| Popis: |
Cortisol is a steroid hormone that binds to the glucocorticoid receptor with a diverse range of functions including metabolic, neurologic and immune responses. Prostglandins are lipid autacoids that participate in a wide range of functions including the inflammatory response and the vasoactivity of blood vessels and smooth muscle. Previously, a direct interaction between the two classes of biomolecules has not been studied, and here it is shown for the first time that there is competitive inhibition of cortisol and prostaglandins at the critical ligand binding domain of glucocorticoid receptors, which are found in nearly every cell and tissue in the human body. To assess molecular similarity that would enable competitive inhibition, it is first noted that cortisol (CORT, C21H30O5) and prostaglandin E2 (PGE2, C20H32O5) are of nearly the same molecular weight, and have nearly the same number of carbon, hydrogen and oxygen elements. The carbon-carbon double bonds on each of the two branches of PGE2, combined with the five-carbon cyclic centering structure, enable a conformational isomer of PGE2 to position the five oxygen-based functional groups at similar spatial positions as the corresponding five oxygen-based functional groups of CORT. Within the gene-regulating ligand binding domain (LBD) of the glucocorticoid receptor (GR), the average inter-molecular spacing of hydrogen bonding to the corresponding identical five functional groups is 1.778 Å for CORT versus 1.746 Å for PGE2. The conformational isomer of PGE2 within the LBD is at a lower energy state than CORT by 54.9%, indicating preference in stability. Both PGE2 and CORT exhibit a hydrophobic core within the LBD of GR, which is compatible with hydrophobic regions of the LBD. With the incorporation of two calcium ions into both PGE2 and CORT, the energy is further reduced by 58.9% and 113% respectively. PGE2 with calcium ion stabilization is lower by 15.5% in comparison to the equivalent arrangement of CORT. Because of the steroid ring structure of CORT, the spacing of the calcium ions is larger at 16.2Å, whereas PGE2, with just a single ring, collapses to 12.3Å. Analysis of experimental data associated with the adrenal response to an injection of lipopolysaccharide (LPS) is presented to indicate competitive inhibition of PGE2 is responsible for an observed lack of phosphorylation of the GR despite the presence of CORT. Competitive inhibition preventing normative cellular processing of cortisol, a stress hormone, by prostaglandins, which are associated with the inflammatory response, may be the causative source of certain signs and symptoms of disease, and thus is of significant medical importance. |
