Prostaglandin endoperoxide H synthases-1 and -2 (PGHS-1 and -2), also known as cyclooxygenases-1 and -2 (COX-1 and COX-2), catalyze the conversion of arachidonic acid (AA) to prostaglandin H2 (PGH2) in the committed step of prostaglandin (PG) biosynthesis. PGHSs are the primary targets of COX inhibitors, which include nonspecific nonsteroidal anti-inflammatory drugs (nsNSAIDs) and COX-2 specific inhibitors called coxibs. COX inhibitors are the most widely used pharmaceutical agents in the U.S. However, the use of these inhibitors carries significant risks. About 20,000 deaths annually are attributable to adverse effects of these drugs, the molecular basis for which is unknown. Using purified human PGHSs, we have discovered that PGHS activities are modulated through an unusual allosteric mechanism by all common fatty acids (FAs) including those that are not PGHS substrates. FAs can stimulate or inhibit PGHS activity with the specific effect being dependent on the PGHS isoform and the FA. The effects occur at physiologic FA concentrations and are observed in cells as well as with purified enzymes. The biochemical basis for the regulation of PGHSs by FAs involves cross-talk between monomers comprising PGHS homodimers. Although the monomers have identical amino acid sequences, the conformations of the two monomers comprising a PGHS homodimer differ. One monomer binds FAs and behaves as an allosteric monomer while the other acts as the catalytic monomer. Finally and importantly, responses of purified human PGHSs to COX inhibitors are modulated by FAs, again depending on the FA, the inhibitor and the PGHS isoform. With different COX inhibitors, FAs can influence binding of an inhibitor to one or to both monomers. The goals of the proposed research are to determine how PGHSs and their responses to widely used COX inhibitors are affected by FAs at the molecular, cellular and whole animal levels. Our underlying hypothesis is that both in vivo PG production and responses to COX inhibitors are significantly modulated by the milieu of FAs in which the enzymes find themselves-the FA tone--and that this FA environment is importantly influenced by the FA composition of the diet. We presume that every individual establishes a FA tone as a consequence of dietary habits in the context of their genetic background. We speculate that certain FA tones predispose susceptible individuals to adverse consequences of COX inhibitors. We expect that our studies delineating FA/COX inhibitor interactions will be a first step leading to changes in the way COX inhibitors are prescribed to people on different diets and to dietary adjustments to provide for the safer use of COX inhibitors.
This research is relevant to public health because it will provide a fundamental understanding of how different kinds of dietary fats can alter responses to common anti- inflammatory and analgesic drugs including aspirin, celecoxib, ibuprofen and naproxen. These drugs cause many adverse cardiovascular, renal and gastrointestinal side effects. Understanding how differences in the fat content of the diet can alter responses to these drugs will lead to changes in the way they are prescribed to people on different diets and will minimize the side effects.
|Dong, Liang; Zou, Hechang; Yuan, Chong et al. (2016) Different Fatty Acids Compete with Arachidonic Acid for Binding to the Allosteric or Catalytic Subunits of Cyclooxygenases to Regulate Prostanoid Synthesis. J Biol Chem 291:4069-78|
|Dong, Liang; Zou, Hechang; Yuan, Chong et al. (2016) Interactions of 2-O-arachidonylglycerol ether and ibuprofen with the allosteric and catalytic subunits of human COX-2. J Lipid Res 57:1043-50|
|Yuan, Chong; Smith, William L (2015) A cyclooxygenase-2-dependent prostaglandin E2 biosynthetic system in the Golgi apparatus. J Biol Chem 290:5606-20|
|Dame, Michael K; Jiang, Yan; Appelman, Henry D et al. (2014) Human colonic crypts in culture: segregation of immunochemical markers in normal versus adenoma-derived. Lab Invest 94:222-34|
|Jiang, Yan; Djuric, Zora; Sen, Ananda et al. (2014) Biomarkers for personalizing omega-3 fatty acid dosing. Cancer Prev Res (Phila) 7:1011-22|
|Kuklev, Dmitry V; Hankin, Joseph A; Uhlson, Charis L et al. (2013) Major urinary metabolites of 6-keto-prostaglandin F2Î± in mice. J Lipid Res 54:1906-14|
|Dong, Liang; Sharma, Narayan P; Jurban, Brice J et al. (2013) Pre-existent asymmetry in the human cyclooxygenase-2 sequence homodimer. J Biol Chem 288:28641-55|
|Zou, Hechang; Yuan, Chong; Dong, Liang et al. (2012) Human cyclooxygenase-1 activity and its responses to COX inhibitors are allosterically regulated by nonsubstrate fatty acids. J Lipid Res 53:1336-47|
|Neilson, Andrew P; Ren, Jianwei; Hong, Yu H et al. (2012) Effect of fish oil on levels of R- and S-enantiomers of 5-, 12-, and 15-hydroxyeicosatetraenoic acids in mouse colonic mucosa. Nutr Cancer 64:163-72|
|Neilson, Andrew P; Djuric, Zora; Ren, Jianwei et al. (2012) Effect of cyclooxygenase genotype and dietary fish oil on colonic eicosanoids in mice. J Nutr Biochem 23:966-76|
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