Structural insights into the ene-reductase synthesis of profens

Waller, J. and Toogood, H. S. and Karuppiah, V. and Rattray, N. J. W. and Mansell, D. J. and Leys, D. and Gardiner, J. M. and Fryszkowska, A. and Ahmed, S. T. and Bandichhor, R. and Reddy, G. P. and Scrutton, N. S. (2017) Structural insights into the ene-reductase synthesis of profens. Organic and Biomolecular Chemistry, 15 (20). pp. 4440-4448. ISSN 1477-0520

[img]
Preview
Text (Waller-etal-OBC-2017-Structural-insights-into-the-ene-reductase-synthesis-of-profens)
Waller_etal_OBC_2017_Structural_insights_into_the_ene_reductase_synthesis_of_profens.pdf
Final Published Version
License: Creative Commons Attribution 3.0 logo

Download (1MB)| Preview

    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.