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  • Title: Newer aspects of the chemical structure and biological activity of bacterial endotoxins.
    Author: Rietschel ET, Brade H, Brade L, Kaca W, Kawahara K, Lindner B, Lüderitz T, Tomita T, Schade U, Seydel U.
    Journal: Prog Clin Biol Res; 1985; 189():31-51. PubMed ID: 2413465.
    Abstract:
    Gram-negative bacteria express at their surface various amphiphiles among which the lipopolysaccharides (endotoxins, O-antigens) have been studied most intensively. Lipopolysaccharides consist of a heteropolysaccharide portion (O-specific chain and core) which is responsible for the O- (and R-) antigenic properties and a covalently bound lipid component, termed lipid A, which contains the endotoxic principle of lipopolysaccharides. The detailed chemical structure of a large number of O-chains and the general architecture of the core oligosaccharide has been established. Recent analyses of the enterobacterial inner core region indicate the presence of a linear trisaccharide of alpha 2.4-linked 3-deoxy-D-manno-2-octulosonic acid (KDO) residues of which only the reducing group is believed to be located in the main core chain. This KDO residue which provides the link between the polysaccharide and the lipid A component appears to be involved in a recently detected ubiquitous immunodeterminant expressed by lipopolysaccharides of various origin. The chemical structure of enterobacterial lipid A's is now known in some detail. Lipid A of Salmonella, Escherichia coli and Proteus consists of a beta 1.6-linked D-glucosamine disaccharide which carries four (R)-3-hydroxytetradecanoyl groups in positions 2, 3, 2' and 3' and two phosphoryl residues in positions 1 and 4'. Up to three of the hydroxy fatty acids (positions 2, 2' and 3') are, at their 3-hydroxyl groups, acylated by non-hydroxylated acyl residues, and to phosphoryl groups non-acylated, nitrogen-containing residues such as 4-amino-4-deoxy-L-arabinopyranose and phosphorylethanolamine may be bound. The hydroxyl group in position 4 of the glucosamine disaccharide is free and that in position 6' serves as the attachment site for KDO (i.e. the polysaccharide component) in lipopolysaccharide. Based on this structure lipid A analogues have been chemically synthesized and analysed for endotoxic activity in vivo and in vitro. In two test systems (pyrogenicity, local Shwartzman reaction) the synthetic part structures exhibited weak or no endotoxic activity, as did a precursor of lipid A biosynthesis which is structurally identical to one of the analogues. In many other systems, however, including lethal toxicity, B-lymphocyte mitogenicity, macrophage activation, induction of cross tolerance, expression of lipid A antigenicity, the synthetic materials were of comparable activity as bacterial free lipid A. These findings support the structural proposals made for lipid A and they prove the previous hypothesis that the endotoxic principle is embedded in lipid A.(ABSTRACT TRUNCATED AT 400 WORDS)
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