Arachidonic acid synthesis

The most abundant and therefore the most common precursor of the eicosanoids is arachidonic acid (eicosatetraenoic acid, w6,20 4,A5,8,ll,14), a polyunsaturated fatty acid with 20 carbons and 4 double bonds (see Fig. 35.1). It is esterified to phospholipids located in the lipid bilayer that constitutes the plasma membrane of the cell. Because arachidonic acid cannot be synthesized de novo in the body, the diet must contain arachidonic acid or other fatty acids from which arachidonic acid can be produced. The major dietary precursor for arachidonic acid synthesis is the essential fatty acid linoleate, which is present in plant oils (see Chapter 33). 

Inhibit 6-desaturase and arachidonic acid synthesis Reduce peroxide tone... 

For this reason it was important to investigate the routes of arachidonic acid synthesis from labeled linoleic acid and the possible incorporation of labeled acids in cell lipids. 

These steioids aie capable of preventing or suppressing the development of the sweUing, redness, local heat, and tenderness which characterize inflammation. They inhibit not only the acute symptoms of the inflammatory process, such as edema, fibrin deposition, and capillary dilatation, but also the chronic manifestations. There is evidence that glucocorticoids induce the synthesis of a protein that inhibits phosphoHpase A 2 (60), diminishing the release of arachidonic acid from phosphoHpids (Fig. 2), thereby reducing chemotaxis and inflammation. 

Extracts from Clavularia viridis and also many other coral species convert arachidonic acid to the prostanoidpreclavulone-A via 8-( f )-hydroperoxy-5,ll,14( Z), QfEj-eicosatetraenoic acid. The carbocyclization is considered to occur from allene oxide and oxidopentadienyl cation intermediates. An enantioselective total synthesis of preclavulone-A was developed to assist the biosynthetic research. 

Lipoxygenation is the major pathway of dioxygenation of arachidonic acid in blood platelets and leads to the 12-5-hydroperoxy acid 12-HPETE and the corresponding 12-hydroxy acid 12-HETE. Several pathways for the synthesis of 12-HETE have been developed. However, despite the availability of this substance, its biological role remains undetermined. 

Total Synthesis of Hepoxylins and Related Metabolites of Arachidonic Acid... 

Hepoxylins are metabolites of arachidonic acid which arise from 12-HPETE in tissues such as pancreatic islet cells (where they stimulate glucose-dependent insulin release) and brain (where they appear to have a neuromodulatory role). The structure of the hepoxylins was confirmed by synthesis which also has provided this scarce material for biological investigation. 

Some fatty acids are not synthesized by mammals and yet are necessary for normal growth and life. These essential fatty aeids include llnoleic and y-linolenic acids. These must be obtained by mammals in their diet (specifically from plant sources). Arachidonic acid, which is not found in plants, can only be synthesized by mammals from linoleic acid. At least one function of the essential fatty acids is to serve as a precursor for the synthesis of eicosanoids, such as... 

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. 

Animal cells can modify arachidonic acid and other polyunsaturated fatty acids, in processes often involving cyclization and oxygenation, to produce so-called local hormones that (1) exert their effects at very low concentrations and (2) usually act near their sites of synthesis. These substances include the prostaglandins (PG) (Figure 25.27) as well as thromboxanes (Tx), leukotrienes, and other hydroxyeicosanoic acids. Thromboxanes, discovered in blood platelets (thrombocytes), are cyclic ethers (TxBg is actually a hemiacetal see Figure 25.27) with a hydroxyl group at C-15. 

In this bromoaspirin-inactivated structure, Ser , which lies along the wall of the tunnel, is bromoacetylated, and a molecule of salicylate is also bound in the tunnel. Deep in the tunnel, at the far end, lies Tyr, a catalytically important residue. Heme-dependent peroxidase activity is implicated in the formation of a proposed Tyr radical, which is required for cyclooxygenase activity. Aspirin and other NSAIDs block the synthesis of prostaglandins by filling and blocking the tunnel, preventing the migration of arachidonic acid to Tyr in the active site at the back of the tunnel. 

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

Type I allergic reactions are inappropriate immune responses to an allergen with preferential synthesis of immunoglobulin E (IgE), a special antibody class, which binds to mast cells and basophilic granulocytes via Fee receptors. Binding of the allergen to the cell-bound IgE initiates the rapid release of allergic mediators, most prominently histamine, and the de novo synthesis of arachidonic acid metabolites and cytokines, which are responsible for the clinical symptoms. 

Calderwood, S.K., Bomstein, B., Famum, E.K.., Stevenson, M.A. (1989). Heat shock stimulates the release of arachidonic acid and the synthesis of prostaglandins and leukotriene B4 in mammalian cells. J. Cell. Physiol. 141, 325-333. 

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