The first example of a mimic of the overall thymidylate synthase reaction

Thymidylate synthase inspired biomodel reagent for the conversion of uracil to thymine

“…For the last step of TSase catalysis, Schultz, 24 Benkovic 25 and Pandit 26 proposed electron and H transfer, whereas Kohen et al 14,27 favoured the transfer of hydride ions for the reduction of methylene group. However, despite the wide range of studies on the operation of TSase, it is still a challenge to have a biomodel reagent 28 that may provide a chemical reaction parallel to all the steps of TSase-catalyzed dUMP conversion to dTMP.…”

ONIOM study of one‐carbon unit transfer from imidazolidine to dUMP analogue

“…The currently accepted action mechanism of the enzyme invokes the following sequence of reactions 8: (1) an initial attack of a nucleophile of the apoenzyme (a cysteineSH) on the 6‐position of the uracil moiety of dUMP, leading to the generation of a powerful nucleophilic center at C5; (2) reaction of the latter with the activated form (CH2N + (5)H4folate) of the folate cofactor and subsequent fragmentation of the resulting ternary complex (apoenzyme–substrate–folate cofactor) into an exocyclic methylene intermediate and H4folate; and (3) reduction of the last‐mentioned intermediate by H4folate, to give dTMP and H2folate. Various steps of the mechanism from dUMP to dTMP have received support from model studies 9, 10 of mechanism‐based inhibitors 11–14. To derive further detailed information of the methylene transfer, we undertake the study with theory method of the reaction of C5‐activated uracil derivatives with imidozolidine as analogues of the ternary complex of the apoenzyme–substrate–folate cofactor.…”