation. | |
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MedLine Citation:
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PMID: 17308304 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Andra B Schromm; Jörg Howe; Artur J Ulmer; Karl-Heinz Wiesmüller; Tobias Seyberth; Günther Jung; Manfred Rössle; Michel H J Koch; Thomas Gutsmann; Klaus Brandenburg |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-02-17 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 282 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2007 Apr |
Date Detail:
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Created Date: 2007-04-09 Completed Date: 2007-05-31 Revised Date: 2008-11-21 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 11030-7 Citation Subset: IM |
Affiliation:
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Research Center Borstel, Leibniz Center for Medicine and Biosciences, Department of Immunochemistry and Biochemical Microbiology, Emmy Noether Group of Immunobiophysics, Division of Biophysics, Borstel, Germany. aschromm@fz-borstel.de |
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Membrane
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drug effects Cells, Cultured Chemistry, Physical Humans Lipopolysaccharides / pharmacology Lipoproteins / chemical synthesis, chemistry, metabolism*, toxicity* Macrophage Activation / drug effects Macrophages / drug effects, enzymology, metabolism Molecular Structure Peptide Fragments / chemical synthesis, chemistry, metabolism*, toxicity* Physicochemical Phenomena Polymyxin B / pharmacology Protein Binding Protein Conformation Toll-Like Receptor 2 / antagonists & inhibitors, metabolism Tumor Necrosis Factor-alpha / biosynthesis |
| Chemical | |
Reg. No./Substance:
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0/Lipopolysaccharides; 0/Lipoproteins; 0/Peptide Fragments; 0/Toll-Like Receptor 2; 0/Tumor Necrosis Factor-alpha; 1404-26-8/Polymyxin B |
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