Figure 6.

Reaction coordinate of pyrophosphorolysis of orotidine by PfOPRT and HsOPRT. The relative energy along the reaction coordinate is arbitrary with the highest energetic point as the transition state. The first reaction barrier represents the dissociation of dianionic orotate. The first energetic local minimum represents the fully developed ribocation expected to form prior to the weak attack of the nucleophile to form the transition state. Ribocations are not expected to be intermediates with significant lifetimes.⁵³ However, intermediacy for the ribocation is neither proved or excluded by the present data. The structures of reactants (orotidine and PPi), products (orotate and RPP) and transition states are shown in stick mode and were optimized at the same level of theory and basis set.