Inhibition of Serine Metabolism by Tetrahydrohomofolate in L1210 Mouse Leukemia Cells

Tetrahydrohomofolate, a reduced folate analogue, inhibited mouse leukemia L1210 grown in vitro. However, it was found to be a substrate for the following enzymes: methylene tetrahydrofolate reductase (EC 1.1.1.68), methylene tetrahydrofolate dehydrogenase (EC 1.5.1.5), 10-formyltetrahydrofolate synthetase (EC 6.3.4.3), and thymidylate synthetase (EC 2.1.1.45). Serine transhydroxymethylase (EC 2.1.2.1) was markedly inhibited by the analogue ( I 50 = 62.5 µM). In whole cell studies, incorporation of [3- 14 C]serine into both nucleic acids and methionine was significantly inhibited by tetrahydrohomofolate. The uptake of [ 3 H]methionine was also inhibited at concentrations of tetrahydrofolate of 50µ M or higher. The inhibition of serine transhydroxymethylase together with the inhibition of methionine uptake may explain, at least in part, the ability of tetrahydrohomofolate to inhibit growth of L1210 cells.