- Lipid A
Lipid A is a
lipidcomponent of an endotoxinheld responsible for toxicityof Gram-negative bacteria. It is the innermost of the three regions of the lipopolysaccharide(LPS, also called endotoxin) molecule, and its hydrophobic nature allows it to anchor the LPS to the outer membrane. While its toxic effects can be damaging, the sensing of lipid A by the human immune system may also be critical for the onset of immune responses to Gram-negative infection, and for the subsequent successful fight against the infection.
Many of the immune activating abilities of LPS can be attributed to the lipid A unit. It is a very potent stimulant of the
immune system, activating cells (for example, monocytes or macrophages) at picogramper milliliter quantities.
When present in the body at high concentrations during a Gram-negative bacterial infection, it may cause shock and death by an "out of control" excessive immune reaction.
Lipid A consists of two
glucosamine(carbohydrate/sugar) units with attached acyl chains (" fatty acids"), and normally containing one phosphategroup on each carbohydrate.
The optimal immune activating lipid A structure is believed to contain 6 acyl chains. Four acyl chains are attached directly to the glucosamine sugars are beta hydroxy acyl chains usually between 10 and 16 carbons in length. Two additional acyl chains are often attached to the beta hydroxy group. "E. coli" lipid A, as an example, typically has four C14 hydroxy acyl chains attached to the sugars and one C14 and one C12 attached to the beta hydroxy groups.
The biosynthetic pathway for Lipid A in "
E. coli" has been determined by the work of Christian R. H. Raetz in the past 20 years.
Inhibition and activation of immune response
Lipid A with a reduced number of acyl chains (for example; four) can serve as an inhibitor of immune activation induced by Gram-negative bacteria, and synthetic versions of these inhibitors are in clinical trials for the prevention of harmful effects caused by
On the other hand, modified versions of lipid A can be used as components of
vaccines ( adjuvants) to improve their effect.
Mechanism of activating cells
Lipid A (and LPS) is believed to activate cells via
Toll-like receptor4 (TLR4), MD-2and CD14on the cell surface.
Lipid A deacylase PagL
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