Enzymatic Machinery for Oxygen-to-Sulfur Substitutions in Nucleotides and Nucleic Acids

Abstract Sulfur is an essential element in biology. Yet, its utilization in biological molecules is far less prevalent than that of oxygen. Nature employs site-specific oxygen-to-sulfur (O-to-S) substitutions as a sophisticated strategy to modulate the chemical properties of biological molecules. In nucleotides and nucleic acids, these sulfur modifications are remarkably versatile, occurring across the phosphate backbone, the nucleobase, and the central furanose ring, playing critical roles in maintaining translational fidelity, conferring bacterial immunity, and enhancing the bioactivity of natural products. This review summarizes the diverse enzymatic machineries and catalytic strategies to achieve these transformations. By comparing these distinct pathways, we highlight how substrates and sulfur species are activated and controlled to facilitate O-to-S substitutions.