BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 15. INTEGRATION OF METABOLIC PATHWAYS. HORMONES

15.14. Eicosanoids

Eicosanoids are derivatives of polyunsaturated Fatty acids synthesized by almost all Cell types, functioning as Hormones via paracrine or autocrine mechanisms. The primary substrate for eicosanoid synthesis (from the Greek eikosi meaning 20) is arachidonic acid, along with certain other polyenic fatty acids (see Chapter "Lipids") (Fig. 15.19). These fatty acids must either be obtained from the diet or synthesized from essential polyunsaturated fatty acids.

Class="center">

Fig. 15.19. Scheme of eicosanoid synthesis from arachidonic acid

Under METABOLISM/18.html">The Influence of specific Enzymes, various classes of eicosanoids are produced in different Tissues: Prostaglandins, thromboxanes, and Leukotrienes. Their main biological effects are associated with The regulation of smooth Muscle contraction, renal Excretion of Water and sodium ions, Blood clotting, and participation in inflammatory responses following tissue damage or infections. An excess of eicosanoids leads to conditions such as Bronchial Asthma and allergic reactions. Eicosanoid receptors are located on neighboring Cells; multiple receptor types exist for each eicosanoid. Inactivation of eicosanoids occurs very rapidly, with a half-life of just a few minutes.

Synthesis begins with the action of phospholipase A₂, which cleaves fatty acids located at the second position of membrane phosphoglyceride molecules. The main group of eicosanoids includes prostaglandins, prostacyclins, and thromboxanes. Their synthesis is initiated by the enzyme cyclooxygenase, which catalyzes the incorporation of four oxygen atoms and The formation of a 5-membered ring (Fig. 15.20). There are two types of this enzyme: cyclooxygenase 1 and 2. The first is synthesized in the body at a constant rate, making it a constitutive enzyme, whereas the Synthesis of the second increases during inflammation. Prostaglandins are designated as PG, followed by letters determined by the Chemical Nature of the substituent in the 5-membered ring, as well as a numerical index indicating the number of double bonds. Thus, type E corresponds to β-hydroxyketones, type F to 1,3-diols, and type A to α,β-unsaturated ketones. Since arachidonic acid is the primary precursor, prostaglandins with index 2 predominate. Prostaglandins belonging to series 1 and 3 are formed from fatty acids containing three and five double bonds, respectively (two bonds are utilized for ring formation, while the remainder stay in the side chain).

The primary prostaglandin PGG2 is an unstable hydroperoxide formed upon The addition of two oxygen molecules.

PGG₂ is reduced by Glutathione peroxidase in the presence of glutathione to PGH₂. Subsequent conversion of PGH₂ depends on the tissue type in which synthesis takes place. For instance, prostacyclins are synthesized predominantly in vascular endothelial cells, whereas thromboxanes are produced mainly in platelets. The prostacyclin molecule contains two rings—one similar to that of prostaglandins, and another formed with the participation of an oxygen atom. During thromboxane synthesis, a six-membered ring containing an oxygen atom is formed. Under normal conditions, vascular endothelial cells produce prostacyclin (PGI₂), which prevents platelet aggregation and vasoconstriction. Upon platelet activation, such as through contact with a damaged blood vessel wall, thromboxanes (TXA₂) are secreted, which conversely stimulate platelet aggregation. Thus, under normal physiological conditions, the blood clotting and anticoagulant systems are kept in a state of balance.

Under pathological conditions or the influence of certain pharmacological agents, this equilibrium can shift in either direction. For example, damage to endothelial cells occurs during the formation of atherosclerotic plaques. This suppresses the synthesis of PGI₂, PGE₂, PGD₂ and activates platelets. Thromboxane is secreted, stimulating thrombus formation at the site of vascular injury and promoting The Development of myocardial infarction.

Fig. 15.20. Formation of primary prostaglandins

Prostaglandins are synthesized in many tissues. For example, in smooth muscle, PGE synthase mediates the formation of PGE₂, whereas PGD synthase directs The production of PGD₂.

The synthesis of PGE₂ occurs in all tissues, being particularly intensive in the Kidneys. Its biological action is linked to smooth muscle relaxation, vasodilation, and the suppression of lymphocyte migration. The synthesis of PGF_2α occurs in most tissues and leads to smooth muscle contraction, vasoconstriction, bronchoconstriction, and uterine contraction.

Prostaglandin synthesis is inhibited by anti-inflammatory drugs. For instance, aspirin and other nonsteroidal anti-inflammatory drugs act as inhibitors of cyclooxygenase. Glucocorticoids induce the synthesis of Proteins that act as inhibitors of phospholipase A₂.

Another pathway for arachidonic acid metabolism involves the enzyme lipoxygenase. This pathway yields molecules with three conjugated double bonds known as leukotrienes, which lack cyclic structures.

Leukotriene synthesis begins with the addition of O₂ to a carbon atom adjacent to a double bond, resulting in the formation of hydroperoxides (Fig. 15.21).

Fig. 15.21. Initial Stages of leukotriene synthesis

Lipoxygenases target the carbon atom at positions 5, 12, or 15 of arachidonic acid depending on the tissue type. For example, leukocytes produce 5-hydroperoxyeicosatetraenoic acids (5-HPETE), which are subsequently reduced to 5-hydroxyeicosatetraenoic acids (5-HETE) or converted into leukotriene LTA₄. The latter can be transformed into leukotriene LTB₄, which stimulates leukocyte chemotaxis and aggregation while increasing vascular permeability. Through the action of glutathione transferase, LTC₄ is formed from LTA₄ via the conjugation of glutathione (Fig. 15.22).

Leukotriene C₄ is converted into LTD₄ by the Cleavage of a glutamic acid residue, and subsequently into LTE₄ by the removal of a Glycine residue. The principal BIOLOGICAL EFFECTS OF leukotrienes are related to inflammatory processes, allergic reactions, and smooth muscle activity.

Fig. 15.22. Synthesis of leukotrienes