Document Detail


Cyclooxygenase Allosterism, Fatty Acid-mediated Cross-talk between Monomers of Cyclooxygenase Homodimers.
MedLine Citation:
PMID:  19218248     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Prostaglandin endoperoxide H synthases (PGHSs) 1 and 2, also known as cyclooxygenases (COXs), catalyze the oxygenation of arachidonic acid (AA) in the committed step in prostaglandin (PG) biosynthesis. PGHSs are homodimers that display half of sites COX activity with AA; thus, PGHSs function as conformational heterodimers. Here we show that, during catalysis, fatty acids (FAs) are bound at both COX sites of a PGHS-2 dimer. Initially, an FA binds with high affinity to one COX site of an unoccupied homodimer. This monomer becomes an allosteric monomer, and it causes the partner monomer to become the catalytic monomer that oxygenates AA. A variety of FAs can bind with high affinity to the COX site of the monomer that becomes the allosteric monomer. Importantly, the efficiency of AA oxygenation is determined by the nature of the FA bound to the allosteric monomer. When tested with low concentrations of saturated and monounsaturated FAs (e.g. oleic acid), the rates of AA oxygenation are typically 1.5-2 times higher with PGHS-2 than with PGHS-1. These different kinetic behaviors of PGHSs may account for the ability of PGHS-2 but not PGHS-1 to efficiently oxygenate AA in intact cells when AA is a small fraction of the FA pool such as during "late phase" PG synthesis.
Authors:
Chong Yuan; Ranjinder S Sidhu; Dmitry V Kuklev; Yuji Kado; Masayuki Wada; Inseok Song; William L Smith
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-02-12
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-04-06     Completed Date:  2009-05-20     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10046-55     Citation Subset:  IM    
Affiliation:
Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
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MeSH Terms
Descriptor/Qualifier:
Catalysis
Catalytic Domain
Cyclooxygenase 1 / metabolism
Cyclooxygenase 2 / metabolism
Dimerization
Dose-Response Relationship, Drug
Fatty Acids / metabolism*
Humans
Kinetics
Micelles
Models, Biological
Models, Chemical
Oleic Acid / chemistry
Prostaglandin-Endoperoxide Synthases / chemistry,  metabolism*
Protein Structure, Tertiary
Grant Support
ID/Acronym/Agency:
GM68848/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/Micelles; 112-80-1/Oleic Acid; EC 1.14.99.1/Cyclooxygenase 1; EC 1.14.99.1/Cyclooxygenase 2; EC 1.14.99.1/PTGS1 protein, human; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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