Reduction of double bonds of α,β-‐unsaturated carboxylic acids and esters by ene-‐reductases remains challenging and it typically requires activation by a second electron-‐withdrawing moiety, such as a halide or second carboxylate group. We showed that profen precursors, 2-‐arylpropenoic acids and their esters, were efficiently reduced by Old Yellow Enzymes (OYEs). The XenA and GYE enzymes showed activity towards acids, while a wider range of enzymes were active towards the equivalent methyl esters. Comparative co-‐crystal structural analysis of profen-‐bound OYEs highlighted key interactions important in determining substrate binding in a catalytically active conformation. The general utility of ene reductases for the synthesis of (R)-‐profens was established
and this work will now drive future mutagenesis studies to screen for the production of pharmaceutically-‐active (S)-‐profens.