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.