Endotoxic activity

The structural components encountered in E. coli are also present in lipid A of other bacterial sources. Thus, a survey of the structures analyzed shows that lipid A, in general, contain two g/wcoconfigured and pyranosidic D-hexosamine residues (2-amino-2-deoxy-D-glucose, GlcpN, or 2,3-diamino-2,3-dideoxy-D-glucose, GlcpN3N, also termed DAG (49,50)], which are present as a ) -(l — 6)-linked disaccharide (monosaccharide backbones have also been identified, but the respective lipid A lack endotoxic activity). The disaccharide is phosphorylated by one or, in most cases, two phosphate... 

Lipid A having Kdo attached at 0-6 comprises a domain of LPS that exhibits a remarkable structural conservatism, as far as the principal architecture is concerned (Fig. 15). This type of structure is found in most Gramnegative bacteria. It is not present in other biomolecules and is thus unique to Gram-negative bacteria and their LPS. It contains those structures that are required for (/) bacterial viability and (//) for optimal expression of endotoxic activity. 

K. R. Myers, A. T. Truchot, J. Ward, Y. Hudson, and J. T. Ulrich, in A. Nowotny, J. J. Spitzer, and E. Ziegler (Eds.), Endotoxin Research Series, Vol. 1, Cellular and Molecular Aspects of Endotoxin Reactions A Critical Determinant of Lipid A Endotoxic Activity, p. 145. Excerpta Medica, Amsterdam/New York/ Oxford, 1990. 

In summary, it was found that some of the synthetic preparations definitively exhibit endotoxic activities. But in all cases, except for antigenicity, the activities, on a weight basis, were much lower than those observed with natural lipid A. 

Galanos, C., Ltideritz, O., Rietschel, E.T., Westphal, O., Brade, H., Brade, L., Freudenberg, M., Schade, U., Imoto, M., Yoshimura, H., Kusumoto, S., Shiba, T. Synthetic and natural Escherichia coli free lipid A express identical endotoxic activities. Eur J Biochem 148 (1985) 1-5. 

Heine, H., Muller-Loennies, S., Brade, L., Lindner, B., Brade, H. Endotoxic activity and chemical structure of lipopolysaccharides from Chlamydia trachomatis serotypes E and L2 and Chlamydophila psittaci 6BC. Eur J Biochem 270 (2003) 440-450. 

Brandenburg, K., Hawkins, L., Garidel, P., Andra, J., Muller, M., Heine, H., Koch, M.H.J., Seydel, U. Structural polymorphism and endotoxic activity of synthetic phospholipid-like amphiphiles. Biochemistry 43 (2004) 4039-4046. 

For the sake of brevity, salient aspects of key structure-activity relationships in one homologous series of twelve mono- and bis-acyl homologated spermine analogues (Fig. 12.8) will be first discussed (Miller et al., 2005). We addressed two questions in this study (i) what is the optimal hydrophobic chain length for effective anti-endotoxic activity, (ii) are symmetrical bis-acyl spermines more effective than mono-acyl compounds We found that a carbon number of 14-16 is optimal in mono-acyl spermines (Fig. 12.9) which are, in general, as potent as... 

The TLR4-MD2 hetero-dimer has complex ligand specificity. It can be activated by structurally diverse LPS molecules, and minor changes in synthetic derivatives of LPS can abolish their endotoxic potency (Raetz and Whitfield, 2002 Rietschel et al., 1994). The diversity in potency of LPS is derived from variance within lipid A, as observed in both the number and the length of fatty acid side chains and the presence of terminal phosphate residues with a variety of modifications. Optimal lipid A potency is achieved with bi-phosphorylated, hexa-acylated, lipid A species (Raetz and Whitfield, 2002). Lipid A moieties that deviate from this pattern often demonstrate a significant decrease in endotoxic activity (Alexander and Rietschel, 2001). 

Bornside, G.H. Bouis, P.J. Cohn, I., Jr. Enhancement of E. Coli infection and endotoxic activity by hemoglobin and ferric ammonium citrate. Surgery 1 0, 68, 350-355. 

Lipid A was first synthesized by Imoto et al. in the mid 1980s [232,233], and the synthetic compound was found to possess all endotoxic activity of LPS. Many derivatives of Lipid A were subsequently synthesized in order to tease apart the importance of different structural elements for endotoxic activity. These investigations have been recently reviewed [234,235]. The tetraacylated lipid A precursor (lipid IVa, O Fig. 14) was found to compete with lipid A for binding to macrophages, but to have endotoxic activity 10 less than that of lipid A [235], with the result that it acts as a lipid A antagonist in human cells. In contrast, synthetic Re LPS (Kd02-lipid A, O Fig. 14) was found to have enhanced immunostimulatory ability compared with lipid A. 

In this species the heptose component consists of equal amounts of L-gly-cero-D-man/io-heptose and D-glycero-D-ma/mo-heptose (Figure 3.15). Analysis of the core of anaerobic Gram-negative bacteria, e.g. Bacteroides and certain photosynthetic bacteria, failed to detect KDO or heptose, suggesting that in these species another sugar links the core to lipid A. Isolated LPS from Bacteroides also has an unusual fatty acid composition and low endotoxic activity. 

Brandenburg, K Howe, J., Gutsman, T, and Garidel, P. (2009) The expression of endotoxic activity in the Limulus test as compared to cytokine production in immune cells. Curr. Med. Chem., 16, 2653-2660. 

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