We　report　here　the　discovery　of　a　novel　ketoreductase　(KRED),　named　KmCR2,　with　a　broad　substrate　spectrum　on　bioreduction　of　sterically　bulky　diaryl-　and　aryl(heteroaryl)methanones.　The　position　of　the　substituent　on　aromatic　rings　(meta　versus　para　or　ortho)　was　revealed　to　control　the　stereospecificity　of　KmCR2.　The　stereoselective　preparation　of　both　enantiomers　of　diaryl-　or　aryl(heteroaryl)methanols　using　strategically　engineered　substrates　with　a　traceless　directing　group　(bromo　group)　showcased　the　potential　application　of　this　substrate-controlled　bioreduction　reaction.　The　combined　use　of　substrate　engineering　and　protein　engineering,　was　demonstrated　to　be　a　useful　strategy　in　efficiently　improving　stereoselectivity　or　switching　stereopreference　of　enzymatic　processes.