Different Fatty Acids Compete with Arachidonic Acid for Binding to the Allosteric or Catalytic Subunits of Cyclooxygenases to Regulate Prostanoid Synthesis

Prostaglandin endoperoxide H synthases (PGHSs), also called cyclooxygenases (COXs), convert arachidonic acid (AA) to PGH(2). PGHS-1 and PGHS-2 are conformational heterodimers, each composed of an (E-allo) and a catalytic (E-cat) monomer. Previous studies suggested that the binding to E-allo 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 E-allo 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 approximate to 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 -3 fish oil FAs, have higher affinities for E-cat than E-allo subunits of PGHSs. Curiously, C-20 -3 eicosapentaenoate preferentially binds E-cat of huPGHS-1 but E-allo of huPGHS-2. PGE(2) 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 -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 E-allo and/or E-cat thereby controlling COX activities.