Human Biochemistry, Volume 1 - Murray R. 1993

Bioenergetics and Carbohydrate and Lipid Metabolism
Metabolism of Unsaturated Fatty Acids and Eicosanoids
Prostanoids

Biosynthesis

The synthesis of prostanoids (Fig. 24.7) is catalyzed by prostaglandin endoperoxide synthase, which exhibits Two Types of activity—cyclooxygenase and peroxidase; two molecules of O₂ are involved in the process. The product of the cyclooxygenase pathway is an endoperoxide derivative, which is subsequently converted into Prostaglandins D, E, and F, as well as thromboxane (TXA₂) and prostacyclin (PGI₂). Cells of a single type produce only one specific prostanoid. Aspirin and indomethacin inhibit cyclooxygenase activity.

Clinical Aspects

Thromboxanes are produced in platelets and, upon entering the bloodstream, cause vasoconstriction and platelet aggregation. Prostacyclins (PGI₂) are synthesized in Blood vessel walls and act as potent inhibitors of platelet aggregation. Thus, thromboxanes and prostacyclins function as antagonists. Greenland Eskimos rarely suffer from Heart diseases; they exhibit reduced platelet aggregation and prolonged blood clotting time. This is believed to result from a high Dietary intake of fish oil containing 20:5 ω3 (eicosapentaenoic acid, EPA), which serves as a precursor for group 3 Prostaglandins and thromboxanes (PG₃ and TX₃) (Fig. 24.6). PG₃ and TX₃ inhibit the release of arachidonate from Phospholipids and The formation of PG₂ and TX₂. PGI₃ possesses antiplatelet aggregation properties as potent as those of PGI₂, whereas TXA₃ is a weaker stimulator of platelet aggregation than TXA₂. Consequently, the net balance of activities decreases the likelihood of aggregation. Furthermore, the plasma concentrations of Cholesterol, triacylglycerols, and low- and very-low-density Lipoproteins are lower in Eskimos, while high-density lipoprotein levels are elevated. All these factors are thought to protect against atherosclerosis and myocardial infarction.

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Fig. 24.5. Conversion of arachidonic acid into prostaglandins and thromboxanes via the cyclooxygenase pathway, and into Leukotrienes via the lipoxygenase pathway. The figure illustrates why Steroids, which completely inhibit eicosanoid formation, are more effective anti-inflammatory agents than aspirin and similar drugs that inhibit only the cyclooxygenase pathway.

Fig. 24.6. The 3 groups of Eicosanoids and their biosynthetic pathways. PG — prostaglandin; PGI — prostacyclin; TX — thromboxane; LT — leukotriene; 1 — cyclooxygenase pathway; 2 — lipoxygenase pathway. The numbers following the abbreviated eicosanoid name indicate the number of double bonds in the molecule, and the final letter designates the specific group of the compound.

Fig. 24.7. Conversion of arachidonic acid into group 2 prostaglandins and thromboxanes. PG — prostaglandin; TX — thromboxane; PGI — prostacyclin; HHT — hydroxyheptadecatrienoic acid. Activities marked with an asterisk belong to the same enzyme, prostaglandin endoperoxide synthase. Groups 1 and 3 prostaglandins and thromboxanes are formed in a similar manner.

Prostaglandins are potent biologically active compounds. At low concentrations (1 ng∙mL^-1), they induce smooth Muscle contraction in animals. Prostaglandins can be used therapeutically for Contraception, stimulating normal labor, Pregnancy termination, preventing or healing gastric ulcers, treating inflammatory conditions, regulating blood pressure, as well as relieving asthma attacks and treating nasal congestion. Prostaglandins increase cAMP levels in platelets, The Thyroid Gland, the corpus luteum, fetal Bone tissue, the anterior pituitary, and Lungs, while decreasing cAMP activity in renal tubular cells and adipose tissue.

Essential Fatty acids and Prostaglandins

Although There is a strong correlation between the effectiveness of various fatty acids as essential nutrients and their ability to be converted into prostaglandins, The Physiological Role of essential fatty acids is not limited to prostaglandin synthesis. For example, their structural role in membrane formation is independent of prostaglandin synthesis. Essential fatty acid deficiency cannot be cured by administration of prostaglandins, and prolonged inhibition of prostaglandin formation does not lead to the symptoms of essential fatty acid deficiency.

Removal and Inactivation of Prostaglandins

The "turn-off" of prostaglandin production is partly achieved through a remarkable property of cyclooxygenase: it is capable of catalyzing its own destruction, functioning effectively as a "suicide" enzyme. The inactivation of synthesized prostaglandins occurs very rapidly, apparently mediated primarily by the enzyme 15-hydroxyprostaglandin dehydrogenase, which is present in almost all mammalian Tissues. It has recently been demonstrated that inhibiting this enzyme with sulfasalazine or indomethacin prolongs the half-life of prostaglandins in the body.