Ribonucleotide Reduction

Abstract Ribonucleotide reductase is an essential enzyme that supplies the deoxyribonucleotides required for DNA synthesis and repair. This one enzyme reduces all four ribonucleotides to the corresponding deoxynucleotides. The enzyme uses a complex radical‐based mechanism to catalyse this reaction. Three main classes of enzymes have been described that differ mainly in the type of cofactor used to generate the catalytic radical. Despite their common reaction mechanism, ribonucleotide reductases show little sequence identity. Crystal structures of enzymes from all classes show a conserved β/α barrel structure in the catalytic domain. Reductase activity is regulated at the protein level by nucleotide allosteric effectors to produce balanced pools of deoxynucleotides. Reductase activity is also coordinated with the cell cycle by activation and repression of gene expression. Key Concepts Deoxyribonucleotides required for DNA synthesis and repair are generated only by reduction of ribonucleotides. One enzyme, ribonucleotide reductase, must reduce all four common ribonucleotides and generate a balanced pool of deoxyribonucleotides to avoid mutations. Although an essential enzyme in all divisions of life, ribonucleotide reductases diverge widely in primary structure and cofactor requirements. Ribonucleotide reductase is regulated both at the protein and gene level and can accommodate to environmental changes in the evolution of diverse organisms. Evolution of ribonucleotide reductases is constrained only by basic catalytic chemistry and protein tertiary structure.