Thursday, November 21, 2024
11/21/2024
Project Summary Thiyl radicals lie at a perilous nexus between essential biological function as cofactors in enzyme catalysis and toxic products of oxidative stress. As a cofactor, cysteine thiyl radicals facilitate a wide range of C‐X (X= H, C, N, O, S, P) bond cleavage and formation reactions with high fidelity, requiring selective thiyl radical generation, active site chemistry, and reduction. Their reactivity, particularly within an active site with many weak C‐H bonds and oxidizable amino acid sidechains presents several alternative fates, clearly manifest in thiyl radicals generated as the product of oxidative stress “off‐ pathway,” where they can form new S−S and S−C bonds, or catalyze other chemical modifications that are deleterious to biological function. Understanding the structure/function relationship that dictates thiyl radical fate holds promise in developing better therapeutics and antibiotics that target thiyl radical enzymes, informing biomimetic or biocatalytic synthetic biology, and mitigating their role in oxidative stress. Understanding the mechanistic and contextual aspects of how thiyl radicals are generated and what dictates their fate in proteins are essential to addressing their impact on human health. Our research group is seeking to define how thiyl radicals that enable catalysis are selectively generated and maintained, how this might inform therapeutic developments, and what determines the fates of orphaned thiyl radicals. To these ends, we are employing genetic, chemical, and spectroscopic tools to understand thiyl radical chemistry within proteins, from generation to termination, with kinetic and thermodynamic resolution. As our proof‐of‐concept, we are applying these tools to the development of mechanism‐based inhibitors for prominent thiyl radical enzymes in the gut, targeting Clostridioides difficile, with precision. More broadly, however, by advancing our understanding of thiyl radical chemistry in diverse protein milieu the resulting discoveries will provide new opportunities to improve or target thiyl radical catalysis and rationalize oxidative stress pathways. Through developments in each area, we will form the foundation of a holistic understanding of thiyl radical chemistry in biology that we anticipate will have wide ranging implications, both in basic and applied life and physical sciences.
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