Metabolism of Polyunsaturated fatty acids / Eicosanoids
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Metabolism of Polyunsaturated fatty acids or Eicosanoids. Prostaglandins and related compounds
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Metabolism of Polyunsaturated fatty acids / Eicosanoids
- 2. Animals have limited ability in desaturating fatty acids. Dietary intake of certain polyunsaturated fatty acids derived from a plant source is necessary. These essential fatty acids give rise to eicosanoic (C20) acids. (from families of eicosanoids) Eicosanoids include prostaglandins, thromboxanes, leukotrienes, and lipoxins.
- 3. Linoleic and -linolenic acids are the only fatty acids known to be essential for the complete nutrition of humans (essential fatty acids.) Arachidonic acid can be formed from linoleic acid Palmitoleic and oleic acids are not essential in the diet, because the tissues are capable of introducing a double bonds at the ∆9 position into the corresponding fatty acids.
- 5. What is Eicosanoids? Eicosanoids are formed from 20 carbon PUFA arachidonic acid
- 6. Formed from C20 polyunsaturated fatty acids Arachidonic acid and some other C20 give rise to eicosanoids; These includes…… prostaglandins (PG), Thromboxanes (TX), Leukotrienes (LT), and Lipoxins (LX). Eicosanoids are physiologically & pharmacologically active compounds. Act as local hormones functioning through G-protein.
- 9. Structure
- 10. Prostaglandins are synthesized by cyclic pathway of arachidonic acid. Cyclooxygenase-a suicide enzyme: Prostaglandin synthesis can be controlled by suicidal activity of the enzyme cyclooxygenase. This enzyme is capable of undergoing self- catalysed destruction to switch off PG synthesis. Synthesis of Prostaglandins
- 11. Synthesis of Prostaglandins Phospholipids (membrane bound) Arachidonic acid Phospholipase-A2 Lysophospholipid PGG2 PGH2 PGI2 PGF2α PGE2 TXA2 Cyclooxygenase Peroxidase 2GSH G-S-S-H Reductase Isomerase Corticosteroids Aspirin Phenylbutazone Indomethacin Ibuprofen Leukotrienes Lipoxygenase - - Inhibitors
- 12. All the eicosanoids are metabolised rapidly. The lungs and liver are the major sites. Two enzymes are involved in this process…… 15-α-hydroxy PG dehydrogenase 13-PG reductase Degradation of Prostaglandins
- 15. Inflammation • PGs are natural mediators of inflammation • PGE2 & PGE1 induce signs of inflammation- redness, heat (vasodilation), swelling, edema, etc Pain & Fever • Pyrogen stimulates PG synthesis & release of PGE2 in the Hypothalamus region of brain where temp is regulated. • PGE2 can enhance the intensity & duration of pain caused by bradykinin & histamine Reproduction • PGE2 and PGF2 have been used to induce parturition as well as to terminate pregnancy. • Cytotec • PGE series of PG may play a role in male infertility Physiological Effect
- 17. PROSTAGLANDINS - FUNCTIONS PGI2 Vasodilatation Inhibits platelet aggregation PGA & PGE class prostaglandins lower blood pressure. Effects on CVS
- 18. PROSTAGLANDINS - FUNCTIONS PGF2 Inducing labor Effects on uterus • Hence, • PGF2 may be used for… • Medical termination of pregnancy. • In inducing labor and • Arresting postpartum hemorrhage.
- 19. PROSTAGLANDINS - FUNCTIONS PGF-Bronchoconstriction PGE-Bronchodilator Effects on Respiratory tract
- 20. PROSTAGLANDINS - FUNCTIONS PGE2 Involved in inflammatory response Effects on Inflammation
- 21. PROSTAGLANDINS - FUNCTIONS PGE2 suppress gastric acid secretion used therapeutically in treatment of acid peptic disease. Effects on GIT
- 22. PROSTAGLANDINS - FUNCTIONS Through the action of hormones by the modulating effect on cAMP production. PG E2 decreases lipolysis, increases calcium mobilization from bone & glycogen synthesis. Metabolic Effects
- 24. First isolated from blood platelets, thrombocytes Subscript number denotes number of double bonds Capital letters – designate class Most common Thromboxanes [TX]
- 25. Increase platelet aggregation Vasoconstriction Mobilize intracellular calcium Smooth muscle contraction Bronchoconstriction Thromboxanes - Functions
- 26. Grouped into 5 classes [A to E] Subscript number denotes number of double bonds LTC4 Leukotrines [LT]
- 27. Leukotrienes are synthesized from arachidonic acids by lipoxygenase pathway in leukocytes, mastocytoma cells, platelets, and macrophages In response to both immunologic & non- immunologic stimuli. Synthesis of Leukotrienes
- 28. Arachidonic acid 5-HPETE 5-Lipoxygenase Glutathione S-transferase H2O Leukotriene A4 Leukotriene C4 Glutathione Glutamate GGT Leukotriene D4 Glycine Dipeptidase Leukotriene E4 Leukotriene B4 Hydrolase
- 30. ….
Editor's Notes
- Almost all mammalian cells except red blood cells produce prostaglandins and their related compounds, the prostacyclins, thromboxanes, leukotrienes and lipoxins, known collectively as eicosanoids since they are all C20 compounds; Greek: eikosi, twenty). The eicosanoids, like endocrine hormones, have profound physiological effects at extremely low concentrations. For example, they mediate the following: (1) the inflammatory response, notably as it involves the joints (rheumatoid arthritis), skin (psoriasis), and eyes; (2) the production of pain and fever; (3) the regulation of blood pressure; (4) the induction of blood clotting; (5) the control of several reproductive functions such as the induction of labor; and (6) the regulation of the sleep/wake cycle. The enzymes that synthesize these compounds and the receptors to which they bind are therefore the targets of intensive pharmacological research. The eicosanoids are also hormonelike in that they bind to G-protein-coupled receptors (Section 19-2B), and many of their effects are intracellularly mediated by cAMP. Unlike endocrine hormones, however, they are not transported in the bloodstream to their sites of action. Rather, these chemically and biologically unstable substances (some decompose within minutes or less in vitro) are local mediators (paracrine hormones; Section 19-1); that is, they act in the same environment in which they are synthesized.
- Almost all mammalian cells except red blood cells produce prostaglandins and their related compounds, the prostacyclins, thromboxanes, leukotrienes and lipoxins, known collectively as eicosanoids since they are all C20 compounds; Greek: eikosi, twenty). The eicosanoids, like endocrine hormones, have profound physiological effects at extremely low concentrations. For example, they mediate the following: (1) the inflammatory response, notably as it involves the joints (rheumatoid arthritis), skin (psoriasis), and eyes; (2) the production of pain and fever; (3) the regulation of blood pressure; (4) the induction of blood clotting; (5) the control of several reproductive functions such as the induction of labor; and (6) the regulation of the sleep/wake cycle. The enzymes that synthesize these compounds and the receptors to which they bind are therefore the targets of intensive pharmacological research. The eicosanoids are also hormonelike in that they bind to G-protein-coupled receptors (Section 19-2B), and many of their effects are intracellularly mediated by cAMP. Unlike endocrine hormones, however, they are not transported in the bloodstream to their sites of action. Rather, these chemically and biologically unstable substances (some decompose within minutes or less in vitro) are local mediators (paracrine hormones; Section 19-1); that is, they act in the same environment in which they are synthesized.
- Prostaglandins are all derivatives of the hypothetical C20 fatty acid prostanoic acid in which carbon atoms 8 to 12 form a cyclopentane ring (Fig. 25-66a). Prostaglandins A through I differ in the substituents on the cyclopentane ring (Fig. 25-66b):PGAs are ,-unsaturated ketones,PGEs are-hydroxy ketones, PGFs are 1,3-diols, etc. In PGF, the C9 OH group is on the same side of the ring as R1; it is on the opposite side in PGF.The numerical subscript in the namerefers to the number of double bonds contained on the side chains of the cyclopentane ring (Fig. 25-66c). In humans, the most prevalent prostaglandin precursor is arachidonic acid (5,8,11,14-eicosatetraenoic acid), a C20 polyunsaturated fatty acid that has four nonconjugated double bonds.The double bond at C14 is six carbon atoms from the terminal carbon atom (the carbon atom), making arachidonic acid an –6 fatty acid. As Sune Bergström and Bengt Samuelsson demonstrated, arachidonic acid is synthesizedsynthesized from the essential fatty acid linoleic acid (also an –6 fatty acid). This occurs via its desaturation with a 6- desaturase to yield -linolenic acid (GLA), followed by elongation and a second desaturation, this time with a 5- desaturase (Fig. 25-67; Section 25-4E). Prostaglandins with the subscript 1 (the “series-1” prostaglandins) are synthesized from dihomo--linolenic acid (DGLA; 8,11,14- eicosatrienoic acid), whereas “series-2” prostaglandins are synthesized from arachidonic acid. -Linolenic acid (ALA), another essential fatty acid since the 15-desaturase required for its synthesis occurs only in plants, is a precursor of 5,8,11,14,17-eicosapentaenoic acid (EPA) and the “series-3” prostaglandins. Since arachidonate is the primary prostaglandin precursor in humans, we shall mostly refer to the series-2 prostaglandins in our examples. Note, however, that when dietary linoleic acid and -linolenic acid are equally available, the relative activities of the 5- and 6- desaturases are important in determining the relative amounts of these prostaglandin precursors. Hvon Euler thought that these compounds originated in the prostate gland (hence their name) but they were later shown to be synthesized in the seminal vesicles.