F

requires a much simpler bioactivation, consisting of its monophosphorylation. Besides TS inhibition, an additional mechanism that explains the cytotoxic effect of these drugs is based on the misincorporation of their nucleotide and deoxynucleotide triphosphates to RNA and DNA, respectively.

The catalytic cycle of TS involves a two-stage process. Initially, dUMP binds to its recognition site and induces a conformational change that opens an adjacent binding site for the cofactor (5,10-CH2-THF). A cysteine residue in the active site undergoes a Michael addition with the unsaturated carbonyl system in dUMP to give intermediate enolate 2.22. The nucleophilic attack of this enolate onto the methyleneiminium cation 2.21, generated from the cofactor, yields the covalent ternary complex 2.23. An enzyme-catalyzed abstraction of the acidic H-5 proton promotes a p-elimination reaction of a molecule of THF (2.24) and generates the methylene intermediate 2.25. The last step of the sequence involves reduction of 2.25 by hydride transfer from 2.24, leading to thymidine monophosphate (TMP) and DHF (Fig. 2.16). The overall reaction involves the oxidation of 5,10-methylene-THF to DHF, which must then be recycled by reduction by DHFR and subsequent methylenation, as will be discussed in Section 5.

Fluorine (1.47 A) and hydrogen (1.20 A) have very similar van der Waals radii, and this allows 5-FdUMP to bind to TS in the same site and with the same affinity

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