N O

HO F Gemcitabine (dFdC)

HO F Gemcitabine (dFdC)

The mechanism of the interaction of gemcitabine diphosphate (2.12) with the active site of RNR is very similar to that of the natural substrate, and it only deviates from the natural course after the formation of the bisulfide bridge, as shown by theoretical calculations.11 The first steps are the abstraction of the 30-OH proton by the Glu-441 residue and the abstraction of the 3'-H atom by the radical sulfur of Cys-439, leading to anion radical 2.13. Protonation of the a-fluorine atom by the Cys-225 thiol group facilitates the elimination of a molecule of HF and the formation of radical 2.14, where the unpaired electron is stabilized by the neighboring carbonyl group and fluorine atom. Transfer of one electron from the Cys-225 anion gives enolate 2.15, which is protonated by Cys-462 to generate the neutral species 2.16. The formation of a bisulfide bond and simultaneous transfer of a proton from Glu-441 back to the 3'-O atom leads to radical 2.17, which on elimination of HF generates the C-2 radical 2.18. Abstraction of a hydrogen atom from the mercapto group of Cys-439 gives the sulfur radical 2.19. Although in the natural substrate Cys-439 does not reach the a face of the ribose ring, the conditions in this case are different because 2.19 cannot be stabilized by hydrogen bonds with the active site residues Glu-441 (which are charged) nor with Cys-225 and Cys-462, which are oxidized to a disulfide. This fact, together with possible interactions with the eliminated HF molecules, allows some degree of deviation of the position of the inhibitor, making possible for Cys-439 to reach the 40-H atom and allowing the generation of the stable radical 2.20 (Fig. 2.10). This prevents the reaction of Cys-439 with Tyr-122 and hence the regeneration of the essential tyrosine radical (see the transformation of 2.4 into 2.5 in Fig. 2.6).

Cys-439

Cys-439

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