Lipopolysaccharide: Wikis

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Structure of a lipopolysaccharide

Lipopolysaccharides (LPS), 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.

Contents

Functions

LPS is the major component of the outer membrane of Gram-negative bacteria, contributing greatly to the structural integrity of the bacteria, and protecting the membrane from certain kinds of chemical attack. LPS also increases the negative charge of the cell membrane and helps stabilize the overall membrane structure. It is of crucial importance to gram negative bacteria, whose death results if it is mutated or removed. LPS is an endotoxin, and induces a strong response from normal animal immune systems.

LPS acts as the prototypical endotoxin because it binds the CD14/TLR4/MD2 receptor complex, which promotes the secretion of pro-inflammatory cytokines in many cell types, but especially in macrophages. In Immunology, the term "LPS challenge" refers to the process of exposing a subject to an LPS which may act as a toxin.

LPS is also an exogenous pyrogen (external fever-inducing substance).

Lipopolysaccharides are of crucial importance to gram negative bacteria, and are therefore candidate targets for new antimicrobial agents.

Some researchers doubt reports of generalized toxic effects attributed to all lipopolysaccharides, particularly for cyanobacteria.[1]

Composition

The saccharolipid Kdo2-Lipid A. Glucosamine residues in blue, Kdo residues in red, acyl chains in black and phosphate groups in green.

It comprises three parts:

  1. O antigen (or O polysaccharide)
  2. Core
  3. Lipid A
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Lipid A

Lipid A is normally a phosphorylated glucosamine disaccharide decorated with multiple fatty acids. These hydrophobic fatty acid chains anchor the LPS into the bacterial membrane and the rest of the LPS projects from the cell surface. The lipid A domain is responsible for much of the toxicity of Gram-negative bacteria. When bacterial cells are lysed by the immune system, fragments of membrane containing lipid A are released into the circulation, causing fever, diarrhea, and possible fatal endotoxic shock (also called septic shock).

Core

The Core domain always contains an oligosaccharide component which attaches directly to lipid A and commonly contains sugars such as heptose and 3-deoxy-D-mannooctulosonic Acid (also known as KDO, keto-deoxyoctulosonate).[2] The LPS Cores of many bacteria also contain non-carbohydrate components, such as phosphate, amino acids, and ethanolamine substitutents.

O-antigen

When LPS contains a repetitive glycan polymer this is referred to as the O antigen, O polysaccharide, or O side chain of the bacteria. The O antigen is attached to the core oligosaccharide, and comprises the outermost domain of the LPS molecule. The composition of the O chain varies from strain to strain, for example there are over 160 different O antigen structures produced by different E. coli strains.[3] The presence or absence of O chains determine whether the LPS is considered rough or smooth. Full length O-chains would render the LPS smooth while the absence or reduction of O-chains would make the LPS rough. [4] Bacteria with rough LPS usually have more penetrable cell membranes to hydrophobic antibiotics since a rough LPS is more hydrophobic. [5] O antigen is exposed on the very outer surface of the bacterial cell, and as a consequence, is a target for recognition by host antibodies.

LPS modifications

The making of LPS can be modified in order to present a specific sugar structure. Those can be recognised by either other LPS (which enables to inhibit LPS toxins) or glycosyltransferases which use those sugar structure to add more specific sugars. It has recently been shown that a specific enzyme in the intestine (alkaline phosphatase) can detoxify LPS by removing the two phosphate groups found on LPS carbohydrates [6]. This may function as an adaptive mechanism to help the host manage potentially toxic effects of gram-negative bacteria normally found in the small intestine.

Variability and effect upon specificity

Toll-like receptors of the innate immune system recognize LPS and trigger an immune response.

O-antigens (the outer carbohydrates) are the most variable portion of the LPS molecule, imparting the antigenic specificity. In contrast, lipid A is the most conserved part. However, —lipid A composition also may vary (e.g., in number and nature of acyl chains even within or between genera). Some of these variations may impart antagonistic properties to these LPS. For example Rhodobacter sphaeroides diphosphoryl lipid A (RsDPLA) is a potent antagonist of LPS in human cells, but is an agonist in hamster and equine cells.

It has been speculated that conical Lipid A (eg from E. coli) are more agonistic, less conical lipid A like those of Porphyromonas gingivalis may activate a different signal (TLR2 instead of TLR4), and completely cylindrical lipid A like that of Rhodobacter sphaeroides is antagonistic to TLRs.[7][8]

Lipopolysaccharide gene clusters are highly variable between different strains, subspecies, species of bacterial pathogens of plants and animals.[9][10]

Immune response

LPS function has been under experimental research for several years due to its role in activating many transcription factors. LPS also produces many types of mediators involved in septic shock.

References

  1. ^ Stewart I, Schluter PJ, Shaw GR (2006). "Cyanobacterial lipopolysaccharides and human health - a review". Environ Health 5: 7. doi:10.1186/1476-069X-5-7. PMID 16563160.  
  2. ^ Hershberger C and Binkley SB (1968). "Chemistry and Metabolism of 3-Deoxy-d-mannooctulosonic Acid. I. STEREOCHEMICAL DETERMINATION". Journal of Biological Chemistry 243 (7): 1578–1584. PMID 4296687. http://www.jbc.org/cgi/reprint/243/7/1578?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=3-Deoxy-D-mannooctulosonic+Acid+&searchid=1&FIRSTINDEX=0&volume=243&issue=7&resourcetype=HWCIT.  
  3. ^ Christian Raetz and Chris Whitfield (2002) Lipopolysaccharide Endotoxins Annu. Rev. Biochem. 71:635-700
  4. ^ Rittig MG et al. (2004). "Smooth and rough lipopolysaccharide phenotypes of Brucella induce different intracellular trafficking and cytokine/chemokine release in human monocytes". Journal of Leukocyte Biology 5 (4): 196–200. doi:10.1189/jlb.0103015. PMID 12960272.  
  5. ^ Tsujimoto H et al. (2003). "Diffusion of macrolide antibiotics through the outer membrane of Moraxella catarrhalis". Journal of Infection and Chemotherapy 74 (4): 1045–1055. doi:10.1007/s101569900025. PMID 11810516.  
  6. ^ Bates J.M. et al. (2007). "Intestinal alkaline phosphatase detoxifies lipopolysaccharide and prevents inflammation in zebrafish in response to the gut microbiota". Cell Host and Microbe 2(6) (6): 371–382. doi:10.1016/j.chom.2007.10.010. PMID 18078689.  
  7. ^ Netea M et al. (2002). "Does the shape of lipid A determine the interaction of LPS with Toll-like receptors?". Trends Immunol 23 (3): 135–9. doi:10.1016/S1471-4906(01)02169-X. PMID 11864841.  
  8. ^ Seydel U, Oikawa M, Fukase K, Kusumoto S, Brandenburg K (2000). "Intrinsic conformation of lipid A is responsible for agonistic and antagonistic activity". Eur J Biochem 267 (10): 3032–9. doi:10.1046/j.1432-1033.2000.01326.x. PMID 10806403.  
  9. ^ Reeves P, Wang L (2002). "Genomic organization of LPS-specific loci". Curr Top Microbiol Immunol 264 (1): 109–35. PMID 12014174.  
  10. ^ Patil P, Sonti R (2004). "Variation suggestive of horizontal gene transfer at a lipopolysaccharide (lps) biosynthetic locus in Xanthomonas oryzae pv. oryzae, the bacterial leaf blight pathogen of rice". BMC Microbiol 4 (1): 40. doi:10.1186/1471-2180-4-40. PMID 15473911.  

See also

External links


Study guide

Up to date as of January 14, 2010

From Wikiversity

Lipopolysaccharides (LPS) are glycolipids present in the membrane of most Gram-Negative bacteria. LPSs are large molecules consisting of a hidrophobic portion (Lipid-A), wich anchors the LPS to the outer-leaflet of the external membrane, an oligosaccharide core, and a polysaccharide (O-antigen) exposed to the outside of the cell. LPSs are also know as endotoxins and elicit strong immune responses in animals. For plant-colonizing bacteria, LPS play an important role in the molecular communication between plant-microbe interaction.


LPSs comprise three parts:

1. O-antigen (or O-polysaccharide) 2. Core oligosaccharide 3. Lipid A


Lipid A

Lipid A is normally a phosphorylated glucosamine disaccharide decorated with multiple fatty acids. These hydrophobic fatty acid chains anchor the LPS into the bacterial membrane and the rest of the LPS projects from the cell surface. The lipid A domain is responsible for much of the toxicity of Gram-negative bacteria. When bacterial cells are lysed by the immune system, fragments of membrane containing lipid A are released into the circulation, causing fever, diarrhea, and possible fatal endotoxic shock (also called septic shock).

Core oligosaccharide

The Core oligosaccharide attaches directly to lipid A and normally contains sugars such as heptose and 3-deoxy-D-mannooctulosonic Acid (also known as KDO, keto-deoxyoctulosonate).

O-antigen

When LPS contains a repetitive glycan polymer this is referred to as the O antigen, O polysaccharide, or O chain of the bacteria. O antigen is attached to the core oligosaccharide, and comprises the outermost domain of the LPS molecule. The composition of the O chain varies from strain to strain, for example there are over 160 different O antigen structures produced by different E. coli strains. The presence or absence of O chains determine whether the LPS is considered rough or smooth. Full length O-chains would render the LPS smooth while the absence or reduction of O-chains would make the LPS rough. Bacteria with rough LPS usually have more penetrable cell membranes to hydrophobic antibiotics since a rough LPS is more hydrophobic. O antigen is exposed on the very outer surface of the bacterial cell, and as a consequence, is a target for recognition by host antibodies.



LPS modifications

The making of LPS can be modified in order to present a specific sugar structure. Those can be recognised by either other LPS (which enables to inhibit LPS toxins) or glycosyltransferases which use those sugar structure to add more specific sugars. It has recently been shown that a specific enzyme in the intestine (alkaline phosphatase) can detoxify LPS by removing the two phosphate groups found on LPS carbohydrates. This may function as an adaptive mechanism to help the host manage potentially toxic effects of gram-negative bacteria normally found in the small intestine.


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