Leukotriene
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2008-07-02T16:26:14Z
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[[Image:Leukotriene A4.svg|thumb|right|[[Leukotriene A4|LTA<sub>4</sub>]] Note the four double bonds, three of them conjugated. This is a common property of A4, B4, C4, D4, and E4.]]
[[Image:Leukotriene B4.svg|right|thumb|[[Leukotriene B4|LTB<sub>4</sub>]]]]
[[Image:Leukotriene C4.svg|thumb|right|[[Leukotriene C4|LTC<sub>4</sub>]] is a cysteinyl leukotriene, as are D4 and E4.]]
[[Image:Leukotriene D4.svg|thumb|right|[[Leukotriene D4|LTD<sub>4</sub>]]]]
[[Image:Leukotriene E4.svg|thumb|right|[[Leukotriene E4|LTE<sub>4</sub>]]]]
'''Leukotrienes''' are naturally produced [[eicosanoid]] [[lipid signaling|lipid mediators]], which may be responsible for the effects an inflammatory response. Leukotrienes use both [[autocrine signalling]] and [[paracrine signalling]] to regulate the body's response. Leukotrienes are produced in the body from [[arachidonic acid]] by the [[enzyme]] 5-[[lipoxygenase]]. Their production by the body is part of a complex response that usually includes the production of [[histamine]].
==Types==
Examples of leukotrienes are LTA<sub>4</sub>, LTB<sub>4</sub>, LTC<sub>4</sub>, LTD<sub>4</sub>, LTE<sub>4</sub>, and LTF<sub>4</sub>.
[[LTC4]], [[LTD4]] and [[LTE4]] are often called '''cysteinyl leukotrienes''' due to the presence of the amino acid in their structure. Collectively, the cysteinyl leukotrienes make up the [[slow reacting substance of anaphylaxis]] (SRS-A).
There has also been postulated the existence of LTG4, a metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an alpha-keto-acid (i.e., the cysteine has been replaced by a pyruvate). Very little is known about this putative leukotriene.
== History and name ==
The name ''leukotriene'', introduced by Swedish biochemist [[Bengt Samuelsson]] in 1979, comes from the words ''[[leukocyte]]'' and ''triene'' (indicating the compound's three [[Conjugated system|conjugated double bonds]]).
What would be later named leukotriene C, "slow reaction smooth muscle-stimulating substance" ([[Slow reacting substance of anaphylaxis|SRS]]) was originally described between 1938 and 1940 by Feldberg and Kellaway.<ref>Feldberg W, Kellaway CH. ''Liberation of histamine and formation of lyscithin-like substances by cobra venom.'' J Physiol 1938;94:187-226.</ref>
<ref>Feldberg W, Holden HF, Kellaway CH. ''The formation of lyscithin and of a muscle-stimulating substance by snake venoms.'' J Physiol 1938;94:232-248.</ref>
<ref>{{cite journal| url=http://ep.physoc.org/cgi/reprint/30/2/121
|author=Kellaway CH, Trethewie ER.
|title=The liberation of a slow reacting smooth-muscle stimulating substance in anaphylaxis
|journal= Q J Exp Physiol
|date= 1940|volume=30|pages=121–145|format=pdf}}</ref>
The researchers isolated SRS from lung tissue after a prolonged period following exposure to snake [[venom]] and [[histamine]].
Leukotrienes are commercially available to the research community.
== Biochemistry ==
=== Synthesis === <!--Leukotriene synthesis redirects here-->
[[Image:Eicosanoid synthesis.svg|thumb|320px|Eicosanoid synthesis. (Leukotrienes at right.)]]
Leukotrienes are synthesized in the cell from [[arachidonic acid]] by [[5-lipoxygenase]]. The catalytic mechanism involves the insertion of an [[oxygen]] moiety at a specific position in the [[arachidonic acid]] backbone.
The lipoxygenase pathway is active in [[leukocytes]], including [[mast cell]]s, [[eosinophil]]s, [[neutrophil]]s, [[monocyte]]s and [[basophil]]s. When such cells are activated, arachidonic acid is liberated from cell membrane phospholipids by [[phospholipase A2]], and donated by the [[5-lipoxygenase activating protein]] (FLAP) to 5-lipoxygenase.
5-[[lipoxygenase]] (5-LO) uses FLAP to convert [[arachidonic acid]] into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which spontaneously [[redox|reduces]] to [[5-hydroxyeicosatetraenoic acid]] (5-HETE). The enzyme 5-LO acts again on 5-HETE to convert it into [[leukotriene A4|leukotriene A<sub>4</sub>]] (LTA<sub>4</sub>), an unstable epoxide.
In cells equipped with [[leukotriene A4 hydrolase|LTA<sub>4</sub> hydrolase]], such as neutrophils and monocytes, LTA<sub>4</sub> is converted to the dihydroxy acid leukotriene LTB<sub>4</sub>, which is a powerful chemoattractant for neutrophils acting at BLT<sub>1</sub> and BLT<sub>2</sub> receptors on the plasma membrane of these cells.
In cells that express [[leukotriene C4 synthase|LTC<sub>4</sub> synthase]], such as mast cells and eosinophils, LTA<sub>4</sub> is conjugated with the tripeptide [[glutathione]] to form the first of the cysteinyl-leukotrienes, LTC<sub>4</sub>. Outside the cell, LTC<sub>4</sub> can be converted by ubiquitous enzymes to form successively LTD<sub>4</sub> and LTE<sub>4</sub>, which retain biological activity.
The cysteinyl-leukotrienes act at their cell-surface receptors [[CysLT1]] and [[CysLT2]] on target cells to contract bronchial and vascular smooth muscle, to increase permeability of small blood vessels, to enhance secretion of mucus in the airway and gut, and to recruit leukocytes to sites of inflammation.
Both LTB4 and the cysteinyl-leukotrienes (LTC<sub>4</sub>, LTD<sub>4</sub>, LTE<sub>4</sub>) are partly degraded in local tissues, and ultimately become inactive metabolites in the liver.
=== Function ===
Leukotrienes act principally on a subfamily of [[G protein coupled receptor]]s. They may also act upon [[peroxisome proliferator-activated receptor]]s. Leukotrienes are involved in asthmatic and allergic reactions and act to sustain inflammatory reactions; several [[leukotriene receptor antagonist]]s (e.g. [[montelukast]] and [[zafirlukast]]) are used to treat [[asthma]]. Recent research points to a role of 5-lipoxygenase in cardiovascular and neuropsychiatric illnesses.<ref>{{cite journal |author=Manev R, Manev H |title=5-Lipoxygenase as a putative link between cardiovascular and psychiatric disorders |journal=Crit Rev Neurobiol |volume=16 |issue=1-2 |pages=181–6 |year=2004 |pmid=15581413 |doi=10.1615/CritRevNeurobiol.v16.i12.190}}</ref>
Leukotrienes are very important agents in the [[inflammatory]] response. Some such as LTB4 have a [[chemotactic]] effect on migrating neutrophils, and as such help to bring the necessary cells to the tissue. Leukotrienes also have a powerful effect in [[bronchoconstriction]], they also increase [[vascular permeability]].
==Leukotrienes in asthma==
Leukotrienes assist in the [[pathophysiology]] of [[asthma]], causing or [[Potentiator|potentiating]] the following [[symptom]]s:
*airflow obstruction
*increased secretion of mucus
*mucosal accumulation
*bronchoconstriction
*infiltration of inflammatory cells in the airway wall
===Role of cysteinyl leukotrienes===
Cysteinyl leukotriene receptors '''[[CysLT1]]''' and '''[[CysLT2]]''' are present on [[mast cells]], [[eosinophil]] and endothelial cells. During cysteinyl leukotriene interaction, they can stimulate proinflammatory activities such as endothelial cell adherence and chemokine production by [[mast cells]]. As well as mediating [[inflammation]], they induce asthma and other inflammatory disorders, thereby reducing the airflow to the alveoli.
In excess, the cysteinyl leukotrienes can induce [[Anaphylaxis|anaphylactic shock]].<ref>{{Harvard reference |Surname=Brocklehurst |Given=W |Title=The release of histamine and formation of a slow-reacting substance (SRS-A) during anaphylactic shock |Journal=J Physiol |Volume=151 |Issue= |Pages=416-35 |Year= 1960|pmid=13804592|URL= http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=13804592&dopt=Citation}}</ref>
Zileuton blocks 5-lipoxygenase inhibiting the synthetic pathway of leukotriene metabolism. Zileuton affects the LTB4 pathway, montelukast doesn't.
===Leukotriene modifiers===
:''See [[leukotriene antagonist]]''
== See also ==
* [[Wittig_reaction#Examples_of_use|A chemical synthesis of Leukotriene A methyl ester]]
==Notes==
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{{reflist}}
==References==
* Lipkowitz, Myron A. and Navarra, Tova (2001) ''The Encyclopedia of Allergies'' (2nd ed.) Facts on File, New York, p. 167, ISBN 0-8160-4404-X
* Samuelsson, Bengt (ed.) (2001) ''Advances in prostaglandin and leukotriene research: basic science and new clinical applications: 11th International Conference on Advances in Prostaglandin and Leukotriene Research: Basic Science and New Clinical Applications, Florence, Italy, June 4-8, 2000'' Kluwer Academic Publishers, Dordrecht, ISBN 1-4020-0146-0
* Bailey, J. Martyn (1985) ''Prostaglandins, leukotrienes, and lipoxins: biochemistry, mechanism of action, and clinical applications'' Plenum Press, New York, ISBN 0-306-41980-7
==External links==
* {{MeshName|Leukotrienes}}
{{Eicosanoids}}
{{Leukotrienes}}
[[Category:Eicosanoids]]
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