Lipid A and bacterial lipopolysaccharides: structure, occurrence and biology

LIPID A and BACTERIAL

LIPOPOLYSACCHARIDES
STRUCTURE, OCCURRENCE AND BIOLOGY
The cell membranes that enclose Gram-negative bacteria, including those of human pathogens
such as Escherichia coli and Salmonella enterica, consist of an asymmetric bilayer, the outer
leaflet of which consists predominantly of lipopolysaccharides with proteins taking up much of the
remaining surface. This may permit growth and survival of bacteria in harsh environments including
those within eukaryotic hosts. The inner membrane consists simply of glycerophospholipids.
Lipopolysaccharides derived from different groups of Gram-negative bacteria have a common
basic structure, consisting of a covalently bound lipid component, termed lipid A, and a hydrophilic
heteropolysaccharide. Lipid A provides the anchor that secures the molecule within the membrane,
while the polysaccharide component interacts with the external environment, including the
defenses of the animal or plant host species.
a
HO
HO

OH
O

HO
O

O HO
HO
_
O

OH
O

_
O
O
GlcN II
O

O
_
O P O
_
O O
O

GlcN I
O

HO
O

NH
O

O
O

O
O

O
O

HO

O
_
NH O P O
_
O

HO

The basic lipopolysaccharide of E. coli, incorporating

lipid A (blue portion of the structure).

W.W. Christie

www.lipidlibrary.co.uk

Lipid A and bacterial lipopolysaccharides: structure, occurrence and biology

Lipid A is a unique and distinctive phosphoglycolipid, the structure of which is highly conserved
among species. All contain D-gluco-configured pyranosidic hexosamine residues (or 2,3-diamino2,3-dideoxy-D-glucose), which are present as (1-6)-linked dimers. The disaccharide contains
-glycosidic and non-glycosidic phosphoryl groups, and (R)-3-hydroxy fatty acids in ester and
amide linkages, of which two are usually further acylated at their 3-hydroxyl group. However,
variations in the fine structure can arise from the type of hexosamine present, the degree of
phosphorylation, the presence of phosphate substituents, and importantly in the nature, chain
length, number, and position of the acyl groups. In the lipid A of E. coli illustrated, the hydroxy fatty
acids are C14 in chain length, and the hydroxy groups of the two (R)-3-hydroxy fatty acids of the
distal G1cN-residue (GlcN II), and not those of the GlcN-residue at the reducing side (GlcN I), are
acylated by non-hydroxy fatty acids (12:0 and 14:0). There are a few important exceptions to this
type of fatty acid pattern. For example, in Rhodobacter sphaeroides, the amide-linked fatty acids of
the disaccharide backbone are as 3-oxo-tetradecanoic acid, while some species contain 2-hydroxy
acids and others have very-long-chain (-1)-hydroxy acids such as 27-hydroxyoctacosanoic acid.
In each bacterial species, the heterosaccharide unit is in two parts an inner core, and an
O-specific chain consisting of a complex polymer of oligosaccharides, which determines the
serological or antigenic specificity of the lipopolysaccharide and is often termed an O-antigen.
Different bacteria synthesise lipopolysaccharide molecules that differ in the length and fine
structure of the O-specific chains. The core polysaccharide is structurally more uniform than the
O-chain, the diversity being found primarily in an outer core region. The inner part of the core
region is composed of the characteristic components heptose, mainly in the L-glycero-D-manno
configuration, and 3-deoxy-D-manno-octulosonic (or 2-keto-3-deoxyoctonic) acid (Kdo). These are
usually substituted by charged phosphate groups, resulting in an accumulation of charge in this
inner region. The minimum structure to have substantial biological activity in E. coli has the di-Kdo
moiety illustrated. At least one Kdo residue is required for bacterial viability.
When bacteria multiply and when they die and break up, lipopolysaccharide is liberated and is then
a powerful bacterial toxin that has been termed endotoxin. The lipid A component, in particular, is
known to be responsible for many of the toxic effects of infections with Gram-negative bacteria.
However, it is also an active immuno-modulator, able to induce non-specific resistance to both
bacterial and viral infections. From both standpoints, it has been the object of intensive study, not
only in humans but also in plants, and the mechanisms are fairly well understood as is the
biosynthetic pathway, a target for drug therapy (see the literature cited below). The observed
effects are partly due to the primary structure of the lipid A moiety, but also to the fact that it adopts
a specific conformation that enhances the activity by enabling binding to specific host molecules. It
is evident that the number, positions, and chain-lengths of the fatty acid constituents have a role in
the toxicity and biological activity of the molecule. On the other hand, it should be recognized that
the existence of lipid A-containing lipopolysaccharide in the most ancient and primitive Gramnegative bacteria demonstrates that it is absolutely required for their survival and is not produced
simply to aggravate humans.

Recommended Reading
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o
o
o

Dow, M., Newman, M.-A. and von Roepenack, E. The induction and modulation of plant defense
responses by bacterial lipopolysaccharides. Annu. Rev. Phytopathol., 38, 241-261 (2000).
Raetz, C.R.H. Bacterial endotoxins: extraordinary lipids that activate eucaryotic signal transduction. J.
Bact., 175, 5745-5753 (1993).
Raetz, C.R.H. and Whitfield, C. Lipopolysaccharide endotoxins. Annu. Rev. Biochem., 71, 635-700
(2002).
Rietschel, E.T. Kirikae, T., Schade, F.U., Mamat, U., Schmidt, G., Loppnow, H., Ulmer, A.J., Zahringer,
U., Seydel, U. and Di Padova, F. Bacterial endotoxin: molecular relationships of structure to activity
and function. FASEB J., 8, 217-225 (1994).
Zahringer, U., Lindner, B. and Rietschel, E.T. Molecular structure of lipid A, the endotoxic center of
bacterial lipopolysaccharides. Adv. Carbohydr. Chem. Biochem., 50, 211-76 (1994).

W.W. Christie

www.lipidlibrary.co.uk

Lipid A and bacterial lipopolysaccharides: structure, occurrence and biology

W.W. Christie

Scottish Crop Research Institute (and Mylnefield Lipid Analysis), Invergowrie,

Dundee (DD2 5DA), Scotland
Last updated: 23.5.2005

W.W. Christie

www.lipidlibrary.co.uk