Chemical synthesis of phosphorylated fundamental structure of lipid a

Inage, Masaru; Chaki, Haruyuki; Kusumoto, Shoichi; Shiba, Tetsuo

doi:10.1016/s0040-4039(01)92910-7

Cited by 34 publications

(6 citation statements)

References 8 publications

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“…4 is similar to that of the lipid A biosynthesis intermediate lipid IV A (precursor Ia) (31) or synthetic compound 406 (16). Lipid IV A has been reported to act as an LPS agonist to murine cells but to behave as an antagonist to human cells (12,18,22).…”

Section: Discussionmentioning

confidence: 71%

Modification of the Structure and Activity of Lipid A inYersinia pestisLipopolysaccharide by Growth Temperature

et al. 2002

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Yersinia pestis strain Yreka was grown at 27 or 37°C, and the lipid A structures (lipid A-27°C and lipid A-37°C) of the respective lipopolysaccharides (LPS) were investigated by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. Lipid A-27°C consisted of a mixture of tri-acyl, tetra-acyl, penta-acyl, and hexa-acyl lipid A's, of which tetra-acyl lipid A was most abundant. Lipid A-37°C consisted predominantly of tri-and tetra-acylated molecules, with only small amounts of penta-acyl lipid A; no hexa-acyl lipid A was detected. Furthermore, the amount of 4-amino-arabinose was substantially higher in lipid A-27°C than in lipid A-37°C. By use of mouse and human macrophage cell lines, the biological activities of the LPS and lipid A preparations were measured via their abilities to induce production of tumor necrosis factor alpha (TNF-␣). In both cell lines the LPS and the lipid A from bacteria grown at 27°C were stronger inducers of TNF-␣ than those from bacteria grown at 37°C. However, the difference in activity was more prominent in human macrophage cells. These results suggest that in order to reduce the activation of human macrophages, it may be more advantageous for Y. pestis to produce less-acylated lipid A at 37°C.Yersinia pestis was isolated as a causative agent of plague in Hong-Kong in 1894 independently by A. Yersin and S. Kitasato (3). Since then, this highly pathogenic bacterium has been investigated, and many virulence factors have been identified, including fraction 1 antigen, murine toxin, Yop proteins, pH 6 antigen, and iron acquisition systems (5, 28). Lipopolysaccharide (LPS) has also been studied for many decades as one of the virulence factors of Y. pestis, and its composition and endotoxic activity have been examined in earlier studies (1,40,41). By use of modern analytical methods, the LPS of Y. pestis was proven to be a rough type LPS without O-antigenic polysaccharide (7,8,25,29,30,35) that contains 3-hydroxy-myristic acid (3-OH-C 14:0 ) as a main fatty acid in the lipid A portion. However, there was a discrepancy in the amounts of the nonhydroxy-fatty acids found. Hartley et al. reported that nearly 90% of fatty acids in the lipid A of Y. pestis strain 195/R (a virulent strain) consisted of 3-OH-C 14:0 (14). On the other hand, considerable amounts of lauric acid (C 12:0 ), palmitic acid (C 16:0 ), and palmitoleic acid (C 16:1 ) were detected in the lipid A of Y. pestis strain EV40 (an avirulent strain) (4, 39). Using the same strain, Aussel et al. (2) proposed a hexa-acylated lipid A structure (four molecules of 3-OH-C 14:0 , one of C 12:0 , and one of C 16:1 ). In our preliminary experiment we isolated the lipid A from Y. pestis strain Yreka (virulent strain) grown at 37°C and found that it contained 3-OH-C 14:0 and only trace amounts of other fatty acids. A possible explanation of the controversy on fatty acids may be differences in strains or culture conditions. Darveau et al. (8) reported that the molecular size of the LPS from Y. pestis strain EV76 ...

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Section: Discussionmentioning

confidence: 71%

Modification of the Structure and Activity of Lipid A inYersinia pestisLipopolysaccharide by Growth Temperature

et al. 2002

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“…Materials. Salmonella minnesota S and Re lipopolysaccharides, free lipid A from S. minnesota Re (6, 7), the synthetic lipid A analogs (10)(11)(12), and the succinylated derivatives are described in an accompanying paper (23). The structures and designations of the synthetic preparations are shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

Mitogenic activities of synthetic lipid A analogs and suppression of mitogenicity of lipid A

Tanamoto¹,

Galanos²,

Lüderitz³

et al. 1984

Infect Immun

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The effect of synthetic lipid A analogs on murine spleen cells was studied. The preparations represented D-glucosamine and D-glucosaminyl-beta 1,6-D-glucosamine disaccharide derivatives substituted in different combinations by ester- and amide-bound fatty acids and by phosphate groups. Significant mitogenic activity was demonstrated with a number of synthetic disaccharide preparations; however, their potency was lower than that of lipid A. The synthetic preparations were not mitogenic for spleen cells from C3H/HeJ mice. Furthermore, the mitogenicity of the synthetic preparations was abolished after binding with polymyxin B. The results indicate that for expression of mitogenicity, a phosphate group at position 1 of the reducing glucosamine and amide-bound acyloxyacyl residues are important factors. Some of the synthetic preparations containing the diglucosamine backbone and expressing relatively low mitogenicity suppressed B-cell mitogenicity of lipid A. Although these preparations were lytic for erythrocytes, they did not affect the viability of the splenic lymphocytes. Suppression was seen when the synthetic preparations were added simultaneously with or after the lipid A mitogen, but optimal suppression was expressed when the preparations were added to the system 3 h before lipid A. Washing of the cells before the addition of lipid A did not affect the results. The suppression was not due to the induction of suppressor cells by the synthetic preparations. The disaccharide preparations did not inhibit T-cell mitogenicity of concanavalin A. In contrast to the disaccharide preparations, the monosaccharide preparations suppressed mitogenicity of both lipid A and concanavalin A, probably because of their direct toxicity for lymphocytes.

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“…Stimulants of prostaglandin release. Lipopolysaccharide (LPS) from Salmonella minnesota R595 (7) and the synthetic lipid A analogs (12)(13)(14) have been described previously (30). The chemical structures of the synthetic preparations used in this study are shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

Endotoxic induction of prostaglandin release from macrophages by nontoxic lipid A analogs synthesized chemically

et al. 1990

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The ability of synthetic lipid A analogs to induce prostaglandin synthesis in macrophages was compared with that of native lipopolysaccharide. The synthetic preparations comprised monomeric or dimeric derivatives of D-glucosamine with different patterns of substitution by phosphate and tetradecanoic, (R)-3-hydroxytetradecanoic, and (R)-3-tetradecanoyloxytetradecanoic acid. All of these preparations are structurally distinct from native lipid A (principally regarding the position of fatty acid substitution) and hence have been previously shown to be endotoxically inactive in many biological tests. It was found that many of these synthetic samples exhibit strong activity in inducing prostaglandin E2 and prostaglandin F2 alpha, with some of them having activity comparable to that of lipopolysaccharide. Experiments with macrophages of C3H/HeJ mice enabled us to differentiate between endotoxin-specific (in the case of dimeric preparations) and endotoxin-nonspecific (for monomeric preparations) mechanisms for the induction of prostaglandins. These results indicate that there is a difference in the mechanism of induction of prostaglandin synthesis between monomeric lipid A's and dimeric or native lipid A structures.

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Chemical synthesis of phosphorylated fundamental structure of lipid a

Cited by 34 publications

References 8 publications

Modification of the Structure and Activity of Lipid A inYersinia pestisLipopolysaccharide by Growth Temperature

Modification of the Structure and Activity of Lipid A inYersinia pestisLipopolysaccharide by Growth Temperature

Mitogenic activities of synthetic lipid A analogs and suppression of mitogenicity of lipid A

Endotoxic induction of prostaglandin release from macrophages by nontoxic lipid A analogs synthesized chemically

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