Fig. 6.

Different mechanisms for the reduction of dihydrofolate. Protonation of N5 of H₂F can occur early to produce H₃F⁺ followed by hydride transfer to C6. Alternatively, hydride transfer to produce H₃F⁻ can precede protonation of N5. H₃F⁻ and H₃F⁺ can be either true intermediates of the reaction or intermediate stages along the reaction coordinate in a single transition state reaction.