Arachidonic acid prostaglandin synthesis from

Arachidonic acid, a 20-carbon fatty acid, is the primary precursor of the prostaglandins and related compounds (see Figure 39.3). Arachidonic acid is present as a component of the phospholipids of cell membranes, primarily phosphatidyl inositol and other complex lipids.1 Free arachidonic acid is released from tissue phospholipids by the action of phospholipase A2 and other acyl hydrolases, via a process controlled by hormones and other stimuli (see Figure 39.3). There are two major pathways in the synthesis of the eicosanoids from arachidonic acid (see Figure 39.3). 

Herrmann F, Lindemann A, Gauss J, Mertelsmann R (1990) Cytokine-stimulation of prostaglandin synthesis from endogenous and exogenous arachidonic acids in polymorphonuclear leukocytes involving activation and new synthesis of cyclooxygenase. Eur J Immunol 20 2513-2516 Herschman HR (1996) Prostaglandin synthase 2. Biochim Bio-phys Acta 1299 125-140... 

FIGURE 9.98 Events taking place in the plasma membrane on stimulation of a cell. Phospha tidylinositol (Pi) and more hi ly phosphoiylated versions of this lipid account for 2 to 8% of the lipids of the plasma membrane of eukaryotic cdIs. The inositol 1,4,5 triphosphate (fP3) moiety of phosphatidyl inositol- 4,8-di phosphate may be hydiulyitec from this lipid immediately after the cell is stimulated. For example, the stimulation of platelets by thrombin or the islets of the pancreas by glucose is followed by the release of 1P3 into the cytoplasm. In some cells, arachidonic acid is hydrolyzed from l-acyl-2-arachidonyl-glyceroL which can Support a burst of prostaglandin. synthesis. 

The antipyretic analgesics, with the non-steroidal anti-inflammatory drugs (NSAIDs), share a common mechanism of action, namely the inhibition of prostaglandin synthesis from arachidonic acid and their release. More precisely their mode of action is thought to result from inhibition of both the constitutive and the... 

A. Arachidonic acid is produced from linoleic acid (an essential fatty acid) by a series of elongation and desaturation reactions. Arachidonic acid is stored in membrane phospholipids, released, and oxidized by a cyclooxygenase (which is inhibited by aspirin) in the first step in the synthesis of prostaglandins, prostacyclins, and thromboxanes. Leukotrienes require a lipoxygenase, rather than a cyclooxygenase, for their synthesis from arachidonic acid. 

E. Arachidonic acid is cleaved from membrane phospholipids by phospholipase A2, which is inhibited by glucocorticoids. It requires essential fatty acids for its synthesis. It can be converted to leukotrienes, or be oxidized by a cyclooxygenase, which is inhibited by aspirin, and converted to prostaglandins and thromboxanes. 

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. 

As the first isolable intermediate in the bioconversion of arachidonic acid into prostaglandins and thromboxanes (Eq. 3), PGG2 is a bicyclic peroxide of immense biological importance. It is difficult to obtain pure from natural sources and the presence of the 15-hydroperoxide group adds a further dimension of chemical lability to that associated with the 9,11-peroxide bridge. The chemical synthesis of PGG2 is thus a landmark in prostaglandin chemistry. It also represents a pinnacle of success for the silver-salt route to bicyclic peroxides. 

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... 

Glucocorticosteroids are the most potent antiinflammatory agents available. They stabilize lysosomal membranes and reduce the concentration of proteolytic enzymes at the site of inflammation. They promote the synthesis of proteins called lipocortins which inhibit phospholipase-A2 and thus inhibit production of arachidonic acid, leukotrienes and prostaglandins. Furthermore, the expression of COX-II and through that the inflammatory effects of the licosanoids is inhibited. Glucocorticosteroids reduce the release of histamine from basophils, decrease capillary permeability and cause vasoconstriction. Glucocorticosteroids stimulate the loss of calcium with the urine and inhibit the resorption of calcium from the gut. 

Another important aspect of the inflammatory cascade is arachidonic acid metabolism, leading to the synthesis of the proinflammatory prostaglandins and leukotrienes. Through the formation of Upocortin, an inhibitor of phospholipase A2, glucocorticoids depress the release of arachidonic acid from phospholipids and hence the production of arachidonic acid metabolites. 

PI is synthesized from free inositol and CDP-diacylglycerol as shown in Figure 17.5. PI is an unusual phospholipid in that it olten contains stearic acid on carbon 1 and arachidonic acid on carbon 2 of the glycerol. PI, therefore, serves as a reservoir of arachidonic j acid in membranes and, thus, provides the substrate fa-prostaglandin synthesis when required (see p. 211 for a discussion of these compounds). 

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