Fatty acids eicosanoids formed from

Leukotriene One of the 20-carbon fatty acid compounds (eicosanoids) formed from arachidonic acid by the lipoxygenase enzyme. Leukotrienes are important in mediating certain allergic and inflammatory responses, especially in respiratory tissues. 

Eicosanoids (prostaglandins, thromboxanes, leuko-trienes, lipoxins) is the name given to a group of 20-carbon unsaturated fatty acids derived principally from arachidorric acid in cell walls. They are shortlived, extremely potent and formed in almost every tissue in the body. Eicosanoids are involved in most types of inflammation and it is on manipulation of their biosynthesis that most present anti-inflammatory therapy is based. Their biosynthetic paths appear in Figure 15.1 and are amplified by the following account. 

The family of compounds referred to as eicosanoids, which includes the prostaglandins (PCs), leukotrienes (LTs) and thromboxanes (TXs), have been shown to play key roles in the inflammatory process (Flower et al 1985). Eicosanoids are derived from 20-carbon essential fatty acids, with arachidonic acid being the most common precursor. Perturbations of cell membranes, whether chemical, physical or immune-mediated, release phospholipids, which are rapidly converted to arachidonic acid by phospholipase A2 and other acylhydrolases. Once released, arachidonic acid and its congeners form the substrates for a number of enzyme systems (Fig. 14.1). Products that contain ring structures (PCs and TXs) are the result of metabolism by the cyclooxygenase (COX) enzymes, while the hydroxylated derivatives of straight-chain fatty acids (LTs) result from the action of various lipoxygenases (Flower et al 1985). 

Unsaturated C2o-fatty acids are precursors of the eicosanoids (D 3.2.6). 3-Acetoxy fatty acids (3-acetoxypalmitic, -stearic and -arachidic acid) are formed from the corresponding hydroxylated acids in floral glands of some families of Angio-spermae. They are collected by bees during pollination (E 5.5.1) either in the free state or as glycerides (D 3.2.4) and used to feed the larvae. 

Eicosanoids are formed from 20-carbon polyunsaturated fatty acids and make up an important group of physiologically and pharmacologically active compounds known as prostaglandins, thromboxanes, leukotrienes, and lipoxins. 

EICOSANOIDS ARE FORMED FROM C20 POLYUNSATURATED FATTY ACIDS... 

The term oxylipin is redefined here as an encompassing term for oxidized compounds which are formed from fatty acids by reaction(s) involving at least one step of mono- or dioxygenase-dependent oxidation [1]. Thus, this term includes eicosanoids as well as biosynthetically related compounds of longer and shorter chain length. 

Eicosanoids Are Formed from 20-Carbon Polyunsaturated Fatty Acids... 

Arachidonic acid is not present in significant amounts in tissues as the free acid but is stored as a fatty acid at the sn-2 position of phospholipids. Prostaglandin biosynthesis is initiated by the interaction of a stimulus with the cell surface. Depending on the cell type, the stimulus can take the form of a hormone, such as angiotensin II or antidiuretic hormone, or a protease such as thrombin (involved in blood clotting), or both hormone and protease. These agents bind to a specific receptor that activates a phospholipase A2 that specifically releases the arachidonic acid from a phospholipid such as phosphatidylcholine. The release of arachidonic acid by phospholipase A2 is believed to be the rate-limiting step for the biosynthesis of eicosanoids. 

Figure 12.1. Overview of eicosanoid metabolism, a Stmetures of eicosanoid precursor fatty acids, and their occurrence in membrane phospholipids (PC is shown as an example). Araehidonie acid is the prototypic precursor eicosatrienoic and eicosapen-tanoic acid differ from it by the a lackingor an additional double bond, respectively, b Conversion of preemsor fatty acids occurs by various enzymes, notably cyclooxygenases and lipoxygenases. Isoprostanes are non-enzymahe derivatives that may form in vivo at appreciable rates one characterishc featme is that they occur as racemic mixtures. Their physiological significance is not entirely clear.

Phospholipids and glycosphingolipids are amphipathic lipid constituents of membranes (Chapter 10). They play an essential role in the synthesis of plasma lipoproteins (Chapter 20) and eicosanoids (Chapter 18). They function in transduction of messages from cell surface receptors to second messengers that control cellular processes (Chapter 30) and as surfactants. Cholesterol is mainly of animal origin and is an essential constituent of biomembranes (Chapter 10). In plasma, cholesterol is associated with lipoproteins (Chapter 20). Cholesterol is a precursor of bile acids formed in the liver of steroid hormones secreted by adrenals, gonads, and placenta and 7-dehydrocholesterol of vitamin D formed in the skin. In tissues, cholesterol exists primarily in the unesterified form (e.g., brain and erythrocytes), although appreciable quantities are esterified with fatty acids in liver, skin, adrenal cortex, and plasma lipoproteins. 

Recently Liu and Weller [84] have reviewed the arachidonic acid metabolism in filarial parasites and other helminths. Arachidonic acid (AA) is a 20 carbon polyunsaturated fatty acid derived from dietary fatty acids. In human tissues, AA is usually present in the esterified form such as glycerolipids, phospholipids and neutral lipids. The free AA, released by phospholipases, undergoes various enzymatic oxygenations to form local mediators such as prostaglandins and leukotrienes, which are collectively known as eicosanoids (Chart 9). These eicosanoids are associated with platelet aggregation, vasodilation, leukocyte inflammatory and immune functions and cellular adhesion [85]. 

The answer is b. (Murray, pp 505-626. Scriver, pp 5029-5250. Sack, pp 121-138. Wilson, pp 287-320.) The essential fatty acid linoleic acid, with 18 carbons and two double bonds at carbons 9 and 18 (C-18 2-A ) is desaturated to form a-linolenic acid (C-18 3-A ), which is sequentially elongated and desaturated to form eicosatrienoic acid (C-20 3-2 8,11,1+) arachidonic acid (C-20 4-A " ), respectively. Many of the eicosanoids (20-carbon compounds)—prostaglandins, thromboxanes, and leukotrienes—are derived from arachidonic acid. The scientific name of arachidonic acid is eicosatetraenoic acid. Arachidonic acid can only be synthesized from essential fatty acids obtained from the diet. Palmitic acid (C-16 0) and oleic acid (C-18 l-A" ) can be synthesized by the tissues. 

Arachidonic acid (20 4n - 6) is one of two major PUFA synthesized by the D6D/D5D pathway (Fig. 4). In many tissues and cell types, 20 4n - 6 is esterified to the sn-2 position of membrane PL, and is used for the eicosanoid-mediated signaling to perform specialized cell functions. Arachidonic acid esterified in PL is a storage form of this fatty acid and is hydrolyzed from the PL by phospholipases prior to enzymatic conversion into eicosanoids (Chapter 13). Eicosanoids are autocrine/paracrine hormones that mediate a variety of localized reactions, such as inflammation, homeostasis, and protection of digestive tract epithelium. D6D deficiency in humans leads to severe food intolerance and growth retardation (J. Nwankwo, 2003). These symptoms are reversed by arachidonic acid supplementation to the diet, which supports the essential role of eicosanoids in the protection of digestive tract mucosa in humans. 

The essential fatty acid linoleic acid is required in the diet for at least three reasons (a) It serves as a precursor of arachidonic acid from which eicosanoids are produced, ib) It covalently binds another fatty acid attached to cerebrosides in the skin, forming an unusual lipid (acylglucosylceramide) that helps to make the skin impermeable to water. This function of linoleic acid may help to explain the red, scaly dermatitis and other skin problems associated with a dietary deficiency of essential fatty acids, (c) It is the precursor of C22 6o)3, an important neuronal fatty acid. 

Because of the increased amounts of omega-6 fatty acids in the Western diet, the eicosanoid metabolic products from AA, specifically prostaglandins, thromboxanes, leukotrienes, hydroxy fatty acids, and hpoxins, are formed in larger quantities than those formed from omega-3 fatty acids, specifically EPA. The eieosanoids from AA are biologically active in very small quantities, and if they are formed in large amounts, they contribute to the formation of thrombus and atheromas to allergic and inflammatory disorders, particularly in susceptible people and to proliferation... 

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