Biology Reference
In-Depth Information
The 1 and 4' positions are mono- or diphosphorylated, and the
disaccharide can be acylated by up to four 3-hydroxy-containing or
nonhydroxylated acyl residues as ester or amide linkages at specific
positions (C2, C3, C2', C3'). Additional fatty acids can be attached
(secondary substitution) in cases where there is a hydroxyl group on the
hydrocarbon moiety. Despite the general structural conservation of lipid
A seen across species, the amount and length of the fatty acid chains can
vary greatly between different bacterial strains. Even LPS samples
derived from the same species of bacteria can vary in structure (Lehmann
and Rupprecht, 1977, Chang and Nowotny, 1975).
Lipid A (
1
, Fig. 6.1)
from
Escherichia coli
, which carries five fatty acids that are fourteen
carbons in length and one which is twelve carbons in length, is
exemplary of this structural class (Reitschel
et al.
, 1996).
The structural details of each lipid A isoform determines whether the
compound will cause a host-mediated response or not. For example,
lengthening the acyl chains leads to a reduction in cytotoxicity, as
evidenced by the lipid A's of
Chlamydia psittaci
,
Bacteroides fragilis
,
and
Legionella pneumophilia
(Heine
et al.
, 2003). Those lipid A
structures featuring either a monosaccharide core or a dimeric structure
with only four acyl side chains are significantly less toxic (Demchenko
et
al.
, 2003). Pentacylated forms of lipid A are less active than the natural
hexaacylated forms, whereas bisacylated and tetraacylated derivatives as
seen in the antagonistic biosynthetic precursor Ia (
2
) (also known as lipid
IVa or compd. 406) are completely inactive (Liu
et al.
, 1997, Flad
et al.
,
1993). Interestingly, synthetic
E. coli
lipid A is less potent than the
natural material. The chirality of the 3-hydroxyacyl chains apparently
plays no role on the biological activity of the substance as both
R
- and
S
-
configurations induce similar responses. The incorporation of at least
one phosphate group is a requirement for bioactivity. These residues
apparently are needed for recognition by the cell-surface receptor(s) for
LPS (Demchenko
et al.
, 2003).
6.1.1.2
Role in disease
LPS via the lipid A component is one of the most potent
immunostimulatory substances known (as low as ng to pg/mL range)
