Thymidylate synthetase regulation

Regulatory control of bacterial thymidylate synthetases by nucleotides has not been reported however, Lorenson et al. (7) investigated that of the chick embryo thymidylate synthetase and found that the 5 -mono-, di-, and triphosphates of adenosine, cytidine, guanosine, and uridine, and of their deoxyribosides, did not inhibit activity. Thus, the activity of the synthetase, from this source at least, does not seem to be subject to allosteric regulation by nucleotides. With crude extracts of Ehrlich ascites... 

In addition to the control of one carbon metabolism by feedback control, regulation of synthesis of the enzymes metabolizing folate derivatives is probably also of importance. The activities of DHF reductase, (Hillcoat et al., 1973) thymidylate synthetase (Rosenberg et al., 1971 Conrad and Ruddle, 1972), serine hydroxymethyl transferase and 10-formyl tetrahydrofolate synthetase (Rosenblatt and Erbe, 1973) increase 4-20 fold as mammalian tissue cultures pass from the lag to logarithmic phase. Control can also occur at the level of entry of the folate cofactors into the cell. 

Because of the rapid synthesis of DNA during differentiation, lymphoid cells would be expected to be particularly sensitive to abnormalities in the regulation of the nucleoside pools that serve as precursors for DNA synthesis. The synthesis of thymidine triphosphate is of particular interest because of its specificity for DNA synthesis. The rate limiting step in the de novo pathway to dUMP involves conversion of dUPM to a dTMP by the folate requiring enzyme thymidylate synthetase, vitro incorporation of 3H-thymidine and 3n-deoxyuridine is reduced in bone marrow cultures from folic acid deficient rats (Sakamato and Takaku, 1973). Thymidylate synthetase activity was elevated when assayed in the presence of adequate cofactor (5,10-methylene THF). A salvage pathway also exists for the direct phosphorylation of thymidine by thymidine kinase. This enzyme can exist in two forms (Ellims et al., ... 

Conrad, A. H. and Ruddle, F. H. (1972) Regulation of thymidylate synthetase activity in cultured mammalian cells, J. Cell, Sci., 10 471. 

---