Amine transaminases offer an environmentally sustainable synthesis route for the production of pure chiral amines. However, their catalytic efficiency towards bulky ketone substrates is greatly limited by steric hindrance and therefore presents a great challenge for industrial synthetic applications. Hereby we report an example of rational transaminase enzyme design to help alleviate these challenges. Starting from the Vibrio fluvialis amine transaminase that has no detectable catalytic activity towards the bulky aromatic ketone 2-acetylbiphenyl, we employed a rational design strategy combining in silico and in vitro studies to engineer the transaminase enzyme with a minimal number of mutations, achieving an high catalytic activity and high enantioselectivity. We found that by introducing two mutations W57G/R415A detectable enzyme activity was achieved. The rationally designed variant, W57F/R88H/V153S/K163F/I259M/R415A/V422A, showed an improvement in reaction rate by > 1716-fold towards the bulky ketone under study, producing the corresponding enantiomeric pure (S)-amine (ee value of > 99%).