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Thymidylate synthase (TS) is inhibited by 5-fluoro-2'-deoxycytidine 5'-monophosphate (FdCMP). From initial velocity measurements, the apparent Ki for the binary FdCMP-enzyme complex was about 20 microM. In the presence of 5,10-methylene-5,6,7,8-tetrahydrofolate (CH2H4folate), FdCMP causes a time-dependent inactivation of the enzyme and formation of a TS-FdCMP-CH2H4 folate complex. The ternary complex contains one mol of inhibitor per monomer of enzyme, and can be readily isolated on nitrocellulose filters. Dissociation of the ternary complex is quite slow (t1/2 approximately 16 h), and yields unchanged FdCMP. As with the corresponding complex formed with 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), the TS-FdCMP-CH2H4 folate complex shows a differential absorbance maximum at 326 nm, and is stable to SDS-PAGE. Taken together, these results indicated that FdCMP is a slow, tight binding inhibitor of TS and has a mechanism of inhibition similar to that of FdUMP.
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