Baeyer-Villiger monooxygenases (BVMOs) can catalyze the asymmetric sulfoxidation to form pharmaceutical prazoles in environmentally friendly approach. In this work, the thermostable BVMO named PockeMO had high sulfoxidation activity towards rabeprazole sulfide to form (R)-rabeprazole but demonstrated significant overoxidation activity to form undesired sulfone by-product. To address this issue, the enzyme was engineered based on the computer assisted comparison for the substrate binding conformations. A mutant S482Y/L532Q (MU2) was obtained with much alleviated overoxidation activity and enhanced sulfoxidation activity towards rabeprazole sulfide. The catalytic efficiency for (R)-rabeprazole oxidation decreased 35 folds and increased 40 folds for the sulfoxidation of lansoprazole sulfide. The structural mechanism for the selectivity improvement was illuminated to find a selectivity decision pocket that was conservatively present in BVMOs composed of 4 loops. In upscaled reaction system, the substrate loading for MU2 increased from 40 mM to 100 mM for the synthesis of enantiopure (R)-rabeprazole. The sulfone content decreased from 16.6 % to 1.2 % compared to PockeMO. Lansoprazole sulfide could also be fully converted into enantiopure (R)-lansoprazole at 50 mM in 4 h by MU2 while PockeMO almost did not have activity. This work indicated the synthetic applicability of MU2 for active pharmaceutical (R)-prazoles.