Lipid A is a

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids includ ...

component of an

endotoxin Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...

held responsible for the

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...

gram-negative bacteria Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...

. It is the innermost of the three regions of the

lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer ...

(LPS), also called

molecule, and its

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, t ...

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 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.

Chemical composition

Lipid A consists of two

glucosamine Glucosamine (C6H13NO5) is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of two polysaccharides, chitosan and chitin. Glucosamine is one of the most ...

(carbohydrate/sugar) units, in an β(1→6) linkage, with attached acyl chains ("

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...

s"), and normally containing one

phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosph ...

group on each

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or m ...

. The optimal immune activating lipid A structure is believed to contain 6 acyl chains. Four acyl chains 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 >32 years. Lipid A structure and effects on eukaryotic cells have been determined and examined, among others, by the groups of Otto Westphal, Chris Galanos, Ernst T. Rietschel and Hajime Takahashi starting already in the 1960s (Gmeiner, Luederitz, Westphal. Eur J Biochem 1969)(Kamio&Takahashi J Biochem 1971)(Luederitz, Galanos et al., J Infect Dis 1973).

Biosynthesis

The enzymes involved in Lipid A synthesis are conserved among ''

Pseudomonas aeruginosa ''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerug ...

'', ''

Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Esc ...

'', '' Bordetella bronchiseptica'', and '' Salmonella''. center, 700px, Synthesis of the UDP-diacylglucosamine precursor of Lipid A center, 700px, Synthesis of Lipid IV_a

Inhibition and activation of immune response

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 The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...

, activating cells (for example,

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

s 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. 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 (

Eritoran Eritoran is an investigational drug for the treatment of severe sepsis, an excessive inflammatory response to an infection. In a phase III clinical trial, eritoran did not perform better than placebo for the treatment of sepsis. It was being d ...

) were in clinical trials for the prevention of harmful effects caused by

gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wa ...

bacterial infections. However, trials were recently discontinued due to lack of efficacy seen in patients with severe sepsis. On the other hand, modified versions of lipid A can be used as components of

vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified.

s ( adjuvants) to improve their effect. Monophosphorylated lipid A (MPL) is an FDA approved adjuvant that consists of a heterogeneous mixture of lipid A from ''Salmonella minnesota'' R595. The major lipid A species present in MPL lacks one of the two phosphate groups and five acyl chains. Other work has shown that the removal of one or two acyl chains from native lipid A can significantly reduce activation of inflammatory responses. The biological activity of LPS depends on the chemical structure of its lipid A. Primarily,

TLR4 Toll-like receptor 4 is a protein that in humans is encoded by the ''TLR4'' gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an ...

is required for activation of

innate immunity The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...

upon recognition of LPS of

Gram-negative bacteria Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...

. The ability of

/ MD-2 system to respond to a distinct lipid A species are clinically important. Pathogenic bacteria may employ LPS with low biological activity of its lipid A to evade proper recognition by the

/MD-2 complex, dampening the host

immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...

and increasing the risk of bacterial dissemination. On the other hand, such lipid A would not be able to induce septic shock in susceptible patients, rendering septic complications more manageable. Yet, defining and understanding how even the smallest structural differences between the very similar lipid A species may affect the activation of the

may provide the mechanism for the fine tuning of the latter and new insights to immunomodulatory processes.

Mechanism of activating cells

Lipid A (and LPS) has been demonstrated to activate cells via Toll-like receptor 4 (

), MD-2 and

CD14 CD14 (cluster of differentiation 14) is a human protein made mostly by macrophages as part of the innate immune system. It helps to detect bacteria in the body by binding lipopolysaccharide (LPS), a pathogen-associated molecular pattern (PAMP). ...

on the cell surface. Consequently, lipid A analogs like

eritoran Eritoran is an investigational drug for the treatment of severe sepsis, an excessive inflammatory response to an infection. In a phase III clinical trial, eritoran did not perform better than placebo for the treatment of sepsis. It was being d ...

can act as TLR4 antagonists. They are being developed as drugs for the treatment of excessive inflammatory responses to infections with gram-negative bacteria.

References

External links