Cyclooxygenase-2

Filipponi et al. [7] studied the differences in the active sites of the two isoforms of cyclooxygenase (COX), an enzyme involved in the biosynthesis of pro-inflammatory prostaglandins. Two isoforms of COX exist a constitutive cyclooxygenase-1 and an inducible cyclooxygenase-2, and it is believed that COX-2 selective inhibitors provide anti-inflammatory agents with a superior safety profile [35]. 

The two enzymes are very similar. The only amino acid difference at the core of the binding site is the mutation Ile523 in COX-1 to the smaller Val523 in COX-2, 

Selective probe-COX-2 interactions occur in a region within the second pocket of COX-2 which is determined by Val523. The most selective probes, which can donate more than one hydrogen, have a high degree of affinity for COX-2 in this region. 

The comparison with experimental data is somewhat complicated by the fact that the entry to the second pocket may be closed by a salt bridge which has to be broken to gain access to the pocket. Nevertheless, good agreement of the selectivity analysis with the selectivity profile of known inhibitors is found. In this case, the authors come to the conclusion, that taking protein flexibility into account with MOVE = 1 better reproduces the experimental data. 

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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. 

Studies of the biosynthesis of PGE2 from arachidonic acid have shown that all three oxygens come from O2 The enzyme involved prostaglandin endoperoxide syn tliase has cyclooxygenase (COX) activity and catalyzes the reaction of arachidonic acids with O2 to give an endoperoxide (PGG2)... 

Covalent bond (Section 1 3) Chemical bond between two atoms that results from their shanng of two electrons COX 2 (Section 26 6) Cyclooxygenase 2 an enzyme that cat alyzes the biosynthesis of prostaglandins COX 2 inhibitors reduce pain and inflammation by blocking the activity of this enzyme... 

AryImethyIenehyda.ntoins. 5-Arylmethylenehydantoins such as (26) are cyclooxygenase and 5-hpoxygenase inhibitors and have been patented as antiinflammatory and antiaHergy agents (120). 

The enzyme system responsible for the biosynthesis of PGs is widely distributed in mammalian tissues and has been extensively studied (2). It is referred to as prostaglandin H synthase (PGHS) and exhibits both cyclooxygenase and peroxidase activity. In addition to the classical PGs two other prostanoid products, thromboxane [57576-52-0] (TxA ) (3) and prostacyclin [35121 -78-9] (PGI2) (4) are also derived from the action of the enzyme system on arachidonic acid (Fig. 1). 

In order for the cyclooxygenase to function, a source of hydroperoxide (R—O—O—H) appears to be required. The hydroperoxide oxidizes a heme prosthetic group at the peroxidase active site of PGH synthase. This in turn leads to the oxidation of a tyrosine residue producing a tyrosine radical which is apparendy involved in the abstraction of the 13-pro-(5)-hydrogen of AA (25). The cyclooxygenase is inactivated during catalysis by the nonproductive breakdown of an active enzyme intermediate. This suicide inactivation occurs, on average, every 1400 catalytic turnovers. 

All prostaglandins are cyclopentanoic acids derived from arachidonic acid. The biosynthesis of prostaglandins is initiated by an enzyme associated with the endoplasmic reticulum, called prostaglandin endoperoxide synthase, also known as cyclooxygenase. The enzyme catalyzes simultaneous oxidation and cyclization of arachidonic acid. The enzyme is viewed as having two distinct activities, cyclooxygenase and peroxidase, as shown in Figure 25.28. 

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. 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Cyclooxygenase is known to exist in two distinct isoforms COX-1 and COX-2 (92JBC21438). The constitutive isoform COX-1 is present in a variety of tissues and is thought to be important in maintaining normal physiological functions such... 

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