This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kawai, M. Articles by Hillcoat, B. L. Search for Related Content PubMed PubMed Citation Articles by Kawai, M. Articles by Hillcoat, B. L.

Interaction of Thymidylate Synthetase and Dihydrofolate Reductase Enzymes in Vitro and in Vivo¹

Department of Biochemistry, McMaster University, Hamilton, Ontario, L8S 4J9 Canada

Thymidylate synthetase and dihydrofolate reductase modify each other's activities in vitro. Folate, dihydrofolate, and methotrexate inhibit thymidylate synthetase in the absence of dihydrofolate reductase, but dihydrofolate and methotrexate appear to prevent the interaction between the two enzymes, thus increasing the activity of thymidylate synthetase. Dihydrofolate reductase, inhibited by thymidylate synthetase, is also reactivated by deoxyuridine 5'-monophosphate, a substrate of thymidylate synthetase. The former behavior seems significant in vivo, but not the latter. Crude extracts of methotrexate-resistant L1210 cells, which have high dihydrofolate reductase activity and low thymidylate synthetase activity, show increased activity of thymidylate synthetase in the presence of methotrexate. With intact cells, the rate of incorporation of deoxyuridine into DNA is enhanced in the presence of low concentrations of methotrexate. Wild-type L1210 cells show neither effect. Methotrexate may thus increase thymidylate synthetase activity in cells possessing relatively large amounts of dihydrofolate reductase and small amounts of thymidylate synthetase.

¹ This work is supported by Medical Research Council of Canada Grant MT-3380.

² Fellow of the Medical Research Council of Canada, to whom reprint requests should be addressed.

Received 12/ 3/73. Accepted 3/22/74.