Information about 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.
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LTC4 is a cysteinyl leukotriene, as are D4 and E4.
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Types
Examples of leukotrienes are LTA4, LTB4, LTC4, LTD4, LTE4, and LTF4.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a metabolite of LTE4 in which the cysteinyl moiety has been oxidized to an alpha-keto-acid (i.e., the cysteine has been replaced by a pyruvate).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 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.[1][2][3] 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
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Eicosanoid synthesis. (Leukotrienes at right.)
The lipoxygenase pathway is active in leukocytes, 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, which converts it in two steps to leukotriene A4, 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 (e.g. montelukast and zafirlukast) are used to treat asthma. Recent research points to a role of 5-lipoxygenase in cardiovascular and neuropsychiatric illnesses.[4]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 vasoconstriction particularly of venules and of bronchoconstriction, they also increase vascular permeability.
Leukotrienes in asthma
Leukotrienes assist in the pathophysiology of asthma, causing or potentiating the following symptoms:- 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 anaphylactic shock.[5]
Leukotriene modifiers
See also
- A chemical synthesis of Leukotriene A methyl ester
Notes
1. ^ Feldberg W, Kellaway CH. Liberation of histamine and formation of lyscithin-like substances by cobra venom. J Physiol 1938;94:187-226.
2. ^ 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.
3. ^ Kellaway CH, Trethewie ER. The liberation of a slow reacting smooth-muscle stimulating substance in anaphylaxis. Q J Exp Physiol 1940;30:121-145.
4. ^ Manev R, Manev H (2004). "5-Lipoxygenase as a putative link between cardiovascular and psychiatric disorders". Crit Rev Neurobiol 16 (1-2): 181-6. PMID 15581413.
5. ^ Brocklehurst, W (1960), "The release of histamine and formation of a slow-reacting substance (SRS-A) during anaphylactic shock", J Physiol 151: 416-35, PMID 13804592
2. ^ 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.
3. ^ Kellaway CH, Trethewie ER. The liberation of a slow reacting smooth-muscle stimulating substance in anaphylaxis. Q J Exp Physiol 1940;30:121-145.
4. ^ Manev R, Manev H (2004). "5-Lipoxygenase as a putative link between cardiovascular and psychiatric disorders". Crit Rev Neurobiol 16 (1-2): 181-6. PMID 15581413.
5. ^ Brocklehurst, W (1960), "The release of histamine and formation of a slow-reacting substance (SRS-A) during anaphylactic shock", J Physiol 151: 416-35, PMID 13804592
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
Autacoids, unsaturated fatty acids: Eicosanoids | |
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| Prostanoids | Prostaglandins - Thromboxanes (A2, B2) |
| Other | Arachidonic acids - Eicosapentaenoic acid - Leukotrienes - Lipoxins |
Arachidonic acids: leukotrienes |
|---|
In biochemistry, eicosanoids are signaling molecules derived from omega-3 (ω-3) or omega-6 (ω-6) fats. They exert complex control over many bodily systems, mainly in inflammation or immunity, and as messengers in the central nervous system.
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Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds and activates a receptor. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms (such as the monoamine neurotransmitters)
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Autocrine signalling is a form of hormonal signalling in which a cell secretes a hormone, or chemical messenger (called the autocrine agent) that binds to autocrine receptors on the same cell, leading to changes in the cell.
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Paracrine signaling is a form of cell signaling in which the target cell is close to ("para" = alongside of or next to, but this strict prefix definition is not meticulously followed here) the signal releasing cell.
The signal chemical is called the paracrine agent.
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The signal chemical is called the paracrine agent.
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Arachidonic acid (AA) is an omega-6 fatty acid 20:4(ω-6). It is the counterpart to the saturated arachidic acid found in peanut oil, (L. arachis – peanut.
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Enzymes are proteins that catalyze (i.e. accelerate) chemical reactions.[1] In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, the products.
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Lipoxygenases are iron-containing enzymes that catalyse the dioxygenation of polyunsaturated fatty acids in reaction:
Lipoxygenases are found in plants, animals and fungi.
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- fatty acid + O2 = fatty acid hydroperoxide
Lipoxygenases are found in plants, animals and fungi.
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Histamine is a biogenic amine involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter.[1] New evidence also indicates that histamine plays a role in chemotaxis of white blood cells.
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Slow reacting substance of anaphylaxis or SRS-A is a mixture of the leukotrienes LTC4, LTD4 and LTE4. Mast cells secrete it during the anaphylactic reaction, inducing inflammation.
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Bengt Ingemar Samuelsson (born May 21, 1934) is a Swedish biochemist.
He was born in Halmstad in southwest Sweden and studied at Stockholm University, where he became a professor in 1967. He shared with Sune K. Bergström and John R.
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He was born in Halmstad in southwest Sweden and studied at Stockholm University, where he became a professor in 1967. He shared with Sune K. Bergström and John R.
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White blood cells or leukocytes are cells of the immune system which defend the body against both infectious disease and foreign materials. Several different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone
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conjugated system is a system of atoms covalently bonded with alternating single and multiple (e.g. double) bonds (e.g., C=C-C=C-C) in a molecule of an organic compound. This system results in a general delocalization of the electrons across all of the adjacent parallel aligned
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Slow reacting substance of anaphylaxis or SRS-A is a mixture of the leukotrienes LTC4, LTD4 and LTE4. Mast cells secrete it during the anaphylactic reaction, inducing inflammation.
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Venom (literally, poison of animal origin) is any of a variety of toxins used by certain types of animals, for the purpose of defense and hunting. Generally, venom is injected while other toxins are absorbed by ingestion or through the skin.
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Histamine is a biogenic amine involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter.[1] New evidence also indicates that histamine plays a role in chemotaxis of white blood cells.
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Arachidonic acid (AA) is an omega-6 fatty acid 20:4(ω-6). It is the counterpart to the saturated arachidic acid found in peanut oil, (L. arachis – peanut.
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Arachidonate 5-lipoxygenase (5-lipoxygenase, 5-LO or Alox5), which transforms EFAs into leukotrienes, is a current target for pharmaceutical intervention in a number of diseases.
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2, −1
(neutral oxide)
Electronegativity 3.44 (Pauling scale)
Ionization energies
(more) 1st: 1313.9 kJmol−1
2nd: 3388.3 kJmol−1
3rd: 5300.5 kJmol−1
Atomic radius 60 pm
Atomic radius (calc.
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(neutral oxide)
Electronegativity 3.44 (Pauling scale)
Ionization energies
(more) 1st: 1313.9 kJmol−1
2nd: 3388.3 kJmol−1
3rd: 5300.5 kJmol−1
Atomic radius 60 pm
Atomic radius (calc.
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Arachidonic acid (AA) is an omega-6 fatty acid 20:4(ω-6). It is the counterpart to the saturated arachidic acid found in peanut oil, (L. arachis – peanut.
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White blood cells or leukocytes are cells of the immune system which defend the body against both infectious disease and foreign materials. Several different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone
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A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in histamine and heparin. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately
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Eosinophil granulocytes, commonly referred to as eosinophils (or less commonly as acidophils), are white blood cells of the immune system that are responsible for combating infection by parasites in vertebrates.
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Neutrophil granulocytes, generally referred to as neutrophils, are the most abundant type of white blood cells and form an integral part of the immune system. Their name arrives from staining characteristics on hematoxylin and eosin (H&E) histological preparations.
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A monocyte is a leukocyte, part of the human body's immune system that protects against blood-borne pathogens and moves quickly (aprox. 8-12 hours) to sites of infection in the tissues. Monocytes are usually identified in stained smears by their large bilobate nucleus.
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Basophils are the least common of the granulocytes, representing about 0.01% to 0.3% of circulating leukocytes (white blood cells). They contain large cytoplasmic granules which obscure the cell nucleus under the microscope.
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Phospholipases A2 (PLA2s) EC 3.1.1.4 are enzymes that specifically hydrolyze the sn-2 fatty acid acyl bond of phospholipids, producing a free fatty acid and a lyso-phospholipid.
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5-Lipoxygenase activating protein, or FLAP, is an enzyme necessary for the activation of 5-lipoxygenase and therefore for the production of leukotrienes.[1] It is bound to the nuclear membrane.
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Leukotriene A4 is a leukotriene.
Leukotriene A4 hydrolase converts it to Leukotriene B4.
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Leukotriene A4 hydrolase converts it to Leukotriene B4.
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Leukotriene A4 hydrolase is an enzyme which converts leukotriene A4 to leukotriene B4.
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External links
- MeSH leukotriene+A4+hydrolase
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Leukotriene C4 synthase (or glutathione S-transferase II) is an enzyme which converts leukotriene A4 and glutathione to create leukotriene C4.
A trimer of Leukotriene C4 synthase is localized on the outer nuclear membrane and endoplasmic reticulum where it forms a
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A trimer of Leukotriene C4 synthase is localized on the outer nuclear membrane and endoplasmic reticulum where it forms a
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