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Structural insights into the ene-reductase synthesis of profens

DOI: 10.1039/C7OB00163K DOI Help

Authors: John Waller (University of Manchester) , Helen Toogood (University of Manchester) , Vijaykumar Karuppiah (University of Manchester) , Nicholas John William Rattray (University of Manchester) , David Mansell (University of Manchester) , David Leys (University of Manchester) , John M. Gardiner (University of Manchester) , Anna Fryszkowska (Dr. Reddy's Laboratories) , Syed Ahmed (University of Manchester) , Rakeshwar Bandichhor (Dr. Reddy's Laboratories) , Prashanth Reddy Gaddameedhi (Dr. Reddy's Laboratories) , Nigel Scrutton (University of Manchester)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Org. Biomol. Chem.

State: Published (Approved)
Published: April 2017
Diamond Proposal Number(s): 12788

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.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography