Lipid A

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Lipid A is a lipid component of an endotoxin held responsible for toxicity of Gram-negative bacteria. However, 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. Lipid A is located at one end of the lipopolysaccharide (LPS, also called endotoxin) molecule, and anchors the LPS to the outer membrane of a Gram-negative bacteria. Many of the immune activating abilities of LPS can be contributed to the lipid A unit. It is a very potent stimulant of the immune system, activating cells (for example, monocytes or macrophages) at picogram per 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.

Chemical composition: Lipid A consists of two glucosamine (carbohydrate/sugar) units with attached acyl chains ("fatty acids"), and normally containing one phosphate group 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.

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 Gram-negative bacterial infections. On the other hand, modified versions of lipid A can be used as components of vaccines (adjuvants) to improve their effect.

Lipid A (and LPS) is believed to activate cells via Toll-like receptor 4 (TLR4), MD-2 and CD14 on the cell surface.

[edit] References

• Raetz and Whitfield; Annu Rev Biochem 2002; 71: 635-700 Raetz and Whitfield; Annu Rev Biochem 2002; 71: 635-700.