Structural insights into the ene-reductase synthesis of profens.

J Waller,N S Scrutton,S T Ahmed,G P Reddy,H S Toogood,N J W Rattray,A Fryszkowska,D Leys,J M Gardiner,R Bandichhor,D J Mansell,V Karuppiah

doi:10.1039/c7ob00163k

Abstract

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.

Highlights

Biocatalysis is an important tool in sustainable chemicals production by enabling mild reaction conditions and often high stereo, regio- and enantio-selectivity.[1]
We showed that profen precursors, 2-arylpropenoic acids and their esters, were efficiently reduced by Old Yellow Enzymes (OYEs)
We studied the reduction of α,β-unsaturated carboxylic acids 5a–c by eight OYE family members[12] and a flavin-independent, 4440 | Org

Summary

Introduction

Biocatalysis is an important tool in sustainable chemicals production by enabling mild reaction conditions and often high stereo-, regio- and enantio-selectivity.[1]. Comparative co-crystal structural analysis of profen-bound OYEs highlighted key interactions important in determining substrate binding in a catalytically active conformation.

Results

Conclusion