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Life on Earth has always been shaped by sulfur. Over 2 billion years ago, before our atmosphere became rich in oxygen, volcanic activity was more prevalent. As a result, sulfur-containing gasses were much more prominent in the early Earth atmosphere, causing it to be weakly reducing as opposed to than the oxidizing conditions today. It was this low-oxygen, high-sulfur atmosphere that allowed the creation of the earliest biomolecules, and life forms, on Earth. We see the legacy of this sulfur-based origin in our aerobic, eukaryotic cells today, which can metabolize reduced sulfur species into ATP.One prominent biological sulfur species today is hydrogen sulfide (H2S), produced in cysteine metabolism and a member of the gasotransmitter family of small, gaseous signaling molecules along with carbon monoxide (CO) and nitric oxide (NO). H2S has gained increasing notice for its abilities to induce vasodilation and angiogenesis and reduce inflammation and oxidative stress, among others. This has motivated the development and use of triggerable H2S donor molecules that more accurately mimic endogenous H2S production than inorganic SH- salts. Recent studies have found that the chemical biology attributed to H2S may be caused by the downstream production of oxidized sulfur species containing sulfane sulfur (S0). S0 is found in polysulfides and can both release H2S in the presence of biological thiols and react with free cysteine residues on proteins to form persulfides (-SSH) in a process known as persulfidation. The ability of S0 to persulfidate proteins has now been implicated in many of the observed effects of H2S treatment, as persulfidation alters structure and function of proteins and serves as a regulatory switch. It is desirable to find ways of understanding and harnessing the power of protein persulfidation, and this necessitates the development of S0 donor molecules.
We have developed systems to achieve this, including libraries of N- acetylcysteine (NAC)- and benzyl-based polysulfides. We also developed a method of solvating elemental sulfur (S8), the only source of pure S0. These systems are compatible with both cell and enzymatic assays and open the door to new S0 discoveries.
This dissertation includes previously published coauthored material. |
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