2.5 - Aspirin - inhibition of cyclooxygenase

2.5 - Aspirin - inhibition of cyclooxygenase

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Aspirin - Different effects on the COX isoforms

Initial investigations into a possible selectivity of aspirin between the two COX isoforms appeared to indicate that aspirin is a selective COX-1 inhibitor. As a measure of the inhibition, the consumption of the substrate arachidonic acid by the COX before and after incubation with aspirin was followed by analysis. With the COX-1, no conversion of arachidonic acid could be determined soon after the addition of aspirin. The arachidonic acid conversion by the COX-2, however, remained almost unchanged!

Aspirin - A Selective COX-1 Inhibitor?

In further experiments, however, it was no longer the consumption of the COX substrate arachidonic acid but the formation of the COX product prostaglandin H2(PGH2) was observed analytically, a completely different picture emerged. Both COX-1 and COX-2 did not produce PGH after incubation with aspirin2 more! However, since the COX-2 continued to convert arachidonic acid, the acetylated COX-2 obviously had to be a different product than PGH2 form. This product was finally available as (15R.) -HETE ((5Z,8Z,11Z,13E.,15R.) -Hydroxyeicosatetraenoic acid) can be identified. Further investigations withC.14-labeled aspirin and the individual COX isoforms also showed that both COX-1 and COX-2 are irreversibly acetylated by aspirin in the same manner at Ser 530.

In summary, it can thus be stated:

Different effects of aspirin on the COX isoforms
  • The COX-1 is irreversibly acetylated at Ser 530 by aspirin. This has the complete inhibition of PGH2-Biosynthesis. Whether the arachidonic acid can no longer enter the cyclooxygenase reaction center of the COX-1 for steric reasons or whether only Tyr 385, which is essential for the cyclooxgenase mechanism, is blocked by the acetyl group on Ser 530, remains unclear at first. It would be conceivable, for example, that the hydrogen bond between Tyr 385 and the acetyl-carbonyl-oxygen atom postulated for the acetylation mechanism remains in place even after the acetylation. Definitely no PGH2 formed and no more arachidonic acid consumed.
  • The COX-2 is also irreversibly acetylated at Ser 530 by aspirin! The COX-2 cannot then use PGH either2 produce more. Since the arachidonic acid continues to be converted by the acetylated COX-2, it can obviously still get into the reaction center. There, however, it is no longer inPGH2converted, but only to (15R.) -HETE. It is believed that Tyr 385 is blocked by the acetyl group on Ser 530 in the manner described above. In contrast to COX-1, however, an alternative mechanism can take place in the acetylated COX-2, which leads to (15R.) -HETE leads. The exact structural reasons for this difference have yet to be clarified.

The biological-pharmacological consequences resulting from the formation of (15R.) -HETE by the acetylated COX-2 and the inhibition of the PGH2Synthesis in both COX isoforms are discussed in the following sections.

Exercise: Aspirin - COX-2 - (15R.>) - HETE


Holtzman, M. J .; Turk, J .; Shornick, L. P. (1992):Identification of a Pharmacologically Distinct Prostaglandin H Synthase inCultured Epithelial Cells. In: J. Biol. Chem.. 267, 21438-21445
  • source
Meade, E. A .; Smith, W. L .; DeWitt, D. L. (1993):Differential Inhibition of Prostaglandin Endoperoxide Synthase (Cyclooxygenase) Isozymes by Aspirin and Other Non-steroidal Antiinflammatory Drugs. 268, 6610-6614
  • source
Lecomte, M .; Laneuville, O .; Ji, C .; DeWitt, D. L .; Smith, W. L. (1994):Acetylation of Human Prostaglandin Endoperoxide Synthase-2 (Cyclooxygenase-2) byAspirin. 269, 13207-13215
  • source
Mancini, J. A .; O'Neill, G. P .; Bayly, C .; Vickers, P. J. (1994):Mutation of serine-516 in human prostaglandin G / H synthase-2 to methionine oraspirin acetylation of this residue stimulates 15-R-HETE synthesis. In: FEBS letters. 342, 33-37
  • source


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