A Promiscuous De Novo Retro-Aldolase Catalyzes Asymmetric Michael Additions via Schiff Base Intermediates

Angewandte Chemie
Xavier GarrabouDonald Hilvert

Abstract

Recent advances in computational design have enabled the development of primitive enzymes for a range of mechanistically distinct reactions. Here we show that the rudimentary active sites of these catalysts can give rise to useful chemical promiscuity. Specifically, RA95.5-8, designed and evolved as a retro-aldolase, also promotes asymmetric Michael additions of carbanions to unsaturated ketones with high rates and selectivities. The reactions proceed by amine catalysis, as indicated by mutagenesis and X-ray data. The inherent flexibility and tunability of this catalyst should make it a versatile platform for further optimization and/or mechanistic diversification by directed evolution.

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Citations

Oct 27, 2015·Journal of the American Chemical Society·Christopher K Prier, Frances H Arnold
Nov 10, 2015·Nature Chemical Biology·Hajo KriesSarah E O'Connor
May 20, 2016·Journal of the American Chemical Society·Xavier GarrabouDonald Hilvert
Jul 8, 2016·The Journal of Organic Chemistry·Atsushi UedaMasakazu Tanaka
Jun 5, 2016·Current Opinion in Biotechnology·Jim Lalonde
Jan 11, 2017·Chemistry : a European Journal·Xavier GarrabouDonald Hilvert
Apr 21, 2017·Chembiochem : a European Journal of Chemical Biology·Mehran RahimiGerrit J Poelarends
Mar 8, 2018·Organic & Biomolecular Chemistry·Vishruth GowdaCoran M H Watanabe
Feb 16, 2018·Angewandte Chemie·Xavier GarrabouDonald Hilvert
May 22, 2018·Chemical Communications : Chem Comm·Miguel A Maria-SolanoSílvia Osuna
Nov 30, 2018·Chembiochem : a European Journal of Chemical Biology·Vasilis TseliouFrancesco G Mutti
Mar 2, 2018·Annual Review of Biochemistry·Cathleen Zeymer, Donald Hilvert
Feb 8, 2018·Critical Reviews in Biochemistry and Molecular Biology·Yajie WangHuimin Zhao
Nov 5, 2016·Chemical Communications : Chem Comm·Adrian Romero-RiveraSílvia Osuna
Dec 21, 2016·Nature Chemistry·Richard ObexerDonald Hilvert
Dec 4, 2019·ChemCatChem·Elizabeth A CaselleIvan V Korendovych
Oct 20, 2020·Chemistry : a European Journal·Vasilis TseliouFrancesco G Mutti
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Dec 1, 2020·ACS Catalysis·Stefan VelikogneWolfgang Kroutil
Jul 24, 2021·Chemical Reviews·Yajie WangHuimin Zhao
May 20, 2020·Journal of the American Chemical Society·Duncan Stuart MacdonaldDonald Hilvert
Dec 12, 2017·ACS Catalysis·Adrian Romero-RiveraSílvia Osuna
Aug 8, 2017·Journal of the American Chemical Society·Cathleen ZeymerDonald Hilvert
Dec 20, 2016·Journal of the American Chemical Society·Xavier GarrabouDonald Hilvert
Feb 18, 2020·ACS Omega·Lieuwe BiewengaGerrit J Poelarends
Jul 4, 2019·The Journal of Physical Chemistry. B·Rui QiPengyu Ren
Sep 8, 2021·Journal of the American Chemical Society·Manfred T Reetz, Marc Garcia-Borràs

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