Prostaglandin synthesis thromboxane

Cyclooxygenase Inhibitors. The synthesis of prostaglandin and thromboxane has been linked with multiple organ failure in animals and humans with sepsis. Bernard et al. (B18) reported the results of a large trial of the cyclooxygenase inhibitor ibuprofen in patients with sepsis. Treatment for 48 hours with... 

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. 

Eicosanoid synthesis. Arachidonic acid is converted by cyclooxygenases into prostaglandins, and thromboxanes. Lipoxygenases convert arachidonic acid into HPETEs, which are then converted to lipoxins, leukotrienes, and 12-HETE (hydroxyeicosatetraenoic acid). Epoxygenases convert arachidonic acid into epoxides. 

Metabolites of arachidonic acid, including prostaglandins (PG), thromboxanes, and leukotrienes, are considered strong candidates as mediators of the inflammatory process. Steroids may exert a primary effect at the inflammatory site by inducing the synthesis of a group of proteins called lipocortins. These proteins suppress the activation of phospholipase A2, thereby decreasing the release of arachidonic acid and the production of proinflammatory eicosanoids (Fig. 60.6). 

T Aspirin (acetylsalicylate Fig. 21-15b) irreversibly inactivates the cyclooxygenase activity of COX by acetylating a Ser residue and blocking the enzyme s active site, thus inhibiting the synthesis of prostaglandins and thromboxanes. Ibuprofen, a widely used nonsteroidal antiinflammatory drug (NSAID Fig. 21-15c), inhibits the same enzyme. The recent discovery that there are two isozymes of COX has led to the development of more precisely targeted NSAIDs with fewer undesirable side effects (Box 21-2). 

Synthesis of prostaglandins and thromboxanes begins with the oxidative cyclization of free arachidonic acid to yield PGH2 by prostaglandin endoperoxide synthase—a microsomal protein that has two catalytic activities fatty acid cyclooxygenase (COX) and peroxidase. There are two isozymes of the synthase COX-1 and COX-2. Leukotrienes are produced by the 5-lipoxygenase pathway. 

Mechanism of NSAID Action Inhibition of Prostaglandin and Thromboxane Synthesis... 

Prostaglandins Prostaglandins and the other eicosanoids (prostacyclins, thromboxanes and leukotrienes) are derived from arachidonate. These compounds all act as local hormones. Aspirin reduces inflammation by inhibiting prostaglandin synthase, the enzyme that catalyzes the first step in prostaglandin synthesis. 

Mammals lack the enzymes to insert double bonds at carbon atoms beyond C-9 in the fatty acid chain. Thus they cannot synthesize linoleate and linole-nate, both of which have double bonds later in the chain than C-9 (linoleate has cis, cis A9, A12 double bonds, and linolenate has all-ris A9, A12, A15 double bonds). Hence, in mammals linoleate and linolenate are called essential fatty acids since they have to be supplied in the diet. These two unsaturated fatty acids are also the starting points for the synthesis of other unsaturated fatty acids, such as arachidonate. This C20 4 fatty acid is the precursor of several biologically important molecules, including the prostaglandins, prostacyclins, thromboxanes and leukotrienes (see Topic Kl). 

Yes, because platelet aggregation depends on the release of thromboxanes from the endothelial cells of blood vessels. Aspirin inhibits cyclooxygenase and thus synthesis of prostaglandins and thromboxanes is inhibited. 

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