title: A Promiscuous De Novo Retro-Aldolase Catalyzes Asymmetric Michael Additions via Schiff Base Intermediates.
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.
authors.affiliation: Laboratory of Organic Chemistry, ETH Zürich, 8093 Zürich (Switzerland); Instituto de Química Avanzada de Cataluña-CSIC, Jordi Girona 18-26, 08034 Barcelona (Spain).
authors.forename: Xavier
authors.initials: X
authors.lastname: Garrabou
authors.forename: Tobias
authors.initials: T
authors.lastname: Beck
authors.forename: Donald
authors.initials: D
authors.lastname: Hilvert
mesh_terms: D000588:Amines / Q000737:chemistry / Q000378:metabolism*; D055162:Biocatalysis; D005634:Fructose-Bisphosphate Aldolase / Q000737:chemistry / Q000378:metabolism*; D007097:Imines / Q000737:chemistry / Q000378:metabolism*; D007659:Ketones / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D012545:Schiff Bases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000588:Amines; D007097:Imines; D007659:Ketones; D012545:Schiff Bases; D005634:Fructose-Bisphosphate Aldolase
keywords: asymmetric catalysis; biocatalysis; directed evolution; enzyme design; enzyme promiscuity