this chapter was a brief introduction to the synthesis and metabolism of eicosanoids. eicosanoids are 20 carbon long polyunsaturated fatty acids derived from membrane phospholipids, mainly arachadonic acid. arachadonic acid can not be synthesized de novo, and is mainly converted from linoleate from the diet. in general, eicosanoids are short lived molecules that affect virtually all tissues and have a multifaceted regulatory role in diverse processes that occur in the body (and by this i mean i have no idea what they do yet)
conversion of arachadonic acid in the phospholipid membrane into the eicosanoids can take several pathways. one is the production of prostaglandins and thromboxanes, which have important, opposing roles in mediating inflammation. prostaglandins are produced on vascular endothelium, inhibit platelet aggregration and stimulate vasodilation. thromboxanes are produced by enzymes on platelets, stimulate platelet formation as well as vasoconstriction.
the synthesis of prostaglandins and thromboxanes occurs when the cyclooxygenase enzyme converts arachadonic acid in the membrane into an unstable endoperoxide, PGG2. PGG2 is then reduced to PGH2, which can be converted by different enzyme isoforms to prostaglandins or thromboxanes. antiinflammatory drugs often target the first enzyme in the synthesis of these inflammation mediating enzymes, cyclooxygenases. these drugs are called COX-2 inhibitors, referring to the two types of cyclooxygenases present in the body. COX-1 is involved in normal physiologic function, whereas COX-2 is used in inflammation.
some other pathways of eicosanoid synthesis: leukotrienes and lipoxins are formed by adding hydroperoxides to the double bonded carbons (which shifts the double bonds over and changes their configuration), followed by conversion to leukotrienes and lipoxins by other enzymes. leukotrienes and lipoxins are involved in increasing vascular permeability, bronchoconstriction, and cytokine production.
isoprostanes are created by free radical modification of arachadonic acid in the phospholipid membrane, which is then cleaved by phosphlipase A2. they are used to assess the level of oxidative damage a person is exposed to. finally, endocannabinoids are synthesized when arachadonic acid is transferred to the amino group on ethanolamine, which is then cleaved from the cell membrane by phospholipase D. endocannabinoids can act as analgesics, by acting retroactively on the presynaptic membranes from which they are released, stimulating continual neurotransmitter release.
questions
1. eicosanoids are synthesized from...
2. what is the major precursor for eicosanoids and where does it come from?
3. describe how arachidonic acid gets released from membrane phospholipids.
4. what are the three major pathways for eicosanoid synthesis?
5. what are the structural characteristics of prostaglandins?
6. what is the difference between the PGE and PGF family of prostaglandins?
7. what are the structural characteristics of thromboxanes?
8. what is the "2 series" of of prostaglandins and thromboxanes?
9. describe the synthesis of the 2 series of prostaglandins from arachadonic acid.
10. how are thromboxanes synthesized?
11. what is PGH2 converted to in the vascular endothelium vs. the platelets?
12. what are the two types of cyclooxidase enzymes and when/where are they present/active?
13. how is aspirin related to prostagladin production?
14. describe the inactivation of prostaglandins.
15. describe the inactivation of thromboxanes.
16. describe the formation of leukotrienes and lipoxins from arachadonic acid.
17. what do lipoxins do?
18. what do leukotrienes do?
19. describe the synthesis of isoprostanes.
20. describe the synthesis of endocannabinoids.
21. what are isoprostanes used as a measure of?
22. what are endocannabinoids used for and why?
23. what does the cytochrome450 pathway produce and what role do the molecules play in the body?
answers
1. 20 carbon long polyunsaturated fatty acids derived from membrane phospholipids.
2. arachidonic acid, which is esterified to membrane phospholipids. it can not be synthesized de novo, so it must be converted from dietary sources, mainly linoleate.
3. arachadonic acid gets released by the activation of phospholipase A2 or C via agonists such as histamine or cytokines.
4. cyclooxygenase, lipoxygenase, cytochrome P450.
5. 20 carbon atoms long, an internal 5 carbon ring, hydroxyl group at C15, double bond at C13.
6. the substituents on the internal ring; PGE has a carboxyl group on carbon 9 and a hydroxyl on carbon 11, whereas PGF has alpha-hydroxyl groups on both carbons 9 and 11.
7. similar to prostaglandins, but the internal ring is 6 membered, with 5 carbons and 1 oxygen. the most common thromboxane, TXA2, also contains an oxygen atom in the middle of the ring.
8. molecules with double bonds between carbons 13 and 14, and 5 and 6.
9. arachadonic acid is converted to an unstable endoperoxide, PGG2 by cyclooxygenase. PGG2 is reduced to PGH2. PGH2 can then be acted on by different isomerases which synthesize different series 2 prostaglandins (PGD synthase creates PGD2, PGE synthase creates PGE2, etc).
10. PGH2 can be converted to thromboxane, TXA2, by TXA synthase.
11. in platelets it is converted to thromboxane, which causes vasoconstriction and platelet aggregation. in vascular endothelium it is converted to PGI2, which inhibits platelet aggregation and causes vasodilation.
12. COX-1 and COX-2. COX-1 is the main enzyme in healthy tissues and COX-2 is present in inflamed tissue.
13. cyclooxidase enzymes are blocked by antiinflammatory drugs such as aspirin.
14. prostaglandins are inactivated within seconds or minutes by oxidation of the 15-OH to a ketone and reduction of the double bond at C13. this creates a dicarboxylic acid that is excreted in the urine.
15. TXA2 is metabolized to the inactive TXB2 by cleavage of the oxygen bridge in the internal ring into two hydroxyl groups.
16. lipoxygenases add a hydroperoxide to one of the double bonded carbons in arachadonic acid, forming 5, 12, or 15-HPETE. this shifts the double bond one carbon further away and changes the configuration from cis to trans. the unstable hydroperoxide group can then be metabolized to form leukotrienes or lipoxins.
17. induce chemotaxis and stimulate superoxide anion production in leukocytes.
18. increase vascular permeability, T-cell proliferation, leukocyte aggregation, cytokine production.
19. isoprostanes are created by free radical damage to arachadonic residues in phospholipid membranes, which are then cleaved and released by phospholipase A2.
20. arachidonic acid group is transferred from the 2-position to the free amino group on ethanolamine, and the modified ethanolamine is then cleaved by phospholipase D.
21. the amount of oxidative stress the person is exposed to.
22. analgesics, because they are released from neurons and work retroactively on the presynaptic membrane to increase neurotransmitter release.
23. epoxides, certain HETE's, which have actions in ocular, vascular, endocrine, and renal systems, the exact role of which is unknown.
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