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Research ArticleArticle

Asymmetric Acetylation of the Cyclooxygenase-2 Homodimer by Aspirin and Its Effects on the Oxygenation of Arachidonic, Eicosapentaenoic, and Docosahexaenoic Acids

Narayan P. Sharma, Liang Dong, Chong Yuan, Kathleen R. Noon and William L. Smith
Molecular Pharmacology June 2010, 77 (6) 979-986; DOI: https://doi.org/10.1124/mol.109.063115
Narayan P. Sharma
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Liang Dong
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Chong Yuan
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Kathleen R. Noon
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William L. Smith
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Abstract

Prostaglandin endoperoxide H synthases (PGHS)-1 and -2, also called cyclooxygenases, convert arachidonic acid (AA) to prostaglandin H2 (PGH2) in the committed step of prostaglandin biosynthesis. Both enzymes are homodimers, but the monomers often behave asymmetrically as conformational heterodimers during catalysis and inhibition. Here we report that aspirin maximally acetylates one monomer of human (hu) PGHS-2. The acetylated monomer of aspirin-treated huPGHS-2 forms 15-hydroperoxyeicosatetraenoic acid from AA, whereas the nonacetylated partner monomer forms mainly PGH2 but only at 15 to 20% of the rate of native huPGHS-2. These latter conclusions are based on the findings that the nonsteroidal anti-inflammatory drug diclofenac binds a single monomer of native huPGHS-2, having an unmodified Ser530 to inhibit the enzyme, and that diclofenac inhibits PGH2 but not 15-hydroperoxyeicosatraenoic acid formation by acetylated huPGHS-2. The 18R- and 17R-resolvins putatively involved in resolution of inflammation are reportedly formed via aspirin-acetylated PGHS-2 from eicosapentaenoic acid and docosahexaenoic acid, respectively, so we also characterized the oxygenation of these omega-3 fatty acids by aspirin-treated huPGHS-2. Our in vitro studies suggest that 18R- and 17R-resolvins could be formed only at low rates corresponding to less than 1 and 5%, respectively, of the rates of formation of PGH2 by native PGHS-2.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • These studies were supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM068848]; and the National Institutes of Health National Heart, Lung, and Blood Institute [Grant HL085149].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.063115.

  • ABBREVIATIONS:

    PGHS
    prostaglandin endoperoxide H synthase
    COX
    cyclooxygenase
    AA
    arachidonic acid
    hu
    human
    nsNSAID
    nonspecific nonsteroidal anti-inflammatory drug
    EPA
    eicosapentaenoic acid
    DHA
    docosahexaenoic acid
    TCA
    trichloroacetic acid
    11-HETE
    11-hydroxyeicosatetraenoic acid
    15-HETE
    15-hydroxyeicosatetraenoic acid
    11-HEPE
    11-hydroxyeicosapentaenoic acid
    15-HEPE
    15-hydroxyeicosapentaenoic acid
    18-HEPE
    18-hydroxyeicosapentaenoic acid
    13-HDHA
    13-hydroxydocosahexaenoic acid
    17-HDHA
    17-hydroxydocosahexaenoic acid
    RvE1
    Resolvin E1, 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid
    17R-RvD1
    17R-resolvin D1, 7S,8R,17R-trihydroxy-4Z,9E,13Z,15E,19Z-docosahexaenoic acid
    PGH2
    prostaglandin H2
    ASA
    acetylsalicylic acid
    HPLC
    high-performance liquid chromatography
    MS/MS
    tandem mass spectrometry
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    15R-HETE
    15R-hydroxy-eicosatetraenoic acid.

  • Received December 13, 2009.
  • Accepted March 1, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (6)
Molecular Pharmacology
Vol. 77, Issue 6
1 Jun 2010
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Research ArticleArticle

Asymmetric Acetylation of the Cyclooxygenase-2 Homodimer by Aspirin and Its Effects on the Oxygenation of Arachidonic, Eicosapentaenoic, and Docosahexaenoic Acids

Narayan P. Sharma, Liang Dong, Chong Yuan, Kathleen R. Noon and William L. Smith
Molecular Pharmacology June 1, 2010, 77 (6) 979-986; DOI: https://doi.org/10.1124/mol.109.063115

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Research ArticleArticle

Asymmetric Acetylation of the Cyclooxygenase-2 Homodimer by Aspirin and Its Effects on the Oxygenation of Arachidonic, Eicosapentaenoic, and Docosahexaenoic Acids

Narayan P. Sharma, Liang Dong, Chong Yuan, Kathleen R. Noon and William L. Smith
Molecular Pharmacology June 1, 2010, 77 (6) 979-986; DOI: https://doi.org/10.1124/mol.109.063115
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