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Prostaglandin
From Wikipedia, the free encyclopedia

(Redirected from Prostaglandins) Jump to: navigation, search E1 - Alprostadil I2 - Prostacyclin A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are mediators and have a variety of strong physiological effects. Although they are technically hormones, they are rarely classified as such. The prostaglandins together with the thromboxanes and prostacyclins form the prostanoid class of fatty acid derivatives. The prostanoid is a subclass of eicosanoids.

Contents
[hide]

1 History and name 2 Biochemistry o 2.1 Biosynthesis o 2.2 Release of prostaglandins from the cell 2.2.1 Cyclooxygenases 2.2.2 Prostaglandin E synthase 2.2.3 Other terminal prostaglandin synthases 3 Function 4 Types 5 Role in pharmacology o 5.1 Inhibition o 5.2 Clinical uses 6 References 7 External links

[edit] History and name

The name prostaglandin derives from the prostate gland. When prostaglandin was first isolated from seminal fluid in 1935 by the Swedish physiologist Ulf von Euler,[1] and independently by M.W. Goldblatt,[2] it was believed to be part of the prostatic secretions. (In fact, prostaglandins

are produced by the seminal vesicles). It was later shown that many other tissues secrete prostaglandins for various functions. The first total syntheses of prostaglandin F2 and prostaglandin E2 were reported by E. J. Corey in 1969.[3] In 1971, it was determined that aspirin-like drugs could inhibit the synthesis of prostaglandins. The biochemists Sune K. Bergstrm, Bengt I. Samuelsson and John R. Vane jointly received the 1982 Nobel Prize in Physiology or Medicine for their research on prostaglandins.

[edit] Biochemistry
[edit] Biosynthesis
Biosynthesis of eicosanoids. (series-2) Prostaglandins are found in most tissues and organs. They are produced by all nucleated cells except lymphocytes. They are autocrine and paracrine lipid mediators that act upon platelets, endothelium, uterine and mast cells. They are synthesized in the cell from the essential fatty acids[4] (EFAs). An intermediate is created from phospholipase-A2, then brought out of one of either the cyclooxygenase pathway or the lipoxygenase pathway to form either prostaglandin and thromboxane or leukotriene. The cyclooxygenase pathway produces thromboxane, prostacyclin and prostaglandin D, E and F. The lipoxygenase enzyme pathway is inactive in leukocytes and in macrophages and synthesizes leukotrienes.

Name

EFA Type Series

Gamma-linolenic acid (GLA) via DGLA -6

series-1

Arachidonic acid (AA)

-6

series-2

Eicosapentaenoic acid (EPA)

-3

series-3

[edit] Release of prostaglandins from the cell

Prostaglandins were originally believed to leave the cells via passive diffusion because of their high lipophilicity. The discovery of the prostaglandin transporter (PGT, SLCO2A1), which mediates the cellular uptake of prostaglandin, demonstrated that diffusion cannot explain the penetration of prostaglandin through the cellular membrane. The release of prostaglandin has now also been shown to be mediated by a specific transporter, namely the multidrug resistance

protein 4 (MRP4, ABCC4), a member of the ATP-binding cassette transporter superfamily. Whether MRP4 is the only transporter releasing prostaglandins from the cells is still unclear. [edit] Cyclooxygenases Prostaglandins are produced following the sequential oxidation of AA, DGLA or EPA by cyclooxygenases (COX-1 and COX-2) and terminal prostaglandin synthases. The classic dogma is as follows:

COX-1 is responsible for the baseline levels of prostaglandins. COX-2 produces prostaglandins through stimulation.

However, while COX-1 and COX-2 are both located in the blood vessels, stomach and the kidneys, prostaglandin levels are increased by COX-2 in scenarios of inflammation. A third form of COX, termed COX-3 is thought to exist in the brain and may be associated with relief of Headaches when on NSAID therapy. [edit] Prostaglandin E synthase Prostaglandin E2 (PGE2) is generated from the action of prostaglandin E synthases on prostaglandin H2 (PGH2). Several prostaglandin E synthases have been identified. To date, microsomal prostaglandin E synthase-1 emerges as a key enzyme in the formation of PGE2. [edit] Other terminal prostaglandin synthases Terminal prostaglandin synthases have been identified that are responsible for the formation of other prostaglandins. For example, hematopoietic and lipocalin prostaglandin D synthases (hPGDS and lPGDS) are responsible for the formation of PGD2 from PGH2. Similarly, prostacyclin (PGI2) synthase (PGIS) converts PGH2 into PGI2. A thromboxane synthase (TxAS) has also been identified. Prostaglandin F synthase (PGFS) catalyzes the formation of 9,11PGF2, from PGD2 and PGF2 from PGH2 in the presence of NADPH. This enzyme has recently been crystallyzed in complex with PGD2[5] and bimatoprost[6] (a synthetic analogue of PGF2).

[edit] Function
There are currently nine known prostaglandin receptors on various cell types. Prostaglandins ligate a sub-family of cell surface seven-transmembrane receptors, G-protein-coupled receptors. These receptors are termed DP1-2, EP1-4, FP, Ip, and TP, corresponding to the receptor that ligates the corresponding prostaglandin (e.g., DP1-2 receptors bind to PGD2). The diversity of receptors means that prostaglandins act on an array of cells and have a wide variety of effects:

cause constriction or dilation in vascular smooth muscle cells cause aggregation or disaggregation of platelets sensitize spinal neurons to pain

decrease intraocular pressure regulate inflammatory mediation regulate calcium movement control hormone regulation control cell growth

Prostaglandins are potent but have a short half-life before being inactivated and excreted. Therefore, they send only paracrine (locally active) or autocrine (acting on the same cell from which it is synthesized) signals.

[edit] Types
The following is a comparison of different types of prostaglandin, prostaglandin I2 (PGI2), prostaglandin E2 (PGE2), and prostaglandin F2 (PGF2).

Type

Receptor

Function vasodilation inhibit platelet aggregation bronchodilatation bronchoconstriction GI tract smooth muscle contraction bronchodilatation GI tract smooth muscle relaxation vasodilatation gastric acid secretion gastric mucus secretion uterus contraction (when pregnant) GI tract smooth muscle contraction lipolysis inhibition autonomic neurotransmitters [7] platelet response to their agonists [8] [1] and atherothrombosis in vivo [9][2] hyperalgesia[7] pyrogenic uterus contraction

PGI2

IP

EP1

EP2

PGE2 EP3

Unspecified PGF2 FP

bronchoconstriction

[edit] Role in pharmacology

[edit] Inhibition
See also: Prostaglandin antagonist and Mechanism of action of aspirin Examples of prostaglandin antagonists are:

NSAIDs (inhibit cyclooxygenase) Corticosteroids (inhibit phospholipase A2 production) COX-2 selective inhibitors or coxibs

However, both NSAIDs and Coxibs can raise the risk of myocardial infarction.

[edit] Clinical uses

Synthetic prostaglandins are used:

To induce childbirth (parturition) or abortion (PGE2 or PGF2, with or without mifepristone, a progesterone antagonist); To prevent closure of patent ductus arteriosus in newborns with particular cyanotic heart defects (PGE1) To prevent and treat peptic ulcers (PGE) As a vasodilator in severe Raynaud's phenomenon or ischemia of a limb In pulmonary hypertension In treatment of glaucoma (as in bimatoprost ophthalmic solution, a synthetic prostamide analog with ocular hypotensive activity) To treat erectile dysfunction or in penile rehabilitation following surgery (PGE1 as alprostadil).[10] To treat egg binding in small birds[11]

[edit] References
1. ^ Von Euler US (1935). "ber die spezifische blutdrucksenkende Substanz des menschlichen Prostata- und Samenblasensekrets" (PDF). Wien Klin Wochenschr 14 (33): 11823. http://www.springerlink.com/content/g602m231xpw85226/fulltext.pdf. 2. ^ Goldblatt MW (May 1935). "Properties of human seminal plasma". J Physiol 84 (2): 20818. PMID 16994667. PMC: 1394818. http://www.jphysiol.org/cgi/pmidlookup?view=long&pmid=16994667. 3. ^ Nicolaou, K. C.; E. J. Sorensen (1996). Classics in Total Synthesis. Weinheim, Germany: VCH. p. 65. ISBN 3-527-29284-5. 4. ^ essential fatty acid (EFA) at Dorland's Medical Dictionary

5. ^ Komoto J, Yamada T, Watanabe K, Takusagawa F (2004). "Crystal structure of human prostaglandin F synthase (AKR1C3)". Biochemistry 43 (8): 218898. doi:10.1021/bi036046x. PMID 14979715. 6. ^ Komoto J, Yamada T, Watanabe K, Woodward D, Takusagawa F (2006). "Prostaglandin F2alpha formation from prostaglandin H2 by prostaglandin F synthase (PGFS): crystal structure of PGFS containing bimatoprost". Biochemistry 45 (7): 198796. doi:10.1021/bi051861t. PMID 16475787. 7. ^ a b Rang, H. P. (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. pp. 234. ISBN 0-443-07145-4. 8. ^ Fabre JE, Nguyen M, Athirakul K, Coggins K, McNeish JD, Austin S, Parise LK, FitzGerald GA, Coffman TM, Koller BH. Journal of Clinical investigation, 2001, 107:603 9. ^ Gross S,Tilly P, Hentsch D, Vonesch JL, Fabre JE. Journal of Experimental Medicine, 2007, 204:311 10. ^ Medscape Early Penile Rehabilitation Helps Reduce Later Intractable ED 11. ^ LaBonde, MS, DVM, Jerry. "Avian Reproductive and Pediatric Disorders" (PDF). Michigan Veterinary Medical Association. http://www.michvma.org/documents/MVC%20Proceedings/Labonde2.pdf. Retrieved on 200801-26.

[edit] External links

MeSH Prostaglandins [show]

vde

Endocrine system: hormones (Peptide hormones Steroid hormones)

Hypothalamus GnRH TRH Dopamine CRH GHRH/Somatostatin

Hypothalamic- Posterior pituitary Vasopressin Oxytocin pituitary (FSH FSHB, LH LHB, TSH TSHB, CGA) Anterior pituitary Prolactin POMC (ACTH, MSH, Endorphins, Lipotropin) GH Adrenal axis Thyroid axis Adrenal cortex: aldosterone cortisol DHEA Adrenal medulla: epinephrine norepinephrine Thyroid: thyroid hormone (T3 and T4) calcitonin Parathyroid: PTH Testis: testosterone AMH inhibin Gonadal axis Ovary: estradiol progesterone activin and inhibin relaxin (pregnancy) Placenta: hCG HPL estrogen progesterone Other end. Pancreas: glucagon insulin somatostatin glands

Pineal gland: melatonin Thymus: Thymosin Thymopoietin Thymulin

[show]
vde

Autacoids, unsaturated fatty acids: Eicosanoids

Precursor H2 D/J D2 E2 (Dinoprostone): Enprostil Sulprostone Prostaglandins (PG) and analogues E1 (Alprostadil): Misoprostol Gemeprost Active E/F F2 (Dinoprost): Bimatoprost Carboprost Latanoprost Tafluprost Travoprost Unoprostone I Thromboxanes (TX) A2 B2 Precursor Arachidonic acid 5-hydroperoxide Initial A4 B4 SRS-A C4 D4 E4 I2 (Prostacyclin/Epoprostenol): Beraprost Iloprost Treprostinil

Retrieved from "http://en.wikipedia.org/wiki/Prostaglandin" Categories: Prostaglandins

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Thromboxane
From Wikipedia, the free encyclopedia

(Redirected from Thromboxanes) Jump to: navigation, search Thromboxane A2 Thromboxane B2 Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. Thromboxane is named for its role in clot formation (thrombosis).

Contents
[hide]

1 Production 2 Mechanism

3 Functions 4 Role of A2 in platelet aggregation 5 Pathology 6 Suppression 7 See also 8 Nota Bene 9 References 10 External links

[edit] Production
Enzymes and substrates associated with thromoboxane and prostacyclin synthesis. Eicosanoid synthesis. It is produced in platelets by thromboxane-A synthase from the endoperoxides produced by the cyclooxygenase (COX) enzyme from arachidonic acid.

[edit] Mechanism
Thromboxane acts by binding to any of the thromboxane receptors, G-protein coupled receptors coupled to the G protein Gq[1].

[edit] Functions
Thromboxane is a vasoconstrictor and a potent hypertensive agent, and it facilitates platelet aggregation. It is in homeostatic balance in the circulatory system with prostacyclin, a related compound. The mechanism of secretion of thromboxanes from platelets is still unclear.

[edit] Role of A2 in platelet aggregation

Thromboxane A2 (TXA2), produced by activated platelets, has prothrombotic properties, stimulating activation of new platelets as well as increasing platelet aggregation. Platelet aggregation is achieved by mediating expression of the glycoprotein complex GP IIb/IIIa in the cell membrane of platelets. Circulating fibrinogen binds these receptors on adjacent platelets, further strengthening the clot.

[edit] Pathology

It is believed that the vasoconstriction caused by thromboxanes plays a role in Prinzmetal's angina.

[edit] Suppression
See also: Mechanism of action of aspirin and Aspirin The widely used drug aspirin acts by inhibiting the ability of the COX enzyme to synthesize the precursors of thromboxane within platelets. Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks.[2] 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A2 release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.[3] One side effect of this is that people who regularly take aspirin will suffer from excessive bleeding whenever the skin is perforated.

[edit] See also

Thromboxane synthase

[edit] Nota Bene

Thromboxane synthetase is misnamed for thromboxane synthase but is often found in the literature.

[edit] References
1. ^ Rat kidney thromboxane receptor: molecular cloning, signal ... 2. ^ [1] American Heart Association: Aspirin in Heart Attack and Stroke Prevention "The American Heart Association recommends aspirin use for patients who've had a myocardial infarction (heart attack), unstable angina, ischemic stroke (caused by blood clot) or transient ischemic attacks (TIAs or "little strokes"), if not contraindicated. This recommendation is based on sound evidence from clinical trials showing that aspirin helps prevent the recurrence of such events as heart attack, hospitalization for recurrent angina, second strokes, etc. (secondary prevention). Studies show aspirin also helps prevent these events from occurring in people at high risk (primary prevention)." 3. ^ Tohgi, H; S Konno, K Tamura, B Kimura and K Kawano (1992). "Effects of low-tohigh doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin". Stroke Vol 23: 14001403. PMID 1412574.

[edit] External links

MeSH Thromboxanes

[hide]
vde

Autacoids, unsaturated fatty acids: Eicosanoids

Precursor Arachidonic acid Precursor H2 D/J D2 E2 (Dinoprostone): Enprostil Sulprostone E1 (Alprostadil): Misoprostol Gemeprost F2 (Dinoprost): Bimatoprost Carboprost Latanoprost Tafluprost Travoprost Unoprostone I2 (Prostacyclin/Epoprostenol): I Beraprost Iloprost Treprostinil Thromboxanes (TX) A2 B2 Precursor Arachidonic acid 5-hydroperoxide Leukotrienes (LT) Nonclassic Initial A4 B4 SRS-A C4 D4 E4 Lipoxins (A4, B4) Virodhamine bronchoconstriction (PGF2, TXA2, LTC4, LTD4, LTE4) vasoconstriction (PGF2, TXA2, TXB2) vasodilation (PGE2, PGI2, LTC4, LTD4, LTE4) By function platelets: induce (TXA2) inhibit (PGD2, PGI2) leukocytes: induce (TXA2, LTB4) inhibit (PGD2, PGE2) labor stimulation: (PGE2 (Dinoprostone), PGF2 (Dinoprost)) see also enzymes Retrieved from "http://en.wikipedia.org/wiki/Thromboxane" Categories: Eicosanoids
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Prostanoids

Prostaglandins (PG) and analogues

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Eicosanoid
From Wikipedia, the free encyclopedia

(Redirected from Eicosanoids) Jump to: navigation, search Pathways in biosynthesis of eicosanoids from arachidonic acid: there are parallel paths from EPA & DGLA. In biochemistry, eicosanoids are signaling molecules made by oxygenation of twenty-carbon essential fatty acids, (EFAs). They exert complex control over many bodily systems, mainly in inflammation or immunity, and as messengers in the central nervous system. The networks of controls that depend upon eicosanoids are among the most complex in the human body. Eicosanoids derive from either omega-3 (-3) or omega-6 (-6) EFAs. The -6 eicosanoids are generally pro-inflammatory; -3's are much less so. The amounts and balance of these fats in a person's diet will affect the body's eicosanoid-controlled functions, with effects on cardiovascular disease, triglycerides, blood pressure, and arthritis. Anti-inflammatory drugs such as aspirin and other NSAIDs act by downregulating eicosanoid synthesis. There are four families of eicosanoidsthe prostaglandins, prostacyclins, the thromboxanes and the leukotrienes. For each, there are two or three separate series, derived either from an -3 or 6 EFA. These series' different activities largely explain the health effects of -3 and -6 fats.[1][2][3][4]

Contents
[hide]

1 Nomenclature 2 Biosynthesis o 2.1 Peroxidation and reactive oxygen species o 2.2 Prostanoid pathways o 2.3 Leukotriene pathways

3 Function and pharmacology o 3.1 The -3 and -6 series 3.1.1 Mechanisms of -3 action o 3.2 Role in inflammation o 3.3 Action of prostanoids o 3.4 Action of leukotrienes 4 History 5 References 6 External links

[edit] Nomenclature
See related detail at Essential Fatty Acid InteractionsNomenclature "Eicosanoid" (eicosa-, Greek for "twenty"; see icosahedron) is the collective term[5] for oxygenated derivatives of three different 20-carbon essential fatty acids:

Eicosapentaenoic acid (EPA), an -3 fatty acid with 5 double bonds; Arachidonic acid (AA), an -6 fatty acid, with 4 double bonds; Dihomo-gamma-linolenic acid (DGLA), an -6, with 3 double bonds.

Current usage limits the term to the leukotrienes (LT) and three types of prostanoids prostaglandins (PG) prostacyclins (PGI), and thromboxanes (TX). This is the definition used in this article. However, several other classes can technically be termed eicosanoid, including the hepoxilins, resolvins, isofurans, isoprostanes, lipoxins, epi-lipoxins, epoxyeicosatrienoic acids (EETs) and endocannabinoids. LTs and prostanoids are sometimes termed 'classic eicosanoids'[6][7][8] in contrast to the 'novel', 'eicosanoid-like' or 'nonclassic eicosanoids'.[9][10][11][12] A particular eicosanoid is denoted by a four-character abbreviation, composed of:

Its two letter abbreviation (above),[13] One A-B-C sequence-letter;[14] and A subscript, indicating the number of double bonds.

Examples are:

The EPA-derived prostanoids have three double bonds, (e.g. PGG3, PGH3, PGI3, TXA3) while its leukotrienes have five, (LTB5). The AA-derived prostanoids have two double bonds, (e.g. PGG2, PGH2, PGI2, TXA2) while its leukotrienes have four, (LTB4).

Furthermore, stereochemistry may differ among the pathways, indicated by Greek letters, e.g. for (PGF2).

[edit] Biosynthesis
Two families of enzymes catalyze fatty acid oxygenation to produce the eicosanoids:

Cyclooxygenase, or COX, generates the prostanoids. Lipoxygenase, or LOX, in several forms. 5-lipoxygenase (5-LO) generates the leukotrienes.

Eicosanoids are not stored within cells, but are synthesized as required. They derive from the fatty acids that make up the cell membrane and nuclear membrane. Eicosanoid biosynthesis begins when cell is activated by mechanical trauma, cytokines, growth factors or other stimuli. (The stimulus may even be an eicosanoid from a neighboring cell; the pathways are complex.) This triggers the release of a phospholipase at the cell membrane. The phospholipase travels to the nuclear membrane. There, the phospholipase catalyzes ester hydrolysis of phospholipid (by A2) or diacylglycerol (by phospholipase C). This frees a 20carbon essential fatty acid. This hydrolysis appears to be the rate-determining step for eicosanoid formation. The fatty acids may be released by any of several phospholipases. Of these, type IV cytosolic phospholipase A2 (cPLA2) is the key actor, as cells lacking cPLA2 are generally devoid of eicosanoid synthesis. The phospholipase cPLA2 is specific for phospholipids that contain AA, EPA or GPLA at the SN2 position. Interestingly, cPLA2 may also release the lysophospholipid that becomes platelet-activating factor.[15]

[edit] Peroxidation and reactive oxygen species

Next, the free fatty acid is oxygenated along any of several pathways; see the Pathways table. The eicosanoid pathways (via lipoxygenase or COX) add molecular oxygen (O2). Although the fatty acid is symmetric, the resulting eicosanoids are chiral; the oxidation proceeds with high stereospecificity. The oxidation of lipids is hazardous to cells, particularly when close to the nucleus. There are elaborate mechanisms to prevent unwanted oxidation. COX, the lipoxygenases and the phospholipases are tightly controlledthere are at least eight proteins activated to coordinate generation of leukotrienes. Several of these exist in multiple isoforms.[4] Oxidation by either COX or lipoxygenase releases reactive oxygen species (ROS) and the initial products in eicosanoid generation are themselves highly reactive peroxides. LTA4 can form adducts with tissue DNA. Other reactions of lipoxygenases generate cellular damage; murine models implicate 15-lipoxygenase in the pathogenesis of atherosclerosis.[16][17] The oxidation in eicosanoid generation is compartmentalized; this limits the peroxides' damage. The enzymes which are biosynthetic for eicosanoids (e.g. glutathione-S-transferases, epoxide hydrolases and carrier proteins) belong to families whose functions are largely involved with cellular detoxification. This suggests that eicosanoid signaling may have evolved from the detoxification of ROS.

The cell must realize some benefit from generating lipid hydroperoxides close-by its nucleus. PGs and LTs may signal or regulate DNA-transcription there; LTB4 is ligand for PPAR.[2] (See diagram at PPAR). Structures of Selected Eicosanoids Prostaglandin E1. The 5-member ring is characteristic of the class. Thromboxane A2. Oxygens Leukotriene B4. Note the 3 have moved into conjugated double bonds. the ring. Leukotriene E4, an example of a cysteinyl leukotriene.

Prostacyclin I2. The second ring distinguishes it from the prostaglandins.

[edit] Prostanoid pathways

See Prostanoid#Biosynthesis. Cyclooxygenase (COX) catalyzes the conversion of the free essential fatty acids to prostanoids by a two-step process. First, two molecules of O2 are added as two peroxide linkages, and a 5member carbon ring is forged near the middle of the fatty acid chain. This forms the short-lived, unstable intermediate Prostaglandin G (PGG). Next, one of the peroxide linkages sheds a single oxygen, forming PGH. (See diagrams and more detail of these steps at Cyclooxygenase). All three classes of prostanoids originate from PGH. All have distinctive rings in the center of the molecule. They differ in their structures. The PGH compounds (parents to all the rest) have a 5-carbon ring, bridged by two oxygens (a peroxide.) As the example in Structures of Selected Eicosanoids figure shows, the derived prostaglandins contain a single, unsaturated 5-carbon ring. In prostacyclins, this ring is conjoined to another oxygen-containing ring. In thromboxanes the ring becomes a 6-member ring with one oxygen. The leukotrienes do not have rings. (See more detail, including the enzymes involved, in diagrams at Prostanoid.) Several drugs lower inflammation by blocking prostanoid synthesis; see detail at Cyclooxygenase, Aspirin and NSAID.

[edit] Leukotriene pathways

See Leukotriene#Biosynthesis. The enzyme 5-lipoxygenase (5-LO) uses 5-lipoxygenase activating protein (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), which may be converted into LTB4 by the enzyme leukotriene A4 epoxide hydrolase. Eosinophils, mast cells, and alveolar macrophages use the enzyme leukotriene C4 synthase to conjugate glutathione with LTA4 to make LTC4, which is transported outside the cell, where a glutamic acid moiety is removed from it to make LTD4. The

leukotriene LTD4 is then cleaved by dipeptidases to make LTE4. The leukotrienes LTC4, LTD4 and LTE4 all contain cysteine and are collectively known as the cysteinyl leukotrienes.

[edit] Function and pharmacology

Metabolic actions of selected prostanoids and leukotrienes[15]

PGD2 Promotion of sleep

TXA2

Stimulation of platelet aggregation; vasoconstriction

Smooth muscle contraction; PGE2 inducing pain, heat, fever; bronchoconstriction

15d-PGJ2

Adipocyte differentiation

PGF2 Uterine contraction

LTB4

Leukocyte chemotaxis

PGI2

Inhibition of platelet aggregation; Anaphylaxis; bronchial smooth Cysteinyl-LTs vasodilation; embryo implantation muscle contraction.

Shown eicosanoids are AA-derived; EPA-derived generally have weaker activity

Eicosanoids exert complex control over many bodily systems, mainly in inflammation or immunity, and as messengers in the central nervous system. They are found in most living things. In humans, eicosanoids are local hormones that are released by most cells, act on that same cell or nearby cells (i.e., they are autocrine and paracrine mediators), and then are rapidly inactivated. Eicosanoids have a short half-life, ranging from seconds to minutes. Dietary antioxidants inhibit the generation of some inflammatory eicosanoids, e.g. trans-resveratrol against thromboxane and some leukotrienes.[18] Most eicosanoid receptors are members of the G protein-coupled receptor superfamily; see the Receptors table or the article eicosanoid receptors.

Receptors: There are specific receptors for all eicosanoids (see also: eicosanoid receptors)

Leukotrienes:

CysLT1 (Cysteinyl leukotriene receptor type 1) CysLT2 (Cysteinyl leukotriene receptor type 2) BLT1 (Leukotriene B4 receptor)

Prostanoids:

PGD2: DP-(PGD2) PGE2: o EP1-(PGE2) o EP2-(PGE2) o EP3-(PGE2) o EP4-(PGE2) PGF2: FP-(PGF2) PGI2 (prostacyclin): IP-(PGI2) TXA2 (thromboxane): TP-(TXA2)

[edit] The -3 and -6 series

Main article: Essential fatty acid interactions

The reduction in AA-derived eicosanoids and the diminished activity of the alternative products generated from -3 fatty acids serve as the foundation for explaining some of the beneficial effects of greater -3 intake.

Kevin Fritsche, Fatty Acids as Modulators of the Immune Response [19]

Arachidonic acid (AA; 20:4 -6) sits at the head of the 'arachidonic acid cascade'more than twenty different eicosanoid-mediated signaling paths controlling a wide array of cellular functions, especially those regulating inflammation, immunity and the central nervous system.[3] In the inflammatory response, two other groups of dietary essential fatty acids form cascades that parallel and compete with the arachidonic acid cascade. EPA (20:5 -3) provides the most important competing cascade. DGLA (20:3 -6) provides a third, less prominent cascade. These two parallel cascades soften the inflammatory effects of AA and its products. Low dietary intake of these less-inflammatory essential fatty acids, especially the -3s, has been linked to several inflammation-related diseases, and perhaps some mental illnesses.

The U.S. National Institutes of Health and the National Library of Medicine state that there is 'A' level evidence ('strong scientific evidence') that increased dietary -3 improves outcomes in hypertriglyceridemia, secondary cardiovascular disease prevention and hypertension. There is 'B' level evidence ('good scientific evidence') for increased dietary -3 in primary prevention of cardiovascular disease, rheumatoid arthritis and protection from ciclosporin toxicity in organ transplant patients. They also note more preliminary evidence showing that dietary -3 can ease symptoms in several psychiatric disorders.[20] Besides the influence on eicosanoids, dietary polyunsaturated fats modulate immune response through three other molecular mechanisms. They (a) alter membrane composition and function, including the composition of lipid rafts; (b) change cytokine biosynthesis and (c) directly activate gene transcription.[19] Of these, the action on eicosanoids is the best explored. [edit] Mechanisms of -3 action EFA sources: Essential fatty acid production and metabolism to form eicosanoids. At each step, the -3 and -6 cascades compete for the enzymes. The eicosanoids from AA generally promote inflammation. Those from EPA and from GLA (via DGLA) are generally less inflammatory, or inactive, or even anti-inflammatory. The figure shows the -3 and -6 synthesis chains, along with the major eicosanoids from AA, EPA and DGLA. Dietary -3 and GLA counter the inflammatory effects of AA's eicosanoids in three ways, along the eicosanoid pathways:

DisplacementDietary -3 decreases tissue concentrations of AA, so there is less to form -6 eicosanoids. Competitive inhibitionDGLA and EPA compete with AA for access to the cyclooxygenase and lipoxygenase enzymes. So the presence of DGLA and EPA in tissues lowers the output of AA's eicosanoids. CounteractionSome DGLA and EPA derived eicosanoids counteract their AA derived counterparts.

[edit] Role in inflammation

Since antiquity, the cardinal signs of inflammation have been known as: calor (warmth), dolor (pain), tumor (swelling) and rubor (redness). The eicosanoids are involved with each of these signs. RednessAn insect's sting will trigger the classic inflammatory response. Short acting vasoconstrictors TXA2are released quickly after the injury. The site may momentarily turn pale. Then TXA2 mediates the release of the vasodilators PGE2 and LTB4. The blood vessels engorge and the injury reddens. SwellingLTB4 makes the blood vessels more permeable. Plasma leaks out into the connective

tissues, and they swell. The process also looses pro-inflammatory cytokines. PainThe cytokines increase COX-2 activity. This elevates levels of PGE2, sensitizing pain neurons. HeatPGE2 is also a potent pyretic agent. Aspirin and NSAIDSdrugs that block the COX pathways and stop prostanoid synthesislimit fever or the heat of localized inflammation.

Pharmacy: Eicosanoid, eicosanoid analogs and receptor agonists/antagonists used as medicines

Medicine

Type

Medical condition or use

Alprostadil

PGE1

Erectile dysfunction, maintaining a patent ductus arteriosus in the fetus

Beraprost

PGI1 analog

Pulmonary hypertension, avoiding reperfusion injury

Bimatoprost

PG analog

Glaucoma, ocular hypertension

Carboprost

PG analog

Labor induction, abortifacient in early pregnancy

Dinoprostone

PGE2

Labor induction

Iloprost

PGI2 analog

Pulmonary arterial hypertension

Latanoprost

PG analog

Glaucoma, ocular hypertension

Misoprostol

PGE1 analog

Stomach ulcers, labor induction, abortifacient

Montelukast

LT receptor antagonist

Asthma, seasonal allergies

Travoprost

PG analog

Glaucoma, ocular hypertension

Treprostinil

PGI analog

Pulmonary hypertension

U46619

Longer lived TX analog

Research only

Zafirlukast

LT receptor antagonist

Asthma

[edit] Action of prostanoids

Main articles: Prostaglandin, Prostacyclin and Thromboxane Prostanoids mediate local symptoms of inflammation: vasoconstriction or vasodilation, coagulation, pain and fever. Inhibition of cyclooxygenase, specifically the inducible COX-2 isoform, is the hallmark of NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin. COX-2 is responsible for pain and inflammation, while COX-1 is responsible for platelet clotting actions. Prostanoids activate the PPAR members of the steroid/thyroid family of nuclear hormone receptors, directly influencing gene transcription.[21]

[edit] Action of leukotrienes

Main article: Leukotriene Leukotrienes play an important role in inflammation. There is a neuroendocrine role for LTC4 in luteinizing hormone secretion.[22] LTB4 causes adhesion and chemotaxis of leukocytes and stimulates aggregation, enzyme release, and generation of superoxide in neutrophils.[23] Blocking leukotriene receptors can play a role in the management of inflammatory diseases such as asthma (by the drugs montelukast and zafirlukast), psoriasis, and rheumatoid arthritis. The slow reacting substance of anaphylaxis comprises the cysteinyl leukotrienes. These have a clear role in pathophysiological conditions such as asthma, allergic rhinitis and other nasal allergies, and have been implicated in atherosclerosis and inflammatory gastrointestinal diseases.[24] They are potent bronchoconstrictors, increase vascular permeability in postcapillary venules, and stimulate mucus secretion. They are released from the lung tissue of asthmatic subjects exposed to specific allergens and play a pathophysiological role in immediate

hypersensitivity reactions.[23] Along with PGD, they function in effector cell trafficking, antigen presentation, immune cell activation, matrix deposition, and fibrosis.[25]

[edit] History
In 1930, gynecologist Raphael Kurzrok and pharmacologist Charles Leib characterized prostaglandin as a component of semen. Between 1929 and 1932, Burr and Burr showed that restricting fat from animal's diets led to a deficiency disease, and first described the essential fatty acids.[26] In 1935, von Euler identified prostaglandin. In 1964, Bergstrm and Samuelsson linked these observations when they showed that the "classical" eicosanoids were derived from arachidonic acid, which had earlier been considered to be one of the essential fatty acids.[27] In 1971, Vane showed that aspirin and similar drugs inhibit prostaglandin synthesis.[28] Von Euler received the Nobel Prize in medicine in 1970, which Samuelsson, Vane, and Bergstrm also received in 1982. E. J. Corey received it in chemistry in 1990 largely for his synthesis of prostaglandins.

[edit] References
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10. ^ O'Brien WF, Krammer J, O'Leary TD, Mastrogiannis DS (1993). "The effect of acetaminophen on prostacyclin production in pregnant women". Am. J. Obstet. Gynecol. 168 (4): 11649. PMID 8475962. 11. ^ Behrendt H, Kasche A, Ebner von Eschenbach C, Risse U, Huss-Marp J, Ring J (2001). "Secretion of proinflammatory eicosanoid-like substances precedes allergen release from pollen grains in the initiation of allergic sensitization". Int. Arch. Allergy Immunol. 124 (1-3): 1215. doi:10.1159/000053688. PMID 11306946. 12. ^ Sarau HM, Foley JJ, Schmidt DB, et al. (1999). "In vitro and in vivo pharmacological characterization of SB 201993, an eicosanoid-like LTB4 receptor antagonist with antiinflammatory activity". Prostaglandins Leukot. Essent. Fatty Acids 61 (1): 5564. doi:10.1054/plef.1999.0074. PMID 10477044. 13. ^ ProstacyclinPGIwas previously classified as prostaglandin and retains its old identifier. 14. ^ Eicosanoids with different letters have placement of double-bonds and different functional groups attached to the molecular skeleton. Letters indicate roughly the order the eicosanoids were first described in the literature. For diagrams for PG [AH] see Cyberlipid Center. "Prostanoids". http://www.cyberlipid.org/prost1/pros0001.htm. Retrieved on 2007-02-05. 15. ^ a b University of Kansas Medical Center (2004). "Eicosanoids and Inflammation" (PDF). http://classes.kumc.edu/som/bioc801/small_group/eicosanoids/eicosanoids-2004.pdf. Retrieved on 2007-01-05. 16. ^ Cyrus, Tillmann (June 1999). "Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo Edeficient mice". J Clin Invest 103 (11): 15971604n. doi:10.1172/JCI5897. http://www.jci.org/cgi/content/abstract/103/11/1597. 17. ^ Schewe T. (2002 Mar-Apr). "15-lipoxygenase-1: a prooxidant enzyme". Biol Chem. 383 (3-4): 365. doi:10.1515/BC.2002.041. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12033428 . Retrieved on 2007-01-09. 18. ^ Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM. (1995 March 31). "The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease". Clin Chim Acta. 235 (2): 20719. doi:10.1016/0009-8981(95)06045-1. PMID 7554275. 19. ^ a b Fritsche, Kevin (August 2006). "Fatty Acids as Modulators of the Immune Response". Annual Review of Nutrition 26: 4573. doi:10.1146/annurev.nutr.25.050304.092610. http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.nutr.25.050304.092610?journalCode =nutr. Retrieved on 2007-01-11. 20. ^ National Institute of Health (2005-08-01). "Omega-3 fatty acids, fish oil, alpha-linolenic acid". http://www.nlm.nih.gov/medlineplus/print/druginfo/natural/patient-fishoil.html. Retrieved on March 26 2006. 21. ^ Bos C, Richel D, Ritsema T, Peppelenbosch M, Versteeg H (2004). "Prostanoids and prostanoid receptors in signal transduction". Int J Biochem Cell Biol 36 (7): 1187205. doi:10.1016/j.biocel.2003.08.006. PMID 15109566. 22. ^ Samuelsson, SE Dahlen, JA Lindgren, CA Rouzer, and CN Serhan (09-04 1987). "Leukotrienes and lipoxins: structures, biosynthesis, and biological effects". Science 237 (4819): 11711176. doi:10.1126/science.2820055. PMID 2820055. http://www.sciencemag.org/cgi/content/abstract/237/4819/1171. Retrieved on 2007-01-22. 23. ^ a b Samuelsson B (May 1983). "Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation". Science 220 (4597): 568575. doi:10.1126/science.6301011. PMID 6301011. http://www.sciencemag.org/cgi/content/abstract/sci;220/4597/568. 24. ^ Capra V (2004). "Molecular and functional aspects of human cysteinyl leukotriene receptors". Pharmacol Res 50 (1): 111. doi:10.1016/j.phrs.2003.12.012. PMID 15082024.

25. ^ Boyce J (2005). "Eicosanoid mediators of mast cells: receptors, regulation of synthesis, and pathobiologic implications". Chem Immunol Allergy 87: 5979. doi:10.1159/000087571. PMID 16107763. 26. ^ Burr, G.O. and Burr, M.M. (1930). "On the nature and role of the fatty acids essential in nutrition" (PDF). J. Biol. Chem. 86 (587). http://www.jbc.org/cgi/reprint/97/1/1.pdf. Retrieved on 2007-01-17. 27. ^ Bergstrm, S., Danielsson, H. and Samuelsson, B. (1964). "The enzymatic formation of prostaglandin E2 from arachidonic acid". Biochim. Biophys. Acta 90 (207). PMID 14201168. 28. ^ Vane, J. R. (23 June 1971). "Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs". Nature New Biol. 231 (25): 2325. PMID 5284360.

[edit] External links

MeSH Eicosanoids [show]

vde

Types of Lipids

[show]
vde

Autacoids
[show]
vde

Autacoids, unsaturated fatty acids: Eicosanoids

Precursor H2 D/J D2 E2 (Dinoprostone): Enprostil Sulprostone Prostaglandins (PG) and analogues Active E1 (Alprostadil): Misoprostol Gemeprost E/F F2 (Dinoprost): Bimatoprost Carboprost Latanoprost Tafluprost Travoprost Unoprostone

I Thromboxanes (TX) A2 B2

I2 (Prostacyclin/Epoprostenol): Beraprost Iloprost Treprostinil

Precursor Arachidonic acid 5-hydroperoxide Initial A4 B4 SRS-A C4 D4 E4

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