Document Detail


Asymmetric acetylation of the cyclooxygenase-2 homodimer by aspirin and its effects on the oxygenation of arachidonic, eicosapentaenoic, and docosahexaenoic acids.
MedLine Citation:
PMID:  20194532     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Prostaglandin endoperoxide H synthases (PGHS)-1 and -2, also called cyclooxygenases, convert arachidonic acid (AA) to prostaglandin H(2) (PGH(2)) 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 PGH(2) 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 PGH(2) 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 PGH(2) by native PGHS-2.
Authors:
Narayan P Sharma; Liang Dong; Chong Yuan; Kathleen R Noon; William L Smith
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-03-01
Journal Detail:
Title:  Molecular pharmacology     Volume:  77     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-05-18     Completed Date:  2010-06-01     Revised Date:  2011-07-28    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  979-86     Citation Subset:  IM    
Affiliation:
Department of Biological Chemistry, University of Michigan Medical School, 1150 West Medical Center Drive, 5301 MSRB III, Ann Arbor, MI 48109-0606, USA.
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MeSH Terms
Descriptor/Qualifier:
Acetylation
Arachidonic Acid / metabolism*
Aspirin / pharmacology*
Base Sequence
Chromatography, Liquid
Chromatography, Thin Layer
Cyclooxygenase 2 / genetics,  metabolism*
DNA Primers
Diclofenac / pharmacology
Dimerization
Docosahexaenoic Acids / metabolism*
Eicosapentaenoic Acid / metabolism*
Humans
Mutagenesis
Oxygen / metabolism*
Tandem Mass Spectrometry
Grant Support
ID/Acronym/Agency:
GM068848/GM/NIGMS NIH HHS; HL085149/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; 15307-86-5/Diclofenac; 1553-41-9/Eicosapentaenoic Acid; 25167-62-8/Docosahexaenoic Acids; 50-78-2/Aspirin; 506-32-1/Arachidonic Acid; 7782-44-7/Oxygen; EC 1.14.99.1/Cyclooxygenase 2
Comments/Corrections

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