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Chemical structure of lipid A as found in E. Coli[1]

Lipid A is a lipid component of an endotoxin held responsible for toxicity of 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.[2] 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.[3]

Contents

Functions

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 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.[1]

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.[1]

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.[2]

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 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.

Mechanism of activating cells

Lipid A (and LPS) is believed to activate cells via Toll-like receptor 4 (TLR4), MD-2 and CD14 on the cell surface. Consequently, lipid A analogs like eritoran can act as TLR4 antagonists. They are being developed as drugs for the treatment of excessive inflammatory responses to infections with Gram-negative bacteria.[4]

See also

Lipid A deacylase PagL

References

  1. ^ a b c Raetz, Christian R. H.; Guan, Ziqiang; Ingram, Brian O.; Six, David A.; Song, Feng; Wang, Xiaoyuan; Zhao, Jinshi (2009). "Discovery of new biosynthetic pathways: the lipid A story". Journal of Lipid Research: S103–S108.  
  2. ^ a b Raetz C, Whitfield C (2002). "Lipopolysaccharide endotoxins" (abstract). Annu Rev Biochem 71: 635–700. doi:10.1146/annurev.biochem.71.110601.135414. PMID 12045108. PMC 2569852. http://arjournals.annualreviews.org/doi/abs/10.1146%2Fannurev.biochem.71.110601.135414?cookieSet=1.  
  3. ^ Tzeng YL, Datta A, Kolli VK, Carlson RW, Stephens DS (May 2002). "Endotoxin of Neisseria meningitidis composed only of intact lipid A: inactivation of the meningococcal 3-deoxy-D-manno-octulosonic acid transferase". J. Bacteriol. 184 (9): 2379–88. doi:10.1128/JB.184.9.2379-2388.2002. PMID 11948150. PMC 134985. http://jb.asm.org/cgi/pmidlookup?view=long&pmid=11948150.  
  4. ^ Tidswell, M; Tillis, W; Larosa, SP; Lynn, M; Wittek, AE; Kao, R; Wheeler, J; Gogate, J et al. (2010). "Phase 2 trial of eritoran tetrasodium (E5564), a Toll-like receptor 4 antagonist, in patients with severe sepsis". Critical care medicine 38 (1): 72–83. doi:10.1097/CCM.0b013e3181b07b78. PMID 19661804.  

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