Activation and Protection from 5-Fluorodeoxyuridylate Inactivation of Mammalian Thymidylate Synthetase by Pyridoxal 5'-Phosphate

Abstract

Rat liver thymidylate synthetase was partially purified by a combination of (NH(4))(2)SO(4) precipitation and Sephadex chromatography. Incubation of these partially purified enzyme preparations with pyridoxal phosphate resulted in as much as a 12-fold increase in enzyme activity. In addition, incubation of partially purified thymidylate synthetase preparations with 5.0 X 10^-5 M pyridoxal phosphate protected the enzyme from 5-fluorodeoxyuridylate inhibition to the extent that 78% of the control activity was retained at 5-fluorodeoxyuridylate concentrations as high as 5.0 X 10^-5 M. These findings are discussed in terms of the reported inhibition of tumor growth in the absence of dietary vitamin B6.

Folinic acid modulation of fluorouracil: tissue kinetics of bolus administration

“…Mechanisms unknown: menadione [25], warfarin [26], alpha-tocopherol [25], pyridoxine [27], guanosine [28] the relationship between FdUMP and dUMP, the natural substrate for TS. Initial FdUMP binding to TS is markedly slowed by dUMP.…”