Modified cyclodextrins solubilize elemental sulfur in water and enable biological sulfane sulfur delivery

An important form of biological sulfur is sulfane sulfur, or S(0), which is found in polysulfide and persulfide compounds as well as in elemental sulfur. Sulfane sulfur, often in the form of S(8), functions as a key energy source in the metabolic processes of thermophilic Archaean organisms found in sulfur-rich environments and can be metabolized both aerobically and anaerobically by different archaeons. Despite this importance, S(8) has a low solubility in water (∼19 nM), raising questions of how it can be made chemically accessible in complex environments. Motivated by prior crystallographic data showing S(8) binding to hydrophobic motifs in filamentous glycoproteins from the sulfur reducing Staphylothermus marinus anaerobe, we demonstrate that simple macrocyclic hydrophobic motifs, such as 2-hydroxypropyl β-cyclodextrin (2HPβ), are sufficient to solubilize S(8) at concentrations up to 2.0 ± 0.2 mM in aqueous solution. We demonstrate that the solubilized S(8) can be reduced with the common reductant tris(2-carboxyethyl)phosphine (TCEP) and reacts with thiols to generate H(2)S. The thiol-mediated conversion of 2HPβ/S(8) to H(2)S ranges from 80% to quantitative efficiency for Cys and glutathione (GSH). Moreover, we demonstrate that 2HPβ can catalyze the Cys-mediated reduction of S(8) to H(2)S in water. Adding to the biological relevance of the developed systems, we demonstrate that treatment of Raw 264.7 macrophage cells with the 2HPβ/S(8) complex prior to LPS stimulation decreases NO(2)(−) levels, which is consistent with known activities of bioavailable H(2)S and sulfane sulfur. Taken together, these investigations provide a new strategy for delivering H(2)S and sulfane sulfur in complex systems and more importantly provide new insights into the chemical accessibility and storage of S(0) and S(8) in biological environments.