Leukotriene

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LTA4 Note the four double bonds, three of them conjugated. This is a common property of A4, B4, C4, D4, and E4.
LTC4 is a cysteinyl leukotriene, as are D4 and E4.

Leukotrienes are fatty signaling molecules. They were first found in leukocytes (hence their name). One of their roles (specifically, leukotriene D4) is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis.[1] Leukotriene antagonists are used to treat these diseases by inhibiting the production or activity of leukotrienes.

Leukotrienes produced within a cell convey signals that act either on the cell producing them (autocrine signalling) or on vicinal cells (paracrine signalling) to regulate the immune response.

Leukotrienes are naturally produced eicosanoid lipid mediators. They are produced in the body from arachidonic acid by the enzyme 5-lipoxygenase. Their production usually accompanies the production of histamine.

Contents

Types

Examples of leukotrienes are LTA4, LTB4, LTC4, LTD4, LTE4, and LTF4.

LTC4, LTD4, LTE4 and LTF4 are often called cysteinyl leukotrienes due to the presence of the amino acid cysteine in their structure. Together, the cysteinyl leukotrienes make up the slow-reacting substance of anaphylaxis (SRS-A). LTF4 is, like LTD4, a metabolyte of LTC4. Instead of lacking the glutaminic residue of glutathion, the glycyne residue has been split off.[2]

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a metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an alpha-keto-acid (i.e., the cysteine has been replaced by a pyruvate).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 double bonds). What would be later named leukotriene C, "slow reaction smooth muscle-stimulating substance" (SRS) was originally described between 1938 and 1940 by Feldberg and Kellaway.[3] [4] [5] 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

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 and other immunocompetent cells, including mast cells, eosinophils, neutrophils, monocytes, and basophils. 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 reduces to 5-hydroxyeicosatetraenoic acid (5-HETE). The enzyme 5-LO acts again on 5-HETE to convert it into leukotriene A4 (LTA4), an unstable epoxide.

In cells equipped with LTA4 hydrolase, such as neutrophils and monocytes, LTA4 is converted to the dihydroxy acid leukotriene LTB4, which is a powerful chemoattractant for neutrophils acting at BLT1 and BLT2 receptors on the plasma membrane of these cells.

In cells that express LTC4 synthase, such as mast cells and eosinophils, LTA4 is conjugated with the tripeptide glutathione to form the first of the cysteinyl-leukotrienes, LTC4. Outside the cell, LTC4 can be converted by ubiquitous enzymes to form successively LTD4 and LTE4, 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 (LTC4, LTD4, LTE4) 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 receptors. They may also act upon peroxisome proliferator-activated receptors. Leukotrienes are involved in asthmatic and allergic reactions and act to sustain inflammatory reactions. Several leukotriene receptor antagonists such as montelukast and zafirlukast are used to treat asthma. Recent research points to a role of 5-lipoxygenase in cardiovascular and neuropsychiatric illnesses.[6]

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 and increase vascular permeability.[7]

Leukotrienes in asthma

Leukotrienes contribute to the pathophysiology of asthma, causing or potentiating the following symptoms:

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 anaphylactic shock.[8]

Leukotriene modifiers

See leukotriene antagonist

See also

Eoxins (14,15-leukotrienes)

Notes

  1. ^ David L. Nelson, Michael M. Cox. Lehninger's Principles of Biochemistry, Fifth Edition. W.H. Freeman and Co., 2008, p. 359.
  2. ^ internet checked april 24, 2012
  3. ^ Feldberg W, Kellaway CH. Liberation of histamine and formation of lyscithin-like substances by cobra venom. J Physiol 1938;94:187-226.
  4. ^ 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.
  5. ^ Kellaway CH, Trethewie ER. (April 1, 1940). "The liberation of a slow reacting smooth-muscle stimulating substance in anaphylaxis" (pdf). Q J Exp Physiol 30 (2): 121–145. http://ep.physoc.org/cgi/reprint/30/2/121. 
  6. ^ Manev R, Manev H (2004). "5-Lipoxygenase as a putative link between cardiovascular and psychiatric disorders". Crit Rev Neurobiol 16 (1–2): 181–6. doi:10.1615/CritRevNeurobiol.v16.i12.190. PMID 15581413. 
  7. ^ Dahlen, Sven-Erik; Bjork, Jakob; Hedqvist, P; Arfors, KE; Hammarström, S; Lindgren, JA; Samuelsson, B (1981). "Leukotrienes promote plasma leakage and leukocyte adhesion in postcapillary venules: in vivo effects with relevance to the acute inflammatory response". Proceedings of the National Academy of Sciences of the United States of America 78 (6): 3887–3891. doi:10.1073/pnas.78.6.3887. JSTOR 10943. PMC 319678. PMID 6267608. //www.ncbi.nlm.nih.gov/pmc/articles/PMC319678/. 
  8. ^ Brocklehurst, WE (1960). "The release of histamine and formation of a slow-reacting substance (SRS-A) during anaphylactic shock". J Physiol 151 (3): 416–35. PMC 1363273. PMID 13804592. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1363273/. 

References

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