A proposed mechanism for the mutagenicity of 5-formyluracil.

5-Formyluracil is a mutagenic base formed in DNA by oxidation of the thymine methyl group. Whereas the thymine methyl group is electron donating, the formyl group is electron withdrawing, predicting increased ionization of the N-3 imino proton under physiological conditions. The pKa values of a series of 5-substituted uracil and deoxyuridine derivatives have been measured. A linear relationship is observed between the electronic inductive property of the 5-substituent and the pKa value of the corresponding imino proton. The pKa value of 5-formyl-2'-deoxyuridine is close to that of the mutagenic nucleoside analogue 5-bromo-2'-deoxyuridine. In analogy with BrU, it is proposed that the mutagenicity of 5-formyluracil results from enhanced mispairing of the ionized form with guanine during DNA replication.