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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, such as regulating the contraction and relaxation of smooth muscle tissue. [1] 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

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,[2] and independently by M.W. Goldblatt,[3] 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 F and prostaglandin E2 were reported by E. J. Corey in 1969.[4]

In 1971, it was determined that aspirin-like drugs could inhibit the synthesis of prostaglandins. The biochemists Sune K. Bergström, Bengt I. Samuelsson and John R. Vane jointly received the 1982 Nobel Prize in Physiology or Medicine for their research on prostaglandins.

Biochemistry

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[5] (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 ω-6 series-1
Arachidonic acid (AA) ω-6 series-2
Eicosapentaenoic acid (EPA) ω-3 series-3

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.

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.

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.

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 9α,11β-PGF2α,β from PGD2 and PGF from PGH2 in the presence of NADPH. This enzyme has recently been crystallyzed in complex with PGD2[6] and bimatoprost[7] (a synthetic analogue of PGF).

Function

There are currently ten 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, IP1-2, 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:

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.

Types

The following is a comparison of different types of prostaglandin, prostaglandin I2 (PGI2), prostaglandin E2 (PGE2), and prostaglandin F (PGF).

Type Receptor Function
PGI2 IP
PGE2 EP1
EP2
EP3
Unspecified
PGF FP

Role in pharmacology

Inhibition

Examples of prostaglandin antagonists are:

Clinical uses

Synthetic prostaglandins are used:

References

  1. ^ Nelson RJ. 2005. An introduction to behavior endocrinology. 3rd ed. Sinauer Associates, Massachusetts. pg. 100.
  2. ^ Von Euler US (1935). "Über die spezifische blutdrucksenkende Substanz des menschlichen Prostata- und Samenblasensekrets" (PDF). Wien Klin Wochenschr 14 (33): 1182–3. http://www.springerlink.com/content/g602m231xpw85226/fulltext.pdf.  
  3. ^ Goldblatt MW (May 1935). "Properties of human seminal plasma". J Physiol 84 (2): 208–18. PMID 16994667. PMC 1394818. http://www.jphysiol.org/cgi/pmidlookup?view=long&pmid=16994667.  
  4. ^ Nicolaou, K. C.; E. J. Sorensen (1996). Classics in Total Synthesis. Weinheim, Germany: VCH. p. 65. ISBN 3-527-29284-5.  
  5. ^ essential fatty acid (EFA) at Dorland's Medical Dictionary
  6. ^ Komoto J, Yamada T, Watanabe K, Takusagawa F (2004). "Crystal structure of human prostaglandin F synthase (AKR1C3)". Biochemistry 43 (8): 2188–98. doi:10.1021/bi036046x. PMID 14979715.  
  7. ^ 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): 1987–96. doi:10.1021/bi051861t. PMID 16475787.  
  8. ^ a b Rang, H. P. (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. pp. 234. ISBN 0-443-07145-4.  
  9. ^ 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
  10. ^ Gross S,Tilly P, Hentsch D, Vonesch JL, Fabre JE. Journal of Experimental Medicine, 2007, 204:311
  11. ^ Medscape Early Penile Rehabilitation Helps Reduce Later Intractable ED
  12. ^ LaBonde, MS, DVM, Jerry. "Avian Reproductive and Pediatric Disorders" (PDF). Michigan Veterinary Medical Association. http://www.michvma.org/documents/MVC%20Proceedings/Labonde2.pdf. Retrieved 2008-01-26.  

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