Formation and Synthesis of Eicosanoids | Lipid Metabolism

In this article we will discuss about the Formation and Synthesis of Eicosanoids.

Formation of Eicosanoids:

1. Eicosanoids formed from arachidonate and some other C₂₀ fatty acids with methylene-interrupted bonds, physiologically and pharmacologically active compounds known as prostaglandins (PG), thromboxane’s (TX), and leukotriene’s (LT). Physi­ologically, they are considered to act as local hormones.

2. Arachidonic acid, usually derived from the 2-position of phospholipids in the plasma membrane by phospholipase A₂ activity, is the substrate for the synthesis of PG₂, TX₂, LT₄ compounds. These two pathways are known as the cyclooxygenase and lipoxygenase pathways, respectively.

3. Three groups of eicosanoids (each com­prising PG, TX and LT) are synthesized from C₂₀ eicosanoic acids derived from essential fatty acids linoleic acid and li­nolenic acid, or directly from arachidonic acid and eicosapentaenoic acid in the diet.

Synthesis of Eicosanoids:

Prostanoid Synthesis by Cyclooxygenase Pathway:

1. Two molecules of O₂ catalyzed by Pros­taglandin endo-peroxide synthase which possesses two separate enzyme activi­ties—Cyclooxygenase and Peroxidase— are responsible for Prostanoid synthesis.

2. The product of the cyclooxygenase path­way, an endo-peroxide (PGH), is converted to Prostaglandins D, E and F as well as to the thromboxane (TXA₂) and Prostacylin (PGI₂).

3. Each cell type produces one type of Prostanoid.

4. Aspirin and indomethacin inhibit Cyclooxygenase.

Cyclooxygenase is a “Suicide Enzyme”:

1. Prostaglandin formation is partly stopped by a remarkable property of Cyclooxyge­nase—that of self-catalyzed destruction (a “suicide enzyme”)

2. The inactivation of Prostaglandin is rapid due to the presence of the enzyme 15- hydroxy-prostaglandin dehydrogenase in most mammalian tissues.

3. The half-life of Prostaglandin in the body can be prolonged by blocking the action of this enzyme with indomethacin or sulfasalazine.

Leukotrienes are Formed by the Lipoxygenase Pathway:

1. The leukotrienes, a family of conjugated trienes, are formed from eicosanoic acids in leukocytes, mastocytoma cells, plate­lets and macrophages by the lipoxygenase pathway in response to both immunologic and non-immunologic stimuli.

2. Oxygen is inserted into 5, 12 and 15 posi­tions of arachidonic acid giving rise to hydro-peroxide (HPETE) by three differ­ent lip-oxygenases (dioxygenases).

3. Only 5-lipoxygenase forms leukotrienes.

4. The first formed is leukotriene A₄, which, in turn, is metabolized to either leukotriene B₄ or leukotriene C₄.

5. Leukotriene C₄ is formed by the addition of glutathione via a thioether bond.

6. The subsequent removal of glutamic acid and glycine generates leukotriene D₄ and Leukotriene E₄.