PubMed · 4294513
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1967-12-14. Encephalitis caused by herpes-simplex virus.. https://doi.org/10.1056/nejm196712142772409
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The effects of a variety of 5-, 5'-, and 3'-substituted deoxyuridine derivatives on the cytoplasmic thymidine kinase (EC 2.7.1.21) purified from a human colon carcinoma cell line, HCT 116, were determined. Of particular interest was elucidation of the structural features important for antagonism of the feedback inhibition of thymidine kinase exerted by thymidine triphosphate. Substitutions at the 5-position altered the potency of the 5'-modified compounds. The replacement of the 5-hydrogen with a methyl group or an iodine greatly increased the affinity of compounds for the thymidine kinase. This was evident for enzyme substrates with 5'-hydroxyl groups [2'-deoxyuridine (dUrd), 2'-deoxythymidine (dThd) and 5-iodo-2'-deoxyuridine (IdUrd)], feedback inhibitors with 5'-triphosphate substitutions (dUTP, dTTP and IdUTP), and for 5'-amino derivatives [5'-amino-2',5'-dideoxyuridine (5'-AdUrd), 5'-amino-2'-5'-dideoxythymidine (5'-AdThd) and 5-iodo-5'-amino-2',5'-dideoxyuridine (5'-AIdUrd)]. Qualitatively, however, the 5-substitutions did not affect the nature of the interactions with dThd kinase. For example, in the presence of dTTP, 5'-AdUrd stimulated dThd kinase activity as much as 5'-AdThd, but approximately a 100-fold greater concentration of 5'-AdUrd was required. Similar results were obtained using intact cells in which substitutions at the 5-position affected the potency, but not the efficacy, of the 5'-amino derivatives to stimulate dThd phosphorylation. In contrast, substitutions at the 5'-position did alter the nature of the interaction with dThd kinase. Thus, the 5'-hydroxyl compounds, dUrd, dThd and IdUrd, did not reverse the enzyme inhibition produced by dTTP nor did they stimulate dThd uptake in intact cells. 5'-Deoxy-5'-(ethylthio)thymidine, 5'-deoxy-5'-[(2-hydroxyethyl)thio]thymidine, and dTMP, but not dTDP, also antagonized the inhibition of dThd kinase produced by dTTP. In comparison to 5'-AdThd, the 3'-amino derivatives, 3'-AdThd and 3'-5'-diAdThd, were much less potent, but still efficacious, antagonists of feedback inhibition. These results indicate that a wide range of dUrd derivatives can disrupt the regulation of dThd kinase and provide leads for the development of new nucleotide analogues.
The deoxyuridine (dU) suppression test evolved out of investigations into the biochemical basis of the megaloblastic changes seen in vitamin B12 and folate deficiency. Although the abnormality in dU suppression which occurs in vitamin B12- or folate-deficient states is assumed to reflect impaired methylation of deoxyuridylate, there is still no direct demonstration that this is so. Furthermore, there is evidence that reactions other than the methylation of deoxyuridylate are involved in the phenomenon of dU suppression. Nevertheless, in clinical practice abnormal dU suppression serves as a sensitive index of the presence of megaloblastosis due to vitamin B12 or folate deficiency. dU suppression is also abnormal in a number of conditions other than vitamin B12 or folate deficiency, but its overall specificity in detecting tissue dysfunction due to these two deficiency states is considerably higher than that of the serum vitamin B12 or red cell folate levels. Consequently, the test enables us simply and rapidly to define those patients in whom macrocytosis is unrelated to a deficiency of vitamin B12 or folate. For these reasons, the dU suppression test has been adopted by several laboratories across the world for investigating patients with (a) possible vitamin B12 or folate deficiency, (b) macrocytosis, and (c) megaloblastic erythropoiesis. Since the dU suppression test is abnormal in transcobalamin II deficiency and in some congenital disorders of vitamin B12 and folate metabolism, it is very useful in the investigation of obscure anaemias in infancy and childhood. In addition, it has contributed to our understanding of the mechanisms underlying the myelotoxicity of certain drugs, and particularly of nitrous oxide.
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