Arachidonic acid, eicosanoids from structure

Arabinose, configuration of. 982 Kiliani-Fischer synthesis on. 995 Arachidic acid, structure of, 1062 Arachidonic acid, eicosanoids from, 1069-1070... 

Leukotriene biosynthesis depends upon the availability of arachidonic acid (8) as the free carboxylic acid as the 5-LOX substrate, which typically requires the action of cytosolic phospholipase to release arachidonic acid (8) from membrane phospholipids [27]. The name leukotriene was conceived to capture two unique attributes of these molecules. The first relates to those white blood cells derived from the bone marrow that have the capacity to synthesize this class of eicosanoids, for example, the polymorph nuclear leukocyte. The last part of the name refers to the unique chemical structure, a conjugated triene retained within these eicosanoids [29,30]. The first step for the leukotriene biosynthesis is the insertion of molecular oxygen at position 5 of arachidonic add (8) to produce 5-HPETE (17) that can be converted to leukotriene (18) by the second catalytic activity... 

Figure 27.3 Structures of some representative eicosanoids. All are derived biologically from arachidonic acid.

Eicosanoids and terpenoids are still other classes of lipids. Eicosanoids, of which prostaglandins are the most abundant kind, are derived biosynthetically from arachidonic acid, are found in all body tissues, and have a wide range of physiological activity. Terpenoids are often isolated from the essential oils of plants, have an immense diversity of structure, and are produced biosynthetically from the five-carbon precursor isopentenyl diphosphate (IPP). lsopentenyl diphosphate is itself biosynthesized from 3 equivalents of acetate in the mevalonate pathway. 

Eicosanoids, also referred to as icosanoids, are so named because of the 20-carbon constituency that identifies this class of oxygenated lipid molecules. A primary synthetic pathway for these molecules involves the phospholipase-mediated cleavage of a membrane phospholipid to produce arachidonic acid [(all-Z)-ik osa-5,8,ll,14-tetraenoic acid]. From this biologically essential intermediate fatty acid, two major subclasses of eicosanoids can be produced 1) leukotrienes, via the action of lipooxygenases, and 2) prostanoids, via the action of cyclooxygenases (COX-1 and COX-2). Examples of chemical structures for a leukotriene (Fig. la) and three types of prostanoids (Fig. Ib-d) underscore their shared arachidonate origin. 

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). 

The thromboxanes are also derivatives of arachidonic acid. They differ from other eicosanoids in that their structures have a cyclic ether. Thromboxane A2 (TXA2), the most prominent member of this group of eicosanoids, is primarily produced by platelets (cell fragments in the blood that initiate blood clot formation). 

Some of the unsaturated fatty acids containing more than one double bond cannot be synthesized by the body For many years it has been known that linolenic acid and linoleic acid, called the essential fatty acids, are necessary for specific biochemical functions and must be supplied in the diet (see Table 18.1). The fimction of linoleic acid became clear in the 1960s when it was discovered that linoleic acid is required for the bios)mthesis of arachidonic acid, the precursor of a class of hormonelike molecules known as eicosanoids. The name is derived from the Greek word eikos, meaning "twenty," because they are all derivatives of twenty-carbon fatty acids. The eicosanoids include three groups of structurally related compounds the prostaglandins, the leukotrienes, and the thromboxanes. 

LIpoxins (LX). Acyclic eicosanoids with conjugated tetraene or pentaene structures and three hydroxy groups. The first identified compounds were designated as L. A and L. B with the index 4 or 5 to indicate the number of their C=C-double bonds. Biosyn-thetically L. are formed from arachidonic acid under the action of various oxidizing enzymes, especially 5- and 15-lipoxygenases. (55,6/J,155)-Trihydroxy-... 

Thromboxanes (TX). Cyclic eicosanoids occurring in all body tissues. The compounds are classified into a TXA- (bicyclic structure with an oxetane ring) and a 7XS- eries (cyclic structure in which the oxetane ring has been hydrolytically cleaved) an index number indicates the number of C,C-double bonds in the molecule. T. are formed in the cyclooxygenase biosynthesis pathway from arachidonic acid and other multiply unsaturated fatty acids, the first biosynthetic steps on the way to the T. and to the prostaglandins are identical (see figure). The multiply unsaturated fatty acids are first released from phosphatidylcholines and other phospholipids of the cell membrane by phospholipase A,. 

Leukotrienes (LTs) are lipid mediators derived enzymatically from arachidonic acid. Structurally, these eicosanoids contain a conjugated triene functionality. LTB4 and LTC4 are the two important leukotrienes. Mass spectrometry has played... 

In addition to inhibiting the metabolism of arachidonic acid, EPA is able to act as a substrate for both COX and 5-LOX, giving rise to derivatives which have a different structure to those produced from arachidonic acid (i.e. 3-series PG and TX and 5-series LT). Thus, the EPA-induced suppression of the production of arachidonic acid-derived eicosanoids may be accompanied by an elevation in the production of EPA-derived eicosanoids. This is most evident for the 5-LOX products of EPA metabolism (Lee et al., 1985 Sperling et al., 1993). The eicosanoids produced from EPA are considered to be less biologically potent than the analogues synthesized from arachidonic acid. 

Figure 1. There are two important families of PUFA the n-6 family based on linoleic acid, and the n-3 family based on a-linolenic acid. Since animals - including humans - cannot produce linoleic or a-linolenic acids themselves, these acids are essential parts of the diet, obtainable only from vegetable sources or from animals which have already derived these acids from a plant source. Once ingested, the two C g acids can be metabolized to important C q and acids through a series of changes involving desaturation and elongation. The same enzymes are required for both families of acids and there is competition for these. The most important acids in these sequences are arachidonic acid in the n-6 series, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the n-3 series. All these acids are important components of phospholipid membranes, and the two acids are also precursors of prostaglandins and other eicosanoids. The locations of the double bonds are indicated in brackets after the abbreviated structure of each fatty acid.

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