Lipid A
Encyclopedia
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. 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.
, activating cells (for example, monocyte
s or macrophage
s) 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.
(carbohydrate/sugar) units with attached acyl chains ("fatty acid
s"), 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 >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).
bacterial infections.
On the other hand, modified versions of lipid A can be used as components of vaccine
s (adjuvant
s) to improve their effect.
on the cell surface (Poltorak, Beutler et al., Blood Cells Mol Dis 1998)(Beutler, Poltorak, J Endotoxin Res 2000)(Park et al., Nature 2009). 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.
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
component of an endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
held responsible for toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
of Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
. It is the innermost of the three regions of the lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
(LPS, also called endotoxin
Endotoxin
Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...
) molecule, and its hydrophobic
Hydrophobe
In chemistry, hydrophobicity is the physical property of a molecule that is repelled from a mass of water....
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.
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 systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, activating cells (for example, monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
s or macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s) 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 glucosamineGlucosamine
Glucosamine is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of the polysaccharides chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, cell walls in fungi and...
(carbohydrate/sugar) units with attached acyl chains ("fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s"), and normally containing one phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
group on each carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
.
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
Christian R. H. Raetz
Christian Rudolf Hubert Raetz was the George Barth Geller Professor of Biochemistry at Duke University. He was elected to the National Academy of Sciences in 2006. His laboratory's research focused on lipid biochemistry and has contributed significantly to the understanding of Lipid A...
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
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-negativeGram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacterial infections.
On the other hand, modified versions of lipid A can be used as components of vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
s (adjuvant
Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
s) to improve their effect.
Mechanism of activating cells
Lipid A (and LPS) has been demonstrated to activate cells via Toll-like receptor 4 (TLR4), MD-2 and CD14CD14
Cluster of differentiation 14 also known as CD14 is a human gene.The protein encoded by this gene is a component of the innate immune system. CD14 exists in two forms. Either it is anchored into the membrane by a glycosylphosphatidylinositol tail or it appears in a soluble form...
on the cell surface (Poltorak, Beutler et al., Blood Cells Mol Dis 1998)(Beutler, Poltorak, J Endotoxin Res 2000)(Park et al., Nature 2009). Consequently, lipid A analogs like eritoran
Eritoran
Eritoran is an investigational drug for the treatment of severe sepsis, an excessive inflammatory response to an infection. It is being developed by Eisai Co. and administered intravenously as eritoran tetrasodium. , a Phase III clinical trial is recruiting patients.-Mechanism of action:Toll-like...
can act as TLR4 antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
. They are being developed as drugs for the treatment of excessive inflammatory responses to infections with Gram-negative bacteria.
External links
- The Lipid Library - Summary of Lipid A and bacterial polysaccharides