Molecular Structure of Lipid a, the Endotoxic Center of Bacterial Lipopolysaccharides

doi:10.1016/S0065-2318(08)60152-3

Advances in Carbohydrate Chemistry and Biochemistry

Volume 50, 1994, Pages 211-276

https://doi.org/10.1016/S0065-2318(08)60152-3 Get rights and content

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INTRODUCTION

Gram-negative bacteria such as the Enterobacteriaceae, Neisseriaceae, and Pseudomonadaceae express at their outer membrane amphiphilic macromolecules termed lipopolysaccharides (LPS, endotoxin), which are of considerable microbiological, genetical, chemical, pharmacological, and, in particular, biomedical interest 1., 2., 3., 4., 5., 6., 7., 8., 9., 9b.. LPS participate in various physiological membrane functions essential for growth and survival of Gram-negative bacteria. LPS also constitute

LIPID A: DEFINITION AND GENERAL PROPERTIES

Lipid A may be obtained by subjecting an LPS preparation to mild acid hydrolysis, by which treatment the ketosidic linkage between the inner core oligosaccharide and lipid A, namely, between Kdo and the distal d-glucosamine residue [GlcN (II)] of the lipid A backbone, is cleaved. Acid hydrolysis must be used, because enzymes that split the ketosidic bond, or mutants that synthesize oligosaccharide-free lipid A are known only for a few cases (26). The acid lability of the linkage between lipid A

PRIMARY STRUCTURE OF LIPID A : BACKBONE, POLAR SUBSTITUENTS, AN FATTY ACIDS

Comparison of endotoxic lipid A of different Gram-negative genera and families reveals that they not only share chemical constituents but that they are also made up according to a similar architectural principle, which is exemplified by the well-studied lipid A of the Escherichia coli Re mutant strain F515 (Fig. 2, for literature compare Ref. 25). This E. coli lipid A is composed of a 2-amino-2-deoxy-6-O-(2-amino-2-deoxy-β-d-glucopyranosyl)-α-d-glucopyranose disaccharide [β-d-GlcpN-(1 → 6)-α-d-Glc

SYNTHETIC LIPID A

Based on the results of chemical analysis, free lipid A has been chemically synthesized [compare 12., 13., 14., 15., 17.]. The first fully synthetic lipid A molecule (preparation 506 or LA-15-PP) corresponds in structure to E. coli lipid A (Fig. 2) carrying a glycosylic (and nonglycosylic) monophosphate. Later, other lipid A and lipid A partial structures were prepared that contain a β-(1 → 6)-linked GlcpN disaccharide, but that differ in the acylation and phosphorylation pattern. These

CONFORMATION OF LIPID A

In parallel with the increasing knowledge on the primary structure of lipid A, calculations and physical investigations have been performed in order to gain insight into the molecular shape and the three-dimensional arrangement of lipid A and LPS.

ENDOTOXOCITY OF LPS AND LIPID A

LPS are endowed with an overwhelming spectrum of biological activities expressed either in vivo after injection into mammalians or in humoral or cellular in vitro systems 1., 3., 4., 6., 20., 118.. In fact, LPS has been postulated as playing a central role in the pathogenesis and manifestations of Gram-negative infection, in general, and of septic shock, in particular. Therefore, one of the driving forces in LPS research has been the search for that region and structure of the macromolecule

SEROLOGY OF LIPID A

In the early seventies, Galanos et al. (241) showed that lipid A may be immunogenic, and acid-treated bacteria (exposing free lipid A on their surface) or free lipid A complexed to suitable carriers were found to be good immunogens for the preparation of anti-lipid A antibodies. Such antisera could be raised with lipid A preparations derived from various Gram-negative bacteria, provided they contained the E. coli- or C. violaceum-type of structure.

The specificity of lipid A antibodies was,

SYNOPSIS: THE STRUCTURE, ACTIVITY, AND FUNCTION OF LIPID A

As the preceding sections show, the term lipid A does not denote a defined molecular entity but rather a family of structurally closely related but not identical phosphoglycolipids. Their structures may differ in the type and number (one or two) of HexpN residues present in the backbone; by the number, location, nature, size, and linkage of acyl residues; by the nature of phosphate substituents; and finally by the degree of phosphorylation of the backbone. Lipid A components of different

ACKNOWLEDGMENTS

The financial support of the Deutsche Forschungs Gemeinschafit (SFB 367, project B2) and Fonds der Chemie (EThR) is greatly appreciated. We thank M. Lohs, F. Richter, B. Köhler and I. Stegelmann-Müller for preparing drawings and photographs. We are particularly grateful to our friends and colleagues H. Brade, E. Coats, H.-D. Grimmecke, O. Holst, M. Kastowsky, S. Kusumoto, H. Labischinski, O. Lüderitz, H. Mayer, G. Seltmann, and U. Seydel for valuable suggestions.

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REFERENCES (295)

O. Lüderitz et al.
Curr. Top. Membr. Transp.
(1982)
H. Brade et al.
Zbl. Bakt. Hyg.
(1988)
E.Th. Rietschel et al.
Immunobiol.
(1993)
M. Kiso et al.
Carbohydr. Res.
(1986)
P. Westerduin et al.
Carbohydr. Res.
(1985)
D. Charon et al.
Am. Chem. Soc. Symp. Ser.
(1983)
A. Boivin et al.
Compt. Rend. Sci. Biol.
(1933)
N. Qureshi et al.
J. Biol. Chem.
(1982)
U. Zähringer et al.
Tetrahedron Lett.
(1985)
M. Imoto et al.
Tetrahedron Lett.
(1983)

(1991)

P. Stütz et al.

S. Kusumoto et al.

Pure Appl. Chem.

(1989)

S. Kusumoto et al.

M. Kiso et al.

Carbohyr. Res.

(1987)

T. Shimizu et al.

Int. J. Immunopharmacol.

(1991)

S. Ikeda et al.

J. Clin. Lab. Immunol.

(1990)

D.C. Morrison et al.

Annu. Rev. Med.

(1987)

M. Pollack

J.M. Griffiss et al.

Rev. Inf. Dis.

(1988)

O. Hoist et al.

Carbohydr. Res.

(1990)

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¹: This article is dedicated to Professor Dr. Dr. med. h.c. Otto Westphal on the occasion of his 80th birthday (February 1st, 1993).

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Molecular Structure of Lipid a, the Endotoxic Center of Bacterial Lipopolysaccharides1

Section snippets

INTRODUCTION

LIPID A: DEFINITION AND GENERAL PROPERTIES

PRIMARY STRUCTURE OF LIPID A : BACKBONE, POLAR SUBSTITUENTS, AN FATTY ACIDS

SYNTHETIC LIPID A

CONFORMATION OF LIPID A

ENDOTOXOCITY OF LPS AND LIPID A

SEROLOGY OF LIPID A

SYNOPSIS: THE STRUCTURE, ACTIVITY, AND FUNCTION OF LIPID A

ACKNOWLEDGMENTS

First page preview

Curr. Top. Membr. Transp.

Zbl. Bakt. Hyg.

Immunobiol.

Carbohydr. Res.

Carbohydr. Res.

Am. Chem. Soc. Symp. Ser.

Compt. Rend. Sci. Biol.

J. Biol. Chem.

Tetrahedron Lett.

Tetrahedron Lett.

Biomed. Mass Spectrom.

Eur. J. Biochem.

J Biol. Chem.

J. Microb. Meth.

Int. J. Mass Spectrom. Ion Processes

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Biochem.

Biochemistry

Eur. J. Biochem.

Eur. J. Biochem.

J. Biol. Chem.

J. Biol. Chem.

J Biol. Chem.

Eur. J. Biochem.

Eur. J. Biochem.

Eur. J. Biochem.

Biological Mass Spectrometry

Eur. J. Biochem.

Arch. Microbiol.

Biochem. Rev.

Prog. Clin. Biol. Res.

Annu. Rev. Biochem.

Sci. Am.

FASEB J.

J. Immunol. Meth.

Pure Appl. Chem.

Carbohyr. Res.

Int. J. Immunopharmacol.

J. Clin. Lab. Immunol.

Annu. Rev. Med.

Rev. Inf. Dis.

Carbohydr. Res.

Molecular Structure of Lipid a, the Endotoxic Center of Bacterial Lipopolysaccharides¹