Identification of promiscuous ene-reductase activity by mining structural databases using active site constellations

Georg Steinkellner, Christian C. Gruber, Tea Pavkov-Keller, Alexandra Binter, Kerstin Steiner, Christoph Winkler, Andrzej Łyskowski, Orsolya Schwamberger, Monika Oberer, Helmut Schwab, Kurt Faber, Peter Macheroux and Karl Gruber ()
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Georg Steinkellner: ACIB GmbH
Christian C. Gruber: ACIB GmbH
Tea Pavkov-Keller: ACIB GmbH
Alexandra Binter: ACIB GmbH
Kerstin Steiner: ACIB GmbH
Christoph Winkler: University of Graz
Andrzej Łyskowski: ACIB GmbH
Orsolya Schwamberger: ACIB GmbH
Monika Oberer: Institute of Molecular Biosciences, University of Graz
Helmut Schwab: ACIB GmbH
Kurt Faber: ACIB GmbH
Peter Macheroux: ACIB GmbH
Karl Gruber: ACIB GmbH

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: Abstract The exploitation of catalytic promiscuity and the application of de novo design have recently opened the access to novel, non-natural enzymatic activities. Here we describe a structural bioinformatic method for predicting catalytic activities of enzymes based on three-dimensional constellations of functional groups in active sites (‘catalophores’). As a proof-of-concept we identify two enzymes with predicted promiscuous ene-reductase activity (reduction of activated C–C double bonds) and compare them with known ene-reductases, that is, members of the Old Yellow Enzyme family. Despite completely different amino acid sequences, overall structures and protein folds, high-resolution crystal structures reveal equivalent binding modes of typical Old Yellow Enzyme substrates and ligands. Biochemical and biocatalytic data show that the two enzymes indeed possess ene-reductase activity and reveal an inverted stereopreference compared with Old Yellow Enzymes for some substrates. This method could thus be a tool for the identification of viable starting points for the development and engineering of novel biocatalysts.

Date: 2014
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DOI: 10.1038/ncomms5150

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