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Small molecule gases such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) have long been recognized as endogenous signaling molecules with diverse physiological roles. Often described as “gasotransmitters”, these molecules complement other small molecule bioregulators (SMBs) that exert biological function across all kingdoms of life. One underappreciated distinction, however, is that many of these molecules – irrespective of whether or not they are gases in their native states outside of biology – exhibit similar molecular signaling potential mediated by protonation-dependent chemical speciation. In this review, we propose the new cross-cutting classification of protic small molecule bioregulators (PSMBs) to describe molecules in which biological function and reactivity are modulated by protonation state. Examples of PSMBs include the canonical gasotransmitter H2S, emerging gasotransmitters (H2Se, HCN), small molecule crosstalk species (e.g., SNO–, SSNO–, SO42–, ONOO–, NO2–, SCN–, OCl–), and other species where protonation state modulation is accessible at physiological pH. Importantly, these species exist in equilibrium between their neutral and anionic forms, with speciation governed by local pH and molecular environment, directly impacting their membrane nucleophilicity, permeability, redox activity, and interaction with metal centers. We describe the evolutionary origins, biosynthesis, and crosstalk of PSMBs, including roles in redox signaling, post-translational modification, and mitochondrial regulation. Reframing these important molecules in a class defined by their protic ability rather than gaseous state does not diminish prior gasotransmitter designations, but rather serves to recognize commonalities in chemical characteristics that drive the unique biological chemistry and regulation. 

In situFTIR spectroscopy can measureK_avalues across different classes of host–guest complexes involving hydrogen and halogen bonding. This approach requires minimal sample preparation and can track host or guest vibrational changes. 

Abstract Persulfides (RSS^–) and thioselenides (RSSe^–) play important roles in biological S and Se transfer reactions, and their interactions with Lewis acidic moieties exert control over reactivity. Here, we report the synthesis and reactivity of mononuclear Zn²⁺persulfide and thioselenide complexes from a unified synthetic strategy of using isolable dichalcogenide precursors. Highlighting the benefits of replacing S with Se, we use⁷⁷Se NMR spectroscopy to reveal the effects of Lewis acid coordination (K⁺, Na⁺, Zn²⁺) on the electronic environment of the terminal Se of the thioselenide (R–S_β–Se_α^–). Coordination of RSSe^–to Zn²⁺polarizes the Se─S bond, rendering the internal sulfur atom (R–S_β–Se_α^–) susceptible to nucleophilic attack and resulting in selenide (Se^2–) release. We also prepared a mononuclear Zn²⁺persulfide complex and probed differences in persulfide nucleophilicity when compared to the parent thiolate. Alkylation of the Zn²⁺persulfide is considerably faster than the Zn²⁺thiolate, supporting the proposed nucleophilicity enhancement of persulfides due to the α‐effect, and providing new insights into persulfide reactivity when coordinated to metals. Taken together, these investigations highlight the utility of small molecule synthetic models in advancing insights into the biological chemistry of metal dichaclogenides. 

Surfactants solubilize S₈ in water and promote thiol-mediated reduction to form H₂S. Anionic and cationic surfactants have different impacts on the resultant reactive sulfur species distribution.