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  2. 2. <ul><li>Prostaglandins and related compounds are collectively known as eicosanoids . </li></ul><ul><li>Most are produced from arachidonic acid , a 20-carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid). </li></ul><ul><li>The eicosanoids are considered &quot; local hormones .&quot; </li></ul><ul><ul><li>They have specific effects on target cells close to their site of formation. </li></ul></ul><ul><ul><li>They are rapidly degraded, so they are not transported to distal sites within the body. </li></ul></ul><ul><li>But in addition to participating in intercellular signaling , there is evidence for involvement of eicosanoids in intracellular signal cascades . </li></ul>INTRODUCTION
  3. 3. DISCOVERY OF PROSTAGLANDINS <ul><li>It was discovered by Ulf Von Euler (1930) </li></ul><ul><li>He extracted from human semen. </li></ul><ul><li>It is secreted from prostate gland . </li></ul><ul><li>Structure of prostaglandins - proposed by Bergstrom (1950). </li></ul>
  4. 4. <ul><ul><li>Examples of eicosanoids : </li></ul></ul><ul><ul><li>prostaglandins </li></ul></ul><ul><ul><li>prostacyclins </li></ul></ul><ul><ul><li>thromboxanes </li></ul></ul><ul><ul><li>leukotrienes </li></ul></ul><ul><ul><li>epoxyeicosatrienoic acids. </li></ul></ul><ul><ul><li>They have roles in: </li></ul></ul><ul><ul><li>inflammation </li></ul></ul><ul><ul><li>fever </li></ul></ul><ul><ul><li>regulation of blood pressure </li></ul></ul><ul><ul><li>blood clotting </li></ul></ul><ul><ul><li>immune system modulation </li></ul></ul><ul><ul><li>control of reproductive processes & tissue growth </li></ul></ul><ul><ul><li>regulation of sleep/wake cycle. </li></ul></ul>
  5. 5. PGE 2 (prostaglandin E 2 ) is an example of a prostaglandin, produced from arachidonic acid .
  6. 6. <ul><li>PGE 2 (prostaglandin E 2 ). </li></ul><ul><li>Prostaglandins all have a cyclopentane ring . </li></ul><ul><ul><li>A letter code is based on ring modifications (e.g., hydroxyl or keto groups). </li></ul></ul><ul><ul><li>A subscript refers to the number of double bonds in the two side-chains. </li></ul></ul><ul><li>Thromboxanes are similar but have instead a 6-member ring . </li></ul>
  7. 7. <ul><li>Prostaglandin receptors: </li></ul><ul><ul><li>Prostaglandins & related compounds are transported out of the cells that synthesize them. </li></ul></ul><ul><ul><li>Most affect other cells by interacting with plasma membrane G-protein coupled receptors . </li></ul></ul><ul><ul><li>♦ Depending on the cell type, the activated G-protein may stimulate or inhibit formation of cAMP , or may activate a phosphatidylinositol signal pathway leading to intracellular Ca ++ release . </li></ul></ul>
  8. 8. <ul><li>Prostaglandin receptors are specified by the same letter code. </li></ul><ul><li>E.g., receptors for E-class prostaglandins are EP . </li></ul><ul><li>Thromboxane receptors are designated TP . </li></ul><ul><li>Multiple receptors for a prostaglandin are specified by subscripts (E.g., EP 1 , EP 2 , EP 3 , etc.). </li></ul><ul><li>Different receptors for a particular prostaglandin may activate different signal cascades. </li></ul><ul><li>Effects of a particular prostaglandin may vary in different tissues, depending on which receptors are expressed. </li></ul><ul><li>E.g., in different cells PGE 2 may activate either stimulatory or inhibitory or G-proteins, leading to either increase or decrease in cAMP formation. </li></ul>
  9. 9. <ul><li>Prostaglandin H 2 Synthase catalyzes the committed step in the “cyclic pathway” that leads to production of prostaglandins, prostacyclins, & thromboxanes. </li></ul><ul><li>Different cell types convert PGH 2 to different compounds. </li></ul>Two major pathways of eicosanoid metabolism. Cyclic pathway:
  10. 10. <ul><li>PGH 2 Synthase is a heme-containing dioxygenase , bound to ER membranes. </li></ul><ul><li>(A dioxygenase incorporates O 2 into a substrate). </li></ul><ul><li>PGH 2 Synthase exhibits 2 activities: cyclooxygenase & peroxidase . </li></ul>
  11. 11. <ul><li>Ibuprofen and related compounds block the hydrophobic channel by which arachidonate enters the cyclooxygenase active site. </li></ul><ul><li>Non-steroidal anti-inflammatory drugs ( NSAIDs ) , such as aspirin and derivatives of ibuprofen, inhibit cyclooxygenase activity of PGH 2 Synthase. </li></ul><ul><ul><li>They inhibit formation of prostaglandins involved in fever, pain, & inflammation. </li></ul></ul><ul><ul><li>They inhibit blood clotting by blocking thromboxane formation in blood platelets. </li></ul></ul>
  12. 12. <ul><li>Aspirin acetylates a serine hydroxyl group near the active site, preventing arachidonate binding. </li></ul><ul><li>The inhibition by aspirin is irreversible . </li></ul><ul><li>However, in most body cells re-synthesis of PGH 2 Synthase would restore cyclooxygenase activity. </li></ul>
  13. 13. <ul><li>Thromboxane A 2 stimulates blood platelet aggregation, essential to the role of platelets in blood clotting. </li></ul><ul><ul><li>Many people take a daily aspirin for its anti-clotting effect, attributed to inhibition of thromboxane formation in blood platelets. </li></ul></ul><ul><ul><li>This effect of aspirin is long-lived because platelets lack a nucleus and do not make new enzyme. </li></ul></ul>
  14. 14. <ul><li>The 1st step of the Linear Pathway for synthesis of leukotrienes is catalyzed by Lipoxygenase . </li></ul><ul><li>Mammals have a family of Lipoxygenase enzymes that catalyze oxygenation of various polyunsaturated fatty acid at different sites. Many of the products have signal roles. </li></ul>
  15. 15. <ul><li>E.g., 5-Lipoxygenase , found in leukocytes, catalyzes conversion of arachidonate to 5-HPETE (5-hydroperoxy-eicosatetraenoic acid). </li></ul><ul><li>5-HPETE is converted to leukotriene-A 4 , which in turn may be converted to various other leukotrienes . </li></ul>
  16. 16. <ul><li>Leukotrienes have roles in inflammation . </li></ul><ul><li>They are produced in areas of inflammation in blood vessel walls as part of the pathology of atherosclerosis . </li></ul><ul><li>Leukotrienes are also implicated in asthmatic constriction of the bronchioles. </li></ul><ul><li>Some leukotrienes act via specific G-protein coupled receptors (GPCRs) in the plasma membrane. </li></ul><ul><li>Anti-asthma medications include: </li></ul><ul><ul><li>inhibitors of 5-Lipoxygenase , e.g., Zyflo (zileuton) </li></ul></ul><ul><ul><li>drugs that block leukotriene-receptor interactions . E.g., Singulair (montelukast) & Accolate (zafirlukast) block binding of leukotrienes to their receptors on the plasma membranes of airway smooth muscle cells. </li></ul></ul>
  17. 17. Thank you