Structural insights into the ene-­‐reductase synthesis of Profens

John Waller; Helen Toogood; Vijaykumar Karuppiah; Nicholas Rattray; David Mansell; David Leys; John Gardiner; Anna Fryszkowska; S.T Ahmed; R Bandichhor; G.P Reddy; Nigel Scrutton

doi:10.1039/C7OB00163K

Structural insights into the ene-‐reductase synthesis of Profens

John Waller, Helen Toogood, Vijaykumar Karuppiah, Nicholas Rattray, David Mansell, David Leys, John Gardiner, Anna Fryszkowska, S.T Ahmed, R Bandichhor, G.P Reddy, Nigel Scrutton

University of Manchester (UOM)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Journal	Organic and Biomolecular Chemistry
Early online date	28 Apr 2017
DOIs	https://doi.org/10.1039/C7OB00163K
Publication status	Published - 2017

Research Beacons, Institutes and Platforms

Manchester Institute of Biotechnology

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10.1039/C7OB00163KLicence: CC BY

Cite this

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title = "Structural insights into the ene-‐reductase synthesis of Profens",

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 establishedand this work will now drive future mutagenesis studies to screen for the production of pharmaceutically-‐active (S)-‐profens.",

author = "John Waller and Helen Toogood and Vijaykumar Karuppiah and Nicholas Rattray and David Mansell and David Leys and John Gardiner and Anna Fryszkowska and S.T Ahmed and R Bandichhor and G.P Reddy and Nigel Scrutton",

year = "2017",

doi = "10.1039/C7OB00163K",

language = "English",

journal = "Organic and Biomolecular Chemistry",

issn = "1477-0520",

publisher = "Royal Society of Chemistry",

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TY - JOUR

T1 - Structural insights into the ene-‐reductase synthesis of Profens

AU - Waller, John

AU - Toogood, Helen

AU - Karuppiah, Vijaykumar

AU - Rattray, Nicholas

AU - Mansell, David

AU - Leys, David

AU - Gardiner, John

AU - Fryszkowska, Anna

AU - Ahmed, S.T

AU - Bandichhor, R

AU - Reddy, G.P

AU - Scrutton, Nigel

PY - 2017

Y1 - 2017

N2 - 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 establishedand this work will now drive future mutagenesis studies to screen for the production of pharmaceutically-‐active (S)-‐profens.

AB - 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 establishedand this work will now drive future mutagenesis studies to screen for the production of pharmaceutically-‐active (S)-‐profens.

U2 - 10.1039/C7OB00163K

DO - 10.1039/C7OB00163K

M3 - Article

SN - 1477-0520

JO - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

ER -