| Prostaglandin |
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A prostaglandin is any member of a group of Lipid compounds that are derived from Fatty Acid s 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 Hormone s, they are rarely classified as such. The prostaglandins together with the Thromboxane s form the Prostanoid class of fatty acid derivatives; the prostanoid class is a subclass of Eicosanoid s. HISTORY AND NAME The name ''prostaglandin'' derives from the Prostate Gland . When prostaglandin was first isolated from Seminal Fluid in 1936 , it was believed to be part of the prostatic secretions. In actuality prostaglandins are produced by the Seminal Vesicles . 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 Prostaglandins are found in virtually all tissues and organs. These are Autocrine and Paracrine lipid mediators that act upon Platelet , Endothelium , Uterine and Mast Cell s, among others. They are synthesized in the cell from the Essential Fatty Acid s (EFAs).
An intermediate is created by Phospholipase-A2 , then passed into 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 pathway is active in Leukocyte s and in Macrophage s and synthesises leukotrienes. Prostaglandins are released through the prostaglandin transporter on the cell's plasma membrane. Cyclooxygenases Prostaglandins are produced following the sequential oxidation of AA, DGLA or EPA by Cyclooxygenase s (COX-1 and COX-2) and terminal prostaglandin synthases. The classic dogma is that COX-1 is responsible for the baseline levels of prostaglandins, whereas 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 . 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 lipocailin 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 idenfitied. Prostaglandin F synthase (PGFS) catalyzes the formation of 9α,11β-PGF2α,β from PGD2 and PGF2α from PGH2 in the presence of NADPH. This enzyme has recently been crystallyzed in complex with PGD2 and bimatoprost (a synthetic analogue of PGF2α). Function There are currently nine known receptors of prostaglandins on various cell types. Prostaglandins ligate a subfamily of cell surface seven-transmembrane receptors, G-protein-coupled Receptor s. 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). Prostaglandins thus act on a variety of cells such as Vascular Smooth Muscle cells causing constriction or dilation, on Platelet s causing aggregation or disaggregation and on spinal Neuron s causing pain. Prostaglandins have a wide variety of actions, including, but not limited to Muscular constriction and mediate inflammation. Other effects include Calcium movement, Hormone regulation and Cell Growth control. Thromboxane is created in Platelet s and causes Vascular Constriction and platelet aggregation. Prostacyclin comes from cells in the blood vessel walls and is antagonistic to thromboxane. Prostaglandins are potent but have a short half-life before being inactivated and excreted. Therefore, they exert only a Paracrine (locally active) or Autocrine (acting on the same cell from which it is synthesized) function. 15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2) is a PGD2 derivative that acts on PPAR intracellular receptors. ROLE IN PHARMACOLOGY NSAID s inhibit cyclooxygenase and reduce prostaglandin synthesis. Corticosteroid s inhibit phospholipase A2 production by boosting production of Lipocortin , an inhibitor protein. Relatively new drugs, known as COX-2 Selective Inhibitor s or coxibs, are used as specific inhibitors of COX-2 (Coxibs). The development of these drugs allowed the circumvention of the negative gastrointestinal effects while effectively reducing inflammation. However, recently, it has been shown that both NSAIDs and Coxibs can raise the risk of Myocardial Infarction , when taken on a chronic basis for at least 18 months. One emerging hypothesis that may explain the cardiovascular effects is that coxibs create an imbalance in circulating TxA2 and PGI2 levels. An increased in the ratio of TxA2/PGI2 could lead to increased platelet aggregation and dysregulation of platelet homeostatis. Synthetic prostaglandins are used:
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