Prostaglandin

From Wikipedia, the free encyclopedia - View original article

 
Jump to: navigation, search

The prostaglandins are a group of hormone-like 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] Prostaglandins are not endocrine hormones, but autocrine or paracrine, which are locally acting messenger molecules. They differ from hormones in that they are not produced at a specific site but in many places throughout the human body. Also, their target cells are present in the immediate vicinity of the site of their secretion (of which there are many).

The prostaglandins, together with the thromboxanes and prostacyclins, form the prostanoid class of fatty acid derivatives, a subclass of eicosanoids.

The abbreviation for "prostaglandin" is PG; specific prostaglandins are named with a letter (which indicates the type of ring structure) followed by a number (which indicates the number of double bonds in the hydrocarbon structure). For example, prostaglandin E1 is abbreviated PGE1 or PGE1, and prostaglandin I2 is abbreviated PGI2 or PGI2. The number is traditionally subscripted when the context allows, but as with many similar subscript-containing nomenclatures, the subscript is simply forgone in many database fields that can store only plain text (such as PubMed bibliographic fields), and readers are used to seeing and writing it without subscript.

History and name[edit]

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] an achievement for which he was awarded the Japan Prize in 1989.

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[edit]

Biosynthesis[edit]

Biosynthesis of eicosanoids

Prostaglandins are found in most tissues and organs. They are produced by almost all nucleated cells. 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 (EFAs).

An intermediate arachidonic acid is created from diacylglycerol via phospholipase-A2, then brought to either the cyclooxygenase pathway or the lipoxygenase pathway to form either prostaglandin and thromboxane or leukotriene respectively. The cyclooxygenase pathway produces thromboxane, prostacyclin and prostaglandin D, E and F. Alternatively, the lipoxygenase enzyme pathway is active in leukocytes and in macrophages and synthesizes leukotrienes.

Release of prostaglandins from the cell[edit]

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 alone 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[edit]

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:

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 and growth.

Prostaglandin E synthase[edit]

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[edit]

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 crystallized in complex with PGD2[5] and bimatoprost[6] (a synthetic analogue of PGF).

Function[edit]

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 such as:

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[edit]

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

TypeReceptorReceptor typeFunction
PGI2IPGs
PGE2EP1Gq
EP2Gs
EP3Gi
Unspecified
PGFFPGq

Role in pharmacology[edit]

Inhibition[edit]

Examples of prostaglandin antagonists are:

Clinical uses[edit]

Synthetic prostaglandins are used:

References[edit]

  1. ^ Nelson, Randy F. (2005). An introduction to behavioral endocrinology (3rd ed.). Sunderland, Mass: Sinauer Associates. p. 100. ISBN 0-87893-617-3. 
  2. ^ Von Euler US (1935). "Über die spezifische blutdrucksenkende Substanz des menschlichen Prostata- und Samenblasensekrets" (PDF). Wien Klin Wochenschr 14 (33): 1182–3. doi:10.1007/BF01778029. 
  3. ^ Goldblatt MW (May 1935). "Properties of human seminal plasma". J Physiol 84 (2): 208–18. PMC 1394818. 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. ^ 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. 
  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): 1987–96. doi:10.1021/bi051861t. PMID 16475787. 
  7. ^ a b Rang, H. P. (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. p. 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. Archived from the original on 2008-02-27. Retrieved 2008-01-26. 

External links[edit]