Arachidonic acid carbon

Prostaglandins have 20 carbon atoms. They are synthesized in the body by oxidation and cyclization of the 20-carbon unsaturated fatty acid arachidonic acid. Carbon-8 through carbon-12 of the chain are looped to form a cyclopentane ring, and an oxygen function (carbonyl or hydroxyl group) is always present at carbon-9. Various numbers of double bonds or hydroxyl groups may also be present elsewhere in the structure. 

Prostaglandins arise from unsaturated C20 carboxylic acids such as arachidonic acid (see Table 26 1) Mammals cannot biosynthesize arachidonic acid directly They obtain Imoleic acid (Table 26 1) from vegetable oils m their diet and extend the car bon chain of Imoleic acid from 18 to 20 carbons while introducing two more double bonds Lmoleic acid is said to be an essential fatty acid, forming part of the dietary requirement of mammals Animals fed on diets that are deficient m Imoleic acid grow poorly and suffer a number of other disorders some of which are reversed on feed mg them vegetable oils rich m Imoleic acid and other polyunsaturated fatty acids One function of these substances is to provide the raw materials for prostaglandin biosynthesis... 

The prostaglandins (qv) constitute another class of fatty acids with aUcycHc structures. These are of great biological importance and are formed by i vivo oxidation of 20-carbon polyunsaturated fatty acids, particularly arachidonic acid [27400-91-5]. Several prostaglandins, eg, PGE [745-65-3] have different degrees of unsaturation and oxidation when compared to the parent compound, prostanoic acid [25151 -18-9]. 

Mammals can add additional double bonds to unsaturated fatty acids in their diets. Their ability to make arachidonic acid from linoleic acid is one example (Figure 25.15). This fatty acid is the precursor for prostaglandins and other biologically active derivatives such as leukotrienes. Synthesis involves formation of a linoleoyl ester of CoA from dietary linoleic acid, followed by introduction of a double bond at the 6-position. The triply unsaturated product is then elongated (by malonyl-CoA with a decarboxylation step) to yield a 20-carbon fatty acid with double bonds at the 8-, 11-, and 14-positions. A second desaturation reaction at the 5-position followed by an acyl-CoA synthetase reaction (Chapter 24) liberates the product, a 20-carbon fatty acid with double bonds at the 5-, 8-, IT, and ITpositions. 

Eicosanoids, so named because they are all derived from 20-carbon fatty acids, are ubiquitous breakdown products of phospholipids. In response to appropriate stimuli, cells activate the breakdown of selected phospholipids (Figure 25.27). Phospholipase Ag (Chapter 8) selectively cleaves fatty acids from the C-2 position of phospholipids. Often these are unsaturated fatty acids, among which is arachidonic acid. Arachidonic acid may also be released from phospholipids by the combined actions of phospholipase C (which yields diacyl-glycerols) and diacylglycerol lipase (which releases fatty acids). 

Figure 7.9 Pathway for the biosynthesis of prostaglandins from arachidonic acid. Steps 2 and 5 are radical addition reactions to 02 steps 3 and 4 are radical additions to carbon-carbon double bonds.

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. 

Second-derivative spectrophotometry has been used to monitor the time-dependent production of cis,tmns-(Xmax 242 nm) and trans, tram- (Xmax 232 nm) diene conjugates of microsomal PUFAs following the exposure of rats to carbon tetrachloride (CCU) (Corongui et al., 1986). These signals have been postulated to be derived from mixtures of peroxidized substrates. Previous studies using chemical model systems have established that autoxidation of linolenic or arachidonic acid results in the production of cis, trans- and tmns, trawr-conjugated diene... 

Prostaglandin Any of a large group of biologically active, carbon-20, unsaturated fatty acids that are produced by the metabolism of arachidonic acid through the cyclooxygenase pathway. 

Schreiber, J., Eling, T. E. and Mason, R. P. The oxidation of arachidonic acid by the cyclooxygenase activity of purified prostaglandin H synthase spin trapping of a carbon-centered free radical intermediate. Arch. Biochem. Biophys. 249 126-136,1986. 

Prostaglandins are a subgroup of a larger family of compounds known collectively as eicosanoids, which are synthesized from arachidonic acid (arachidonate) this is a 20-carbon omega-6 unsaturated fatty acid (C20 4). The source of the arachidonic acid for PG synthesis is the cell membrane. Most membrane phospholipids have an unsaturated fatty acid as arachidonate at carbon 2 on the glycerol backbone to help maintain membrane fluidity. The arachidonic acid released from the membrane by the... 

Manoalide (164), a marine natural product which inhibits the release of arachidonic acid from phospholipids by phospholipase A2 [397,398], showed topical anti-inflammatory activity in mouse ear models [399]. Activity in ISN and cRBL (< 1 M) have also been reported [400]. A series of analogues consisting of the furanone ring of manoalide bearing simple unsaturated 16-20 carbon chains showed similar activity in rabbit neutrophils and isolated guinea-pig neutrophil 5-LO [401] interestingly, however, topical anti-inflammatory activity was seen in phorbol ester ear oedema but not in AAE [399]. The importance of 5-LO inhibition to the anti-inflammatory activity of manoalide is unknown effects on phospholipase C and calcium channels have also been shown [402, 403]. 

Fatty acids, such as linoleic, hnolenic, and arachidonic acids, contain two or more cis carbon-carbon double bonds and are referred to as polyunsaturated fatty acids. Several of these fatty acids, including linoleic and linolenic acids, are required nutrients for humans and must be part of a healthy diet. They are termed essential fatty acids, of which there are eight. These fatty acids cannot be synthesized by human beings but are essential to human health. Therefore, they must be consumed in adequate amounts in a healthy diet, specifically in the form of ingested plant-derived foods. A diet devoid of the essential fatty acids eventually results in a fatal condition characterized by inflammation of the skin (dermatitis), failure of wounds to heal, and poor growth. The essential fatty acids serve as precursors for complex molecules termed eicosanoids, to which we return below. 

The key substrate for synthesis of the eicosanoids is the omega-6,20-carbon fatty acid arachidonic acid ... 

A separate very long-chain-acyl-CoA synthetase is present in peroxisomes for the activation of very long-chain fatty acids, such as arachidonate (20 carbon atoms). These fatty acids are degraded exclusively in the peroxisomes. 

Figure 1.9. Overview of the biosynthesis of ecosanoids. The 20 carbon fatty acid arachidonic acid is released from cell membrane phospholipids by the actions of phospholipase A2. Free arachidonic acid forms the precursor of prostaglandins and thromboxanes via the multi-enz5une cyclooxygenase pathway, while leukotrienes are formed via the lipoxygenase pathway...

The eicosanoids, so called because of their derivation from a 20-carbon unsaturated fatty acid, arachidonic acid (eicosatetraenoic acid), are obtained from membrane phospholipids and synthesized de novo at the time of cellular stimulation. Arachidonic acid is cleaved from membrane-bound phosphatidylcholine by the enzyme phospholipase A2. Alternatively, arachidonic acid may be derived by the sequential actions of phospholipase C and diacylglyceryl lipase. Arachidonic acid can then follow either of two enzymatic pathways that result in the production of inflammatory mediators. The pathway initiated by cyclooxygenase (COX) produces prostaglandins the lipoxygenase pathway generates leukotrienes (Fig. 36.2). 

Prostaglandin (PC). Components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. 

Prostaglandins (PG s) and leukotrienes (LT s) are biologically active derivatives of 20 carbon atom polyunsaturated essential fatty acids, which contains 3, 4 or 5 double bonds (e.g. 5,8,11,14-eicosatetraenoic acid i.e., arachidonic acid). 

In human being, arachidonic acid is the most important precursor for the biosynthesis of eicosanoids. Arachidonic acid is formed from linoleic acid in most mammalians by desaturation and carbon elongation to dihomog-linolenic acid and subsequent desaturation. 

---