Thymidylate synthetase - substrate complex formation

The complexes that thymidylate synthetase (TSase) forms with various potent inhibitors have been intensively studied and thoroughly reviewed. Of particular significance is the covalent ternary complex of TSase-FdUMP-5,10-CH2H4PteGlu. FdUMP is the active metabolite of the widely used anti-cancer drug 5-fluorouracil. This complex is thought to be analogous to a steady-state intermediate of the normal enzyme reaction with the substrate dUMP. In this review, we examine the properties of TSase-dUMP complexes in order to determine if there is an experimental basis for drawing a close analogy between dUMP and FdUMP in their interaction with TSase, and also to evaluate data indicating a potential chemotherapeutic value for TSase-dUMP complexes formed in the presence of folate analogs.