A novel procedure has been applied to compute experimentally unobserved intrinsic kinetic isotope effects upon the rearrangement of chorismate to prephenate catalyzed by B. subtilis chorismate mutase. In this modified QM/MM approach, the "low-level" QM description of the quantum region is corrected during the optimization procedure by means of a "high-level" calculation in vacuo, keeping the QM-MM interaction contribution at a quantum "low-level". This allows computation of energies, gradients, and Hessians including the polarization of the QM subsystem and its interaction with the MM environment, both terms calculated using the low-level method at a reasonable computational cost. New information on an important enzymatic transformation is provided with greater reliability than has previously been possible. The predicted kinetic isotope effects on V-max/K-m are 1.33 and 0.86 (at 30 degreesC for 5-H-3 and 9-H-3(2) substitutions, respectively, and 1.011 and 1.055 at 22 degreesC) for 1-C-13 and 7-O-18 substitutions, respectively.