Tetrahydrodeoxyuridylate: A potent inhibitor of deoxycytidylate deaminase

Abstract

Deoxycytidylate deaminase is inhibited competitively by tetrahydrodeoxyuridine 5′-monophosphate with a K i of 1.0–2.0 × 10 −8 m. The potential effectiveness of the inhibition as revealed by the K m K i ratio is of the order of 3.0–6.0 × 10 4. Although the deamination of deoxycytidine and cytidine in a chick embryo mince system is impaired rather drastically by tetrahydrodeoxyuridine and tetrahydrouridine, respectively, DNA synthesis is not greatly affected. Tetrahydrodeoxyuridine appears to impose a sparing effect on deoxycytidine utilization and limits the incorporation of cytidine into the thymidylate of DNA. Tetrahydrouridine severely inhibits cytidine deamination, but does not affect its incorporation into DNA. The most probable site of action of these compounds in vivo is deoxycytidylate deaminase. Of the two known pathways for the formation of deoxyuridylate, the deamination of deoxycytidylate and the ribonucleotide reductase conversion of uridine diphosphate to deoxyuridine diphosphate, the results suggest that most of the DNA thymidylate is provided by the latter. Cytidine and deoxycytidine can still be deaminated in the chick embryo mince system, in spite of sufficient tetrahydrodeoxyuridine and tetrahydrodeoxyuridylate to inhibit deoxycytidine and deoxycytidylate deaminases completely, a result that suggests an alternate pathway for the formation of deoxyuridine nucleotides from deoxycytidine nucleotides.