Regulation of both the activity and the specificity of ribonucleotide reductase is essential to maintain balanced quantities of DNA precursors. The large R1 subunit contains two classes of regulatory sites (two of each site per molecule in the E. coli enzyme).

Activity Sites - These bind either ATP or dATP with relatively low affinity.

Specificity Sites - These bind ATP, dATP, dGTP, or dTTP with relatively high affinity.

The binding of ATP at the activity sites enhances the catalytic efficiency of the enzyme for all substrates, whereas dATP binding at the activity sites acts as a general inhibitor of all four reactions.

Binding of nucleotides at the specificity sites modulates the activities of the enzyme toward different substrates, so as to maintain balanced rates of production of the four dNTPs. Table 22.2 summarizes the complex regulatory effects of binding at both the activity and specificity binding sites.

Mutations in ribonucleotide reductase that affect either the activity or specificity sites can render the enzyme less susceptible to inhibition by dNTP effectors. Cells carrying these kinds of mutations display both abnormalities in the quantities of dNTPs they contain and so-called mutator phenotypes. That is, cells with mutator phenotypes show increased rates of spontaneous mutation at all genetic loci tested. These findings suggest that when dNTP concentrations are altered at DNA replication sites, the likelihood is increased for replication errors, which lead to mutations.

INTERNET LINK: Mutation