Cyclooxygenase activation

Both methods suggest that the chemical structure of A A (cis double bonds connected by two single bonds) allows the fatty acid to access the cyclooxygenase active site of PGHS-1 through a narrow hydrophobic channel and to bind in a shape favorable for the cyclooxygenation reaction. 

FIGURE 25.29 (a) The structures of several commou analgesic agents. Acetaminophen is marketed under the tradename Tylenol. Ibuprofen is sold as Motrin, Nuprin, and Advil, (b) Acetylsalicylate (aspirin) inhibits the cyclooxygenase activity of endoperoxide synthase via acetylation (covalent modification) of Ser ... 

The cyclooxygenase active site lies at the end of a long, narrow, hydrophobic tunnel or channel. Three of the u-helices of the membrane-binding domain lie at the entrance to this tunnel. The... 

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. 

Patrignani P, Panara MR, Greco A et al (1994) Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther 271 1705-1712... 

A thrombotic tendency is present in diabetes due to an imbalance between prostacyclin and thromboxane. Lipid peroxides and newly generated free radicals are thought to inhibit the vasodilator and anti-platelet effects of endothelial-derived prostacyclin, but stimulate platelet cyclooxygenase activity, thereby promoting the production of thromboxane A2. This leads to vasoconstriction and platelet aggregation - the concept of peroxide vascular tone (Halliwell and Gutteridge, 1989). 

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. 

Platelet Inhibition Ginger extract has been found to inhibit platelet aggregation induced by arachidonic acid, epinephrine, ADP, and collagen (Srivastava 1984). The extract s ability to inhibit cyclooxygenase activity and thromboxane levels correlated well with inhibition of platelet aggregation (Srivastava 1984 Mustafa et al. 1993). The type of preparation used also affects platelet inhibition, because roasted and charcoal of ginger were effective, while ether extracts of raw and dried ginger were not (Wu et al. 1993). 

Acetylsalicylic acid and related non-steroidal anti-inflammatory drugs (NSAIDs) selectively inhibit the cyclooxygenase activity of prostaglandin synthase [2] and consequently the synthesis of most eicosanoids. This explains their analgesic, antipyretic, and antirheumatic effects. Frequent side effects of NSAIDs also result from inhibition of eicosanoid synthesis. For example, they impair hemostasis because the synthesis of thromboxanes by thrombocytes is inhibited. In the stomach, NSAIDs increase HCl secretion and at the same time inhibit the formation of protective mucus. Long-term NSAID use can therefore damage the gastric mucosa. 

Pharmacology Nonsteroidal anti-inflammatory drugs have analgesic, antipyretic, and anti-inflammatory activities. Major mechanism is believed to be inhibition of cyclooxygenase activity and prostaglandin synthesis. 

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). 

Lehmann, W.D. 1994. Regio- and stereochemistry of the dioxygenation reaction catalyzed by (S)-type lipoxygenases or by the cyclooxygenase activity of prostaglandin H synthases. Free Radical Biol. Med. 16 241-253. 

Tylenol inhibits the peroxidase activity and aspirin inhibits the cyclooxygenase activity. 22.46 because dead heart muscles spill their enzyme contents into the serum 22.48 They are both basic amino acids. 

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