Models of folate coenzymes 16

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

“…The thymidylate synthase catalyzed conversion of 2′‐deoxyuridine‐5′‐monophosphate (dUMP) to 2′‐deoxythymidine‐5′‐monophosphate (dTMP) involves the overall transfer of a “CH 3 ” group from the folate cofactor 5,10‐methylenetetrahydrafolate (5,10‐CH2‐H4folate) to the uridine derivative 7. 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.…”

“…In the literature 8, 6‐aminouracil derivatives reactant 1 (Fig. 1, R1, R2H, H; H, Me; H, CH2Ph; Me, Me; H, Ph) reacting with imidozolidine reactant 2 (Fig.…”