Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer
Liang Dong1, Alex J Vecchio, Narayan P Sharma
1Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
The Journal of Biological Chemistry
|April 7, 2011
Summary
Human prostaglandin endoperoxide H synthase-2 (PGHS-2) functions as a heterodimer, not a homodimer. Free fatty acid levels in cells regulate PGHS-2 activity and drug responses.
Area of Science:
- Biochemistry
- Enzymology
- Pharmacology
Background:
- Prostaglandin endoperoxide H synthases (PGHS), also known as cyclooxygenases (COXs), catalyze the conversion of arachidonic acid to prostaglandin endoperoxide H(2).
- PGHS enzymes are key targets for nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (coxibs).
- Human PGHS-2 was previously thought to function as a homodimer, with each monomer possessing peroxidase and COX active sites.
Purpose of the Study:
- To elucidate the functional quaternary structure and regulatory mechanisms of human PGHS-2.
- To investigate the role of fatty acids and inhibitors in modulating PGHS-2 activity.
- To understand how cellular fatty acid composition influences PGHS-2 response to inhibitors.
Main Methods:
- Biochemical assays and structural analysis (implied by co-crystal data mentioned).
- Investigation of ligand binding (heme, substrates, inhibitors, fatty acids) to different PGHS-2 monomers.
- Characterization of the allosteric regulation of the catalytic monomer by the allosteric monomer.
Main Results:
- Human PGHS-2 functions as a conformational heterodimer, comprising a catalytic (E(cat)) and an allosteric (E(allo)) monomer.
- Heme binds to E(cat), while substrates and inhibitors bind to both E(cat) and E(allo), with higher affinity for E(allo) in the case of arachidonic acid.
- Free fatty acids and COX inhibitors modulate PGHS-2 activity and inhibitor efficacy by binding to E(allo), influencing E(cat) function.
Conclusions:
- The heterodimeric nature of PGHS-2 is critical for its catalytic activity and regulation.
- Cellular free fatty acid levels ('FA tone') are a key determinant of PGHS-2 activity and drug response.
- Dietary variations in fatty acid composition may impact prostanoid synthesis and NSAID/coxib efficacy.
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