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A family of native amine dehydrogenases for the asymmetric reductive amination of ketones

DOI: 10.1038/s41929-019-0249-z DOI Help

Authors: Ombeline Mayol (CEA, CNRS, Univ Evry, Université Paris-Saclay) , Karine Bastard (CEA, CNRS, Univ Evry, Université Paris-Saclay) , Lilian Beloti (University of York) , Amina Frese (University of York) , Johan Turkenburg (University of York) , Jean-louis Petit (CEA, CNRS, Univ Evry, Université Paris-Saclay) , Aline Mariage (CEA, CNRS, Univ Evry, Université Paris-Saclay) , Adrien Debard (CEA, CNRS, Univ Evry, Université Paris-Saclay) , Virginie Pellouin (CEA, CNRS, Univ Evry, Université Paris-Saclay) , Alain Perret (CEA, CNRS, Univ Evry, Université Paris-Saclay) , Véronique De Berardinis (CEA, CNRS, Univ Evry, Université Paris-Saclay) , Anne Zaparucha (CEA, CNRS, Univ Evry, Université Paris-Saclay) , Gideon Grogan (University of York) , Carine Vergne-vaxelaire (CEA, CNRS, Univ Evry, Université Paris-Saclay)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Catalysis , VOL 55

State: Published (Approved)
Published: March 2019
Diamond Proposal Number(s): 9948

Abstract: The asymmetric reductive amination of ketones enables the one-step synthesis of chiral amines from readily available starting materials. Here we report the discovery of a family of native NAD(P)H-dependent amine dehydrogenases (nat-AmDHs) competent for the asymmetric reductive amination of aliphatic and alicyclic ketones, adding significantly to the biocatalytic toolbox available for chiral amine synthesis. Studies of ketone and amine substrate specificity and kinetics reveal a strong preference for aliphatic ketones and aldehydes, with activities of up to 614.5 mU mg−1 for cyclohexanone with ammonia, and 851.3 mU mg−1 for isobutyraldehyde with methylamine as the amine donor. Crystal structures of three nat-AmDHs (AmDH4, MsmeAmDH and CfusAmDH) reveal the active site determinants of substrate and cofactor specificity and enable the rational engineering of AmDH4 for the generated activity towards pentan-2-one. Analysis of the three-dimensional catalytic site distribution among bacterial biodiversity revealed a superfamily of divergent proteins with representative specificities ranging from amino acid substrates to hydrophobic ketones.

Journal Keywords: Asymmetric synthesis; Biocatalysis; Oxidoreductases; Protein analysis; X-ray crystallography

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography