Parabens are alkyl esters of p-hydroxybenzoic acid used as preservatives in a wide range of food, pharmaceutical, and cosmetic products. Despite their common use for over 50 years, their mechanism of action is still unclear. In this study we examined the effects of ethyl and propyl paraben, on gating of the E. coli mechanosensitive channel of large conductance (MscL) reconstituted into azolectin liposomes. We found that propyl and ethyl paraben spontaneously activate MscL. Moreover, the addition of propyl paraben caused an increase in MscL activity and the lowering of p(1/2), the pressure at which the MscL was opened 50% of the time, the DeltaG(o), the free energy required to open the MscL, and the parameter alpha, which describes the channel sensitivity to pressure. In addition, in silico studies showed that propyl paraben binds to the channel gate of the MscL. The mechanosensitive channel of small conductance was also found to be spontaneously activated by parabens. In summary, our study indicates that one of the previously unidentified mechanisms of action of parabens as antimicrobial agents is via an interaction with the mechanosensitive channels to upset the osmotic gradients in bacteria.
The interaction of histamine with beef lung heparin has been characterized by 'H and I3C NMR spectroscopy. IH chemical shifts provide evidence that histamine forms a complex with heparin both at low pD where 2-Osulfo-a-~-idopyranosyluronic acid (IdoA-2s) residues are in the carboxylic acid form and at higher pD where the carboxyl groups are deprotonated. At low pD, the chemical shift data are consistent with weak delocalized binding of the diprotonated form of histamine by the highly negatively charged polymer. However, as the pD is increased and the carboxylic acid groups are titrated, a binding region with a high affinity for diprotonated histamine is created. It is proposed that, in this binding site, the ammonium group of histamine is hydrogen-bonded to the carboxylate group of an IdoA-2S residue while the imidazolium ring is located in a region surrounded on three sides by the sulfamido group of a 2-deoxy-2-sulfamido-6.Osulfo-a-Dglucopyr (GlcNS03-6S) residue and the 2-Osulfate and carboxylate groups of a second IdoA-2S residue. Evidence for site specific binding includes displacement of chemical shift titration curves to lower pD and increased shielding of specific heparin protons from the imidazole ring current. Similar 'H NMR measurements on the heparin-imidazole and heparin-N-acetylhistamine systems indicate that the highly negatively charged binding site created by deprotonation of the carboxylic acid groups has a high affinity in general for positively charged imidazolium rings. Nuclear Overhauser enhancements obtained from two-dimensional NOESY spectra of heparin at pD 2.4 and 7.4 indicate that, when the carboxylic acid groups of heparin are titrated, its conformation changes by a small rotation around the (IdoA-2S)-( 1-+4)-(GlcNS03-6S) glycosidic bond. This study provides evidence for the first time of the site specific binding of a biological molecule by the repeating (IdoA-2S)-( 1+4)-(GlcNS03-6s) disaccharide unit of heparin.
Many studies have focused on histidine behaviors in misfolding diseases. However, histidine behaviors on mature fibrils are still unknown. In the current study, we investigated mature fibrils with various histidine states to understand the structural properties of the histidine tautomeric effect on mature fibrils. Our results show that substituting chain 1 with different histidine states affects Aβ structural properties in A2, D7–G9, H14–Q15, S26–N27, and G33–G37 regions. The binding free energies with substituted fibrils were influenced not only along the axial direction, but also between duplex fibrils. Our results suggest that substituted (εδδ) preferentially disturbed the stability among the current mature fibrils. Further, H-bonded network differences indicate that twisted morphologies in mature fibrils are derived from the position and orientation of the imidazole ring in histidines. Our current study helps to elucidate histidine behaviors on mature fibrils, which will present opportunities to understand the misfolding mechanisms.
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