title: Different Fatty Acids Compete with Arachidonic Acid for Binding to the Allosteric or Catalytic Subunits of Cyclooxygenases to Regulate Prostanoid Synthesis.
abstract: Prostaglandin endoperoxide H synthases (PGHSs), also called cyclooxygenases (COXs), convert arachidonic acid (AA) to PGH2. PGHS-1 and PGHS-2 are conformational heterodimers, each composed of an (Eallo) and a catalytic (Ecat) monomer. Previous studies suggested that the binding to Eallo of saturated or monounsaturated fatty acids (FAs) that are not COX substrates differentially regulate PGHS-1 versus PGHS-2. Here, we substantiate and expand this concept to include polyunsaturated FAs known to modulate COX activities. Non-substrate FAs like palmitic acid bind Eallo of PGHSs stimulating human (hu) PGHS-2 but inhibiting huPGHS-1. We find the maximal effects of non-substrate FAs on both huPGHSs occurring at the same physiologically relevant FA/AA ratio of ∼20. This inverse allosteric regulation likely underlies the ability of PGHS-2 to operate at low AA concentrations, when PGHS-1 is effectively latent. Unlike FAs tested previously, we observe that C-22 FAs, including ω-3 fish oil FAs, have higher affinities for Ecat than Eallo subunits of PGHSs. Curiously, C-20 ω-3 eicosapentaenoate preferentially binds Ecat of huPGHS-1 but Eallo of huPGHS-2. PGE2 production decreases 50% when fish oil consumption produces tissue EPA/AA ratios of ≥0.2. However, 50% inhibition of huPGHS-1 itself is only seen with ω-3 FA/AA ratios of ≥5.0. This suggests that fish oil-enriched diets disfavor AA oxygenation by altering the composition of the FA pool in which PGHS-1 functions. The distinctive binding specificities of PGHS subunits permit different combinations of non-esterified FAs, which can be manipulated dietarily, to regulate AA binding to Eallo and/or Ecat thereby controlling COX activities.
authors.affiliation: From the Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Liang
authors.initials: L
authors.lastname: Dong
authors.affiliation: From the Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Hechang
authors.initials: H
authors.lastname: Zou
authors.affiliation: From the Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Chong
authors.initials: C
authors.lastname: Yuan
authors.affiliation: From the Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Yu H
authors.initials: YH
authors.lastname: Hong
authors.affiliation: From the Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Kuklev
authors.affiliation: From the Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109 smithww@umich.edu.
authors.forename: William L
authors.initials: WL
authors.lastname: Smith
mesh_terms: D000494:Allosteric Regulation; D016718:Arachidonic Acid / Q000737:chemistry*; D051545:Cyclooxygenase 1 / Q000737:chemistry*; D051546:Cyclooxygenase 2 / Q000737:chemistry*; D006801:Humans; D019308:Palmitic Acid / Q000737:chemistry*; D044262:Prostaglandin H2 / Q000096:biosynthesis* / Q000737:chemistry; D011485:Protein Binding; D013379:Substrate Specificity
chemical_list: D016718:Arachidonic Acid; D019308:Palmitic Acid; D044262:Prostaglandin H2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human
keywords: allosteric regulation; cyclooxygenase (COX); docosahexaenoic acid; eicosanoid; eicosapentaenoic acid; fatty acid; half-sites; palmitic acid; prostaglandin; ω-3 fatty acid