A family of Native Amine Dehydrogenases for the Asymmetric Reductive Amination of Ketones

Gideon James Grogan; Amina Frese; Johan Turkenburg; Lilian Beloti; Ombeline Mayol; Karine Bastard; Jean-Louis Petit; Adrien Debard; Virginie Pellouin; Aline Mariage; Alain Perret; Veronique de Berardinis; Anne Zaparucha; Carine Vergne-Vaxelaire

doi:10.1038/s41929-019-0249-z

A family of Native Amine Dehydrogenases for the Asymmetric Reductive Amination of Ketones

Gideon James Grogan, Amina Frese, Johan Turkenburg, Lilian Beloti, Ombeline Mayol, Karine Bastard, Jean-Louis Petit, Adrien Debard, Virginie Pellouin, Aline Mariage, Alain Perret, Veronique de Berardinis, Anne Zaparucha, Carine Vergne-Vaxelaire

Chemistry

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

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 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 generated activity towards pentan-2-one. Analysis of the 3D-catalytic site distribution among bacterial biodiversity revealed a superfamily of divergent proteins with representative specificities ranging from amino acid substrates to hydrophobic ketones.

Original language	English
Pages (from-to)	324-333
Number of pages	10
Journal	Nature Catalysis
Volume	2
Issue number	4
Early online date	18 Mar 2019
DOIs	https://doi.org/10.1038/s41929-019-0249-z
Publication status	Published - 1 Apr 2019

Bibliographical note

This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

Access to Document

10.1038/s41929-019-0249-z

Vergne-Vaxelaire_Accepted_Author_Manuscript
This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.
Accepted author manuscript, 2.99 MB

Cite this

Grogan, G. J., Frese, A., Turkenburg, J., Beloti, L., Mayol, O., Bastard, K., Petit, J-L., Debard, A., Pellouin, V., Mariage, A., Perret, A., de Berardinis, V., Zaparucha, A., & Vergne-Vaxelaire, C. (2019). A family of Native Amine Dehydrogenases for the Asymmetric Reductive Amination of Ketones. Nature Catalysis, 2(4), 324-333. https://doi.org/10.1038/s41929-019-0249-z

@article{8f393a9132de40d6b222961780ff0efb,

title = "A family of Native Amine Dehydrogenases for the Asymmetric Reductive Amination of Ketones",

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 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 generated activity towards pentan-2-one. Analysis of the 3D-catalytic site distribution among bacterial biodiversity revealed a superfamily of divergent proteins with representative specificities ranging from amino acid substrates to hydrophobic ketones.",

author = "Grogan, {Gideon James} and Amina Frese and Johan Turkenburg and Lilian Beloti and Ombeline Mayol and Karine Bastard and Jean-Louis Petit and Adrien Debard and Virginie Pellouin and Aline Mariage and Alain Perret and {de Berardinis}, Veronique and Anne Zaparucha and Carine Vergne-Vaxelaire",

note = " This is an author-produced version of the published paper. Uploaded in accordance with the publisher{\textquoteright}s self-archiving policy. Further copying may not be permitted; contact the publisher for details. ",

year = "2019",

month = apr,

day = "1",

doi = "10.1038/s41929-019-0249-z",

language = "English",

volume = "2",

pages = "324--333",

journal = "Nature Catalysis",

issn = "2520-1158",

publisher = "Nature Publishing Group",

number = "4",

}

TY - JOUR

T1 - A family of Native Amine Dehydrogenases for the Asymmetric Reductive Amination of Ketones

AU - Grogan, Gideon James

AU - Frese, Amina

AU - Turkenburg, Johan

AU - Beloti, Lilian

AU - Mayol, Ombeline

AU - Bastard, Karine

AU - Petit, Jean-Louis

AU - Debard, Adrien

AU - Pellouin, Virginie

AU - Mariage, Aline

AU - Perret, Alain

AU - de Berardinis, Veronique

AU - Zaparucha, Anne

AU - Vergne-Vaxelaire, Carine

N1 - This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - 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 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 generated activity towards pentan-2-one. Analysis of the 3D-catalytic site distribution among bacterial biodiversity revealed a superfamily of divergent proteins with representative specificities ranging from amino acid substrates to hydrophobic ketones.

AB - 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 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 generated activity towards pentan-2-one. Analysis of the 3D-catalytic site distribution among bacterial biodiversity revealed a superfamily of divergent proteins with representative specificities ranging from amino acid substrates to hydrophobic ketones.

UR - http://www.scopus.com/inward/record.url?scp=85064263704&partnerID=8YFLogxK

U2 - 10.1038/s41929-019-0249-z

DO - 10.1038/s41929-019-0249-z

M3 - Article

VL - 2

SP - 324

EP - 333

JO - Nature Catalysis

JF - Nature Catalysis

SN - 2520-1158

IS - 4

ER -

A family of Native Amine Dehydrogenases for the Asymmetric Reductive Amination of Ketones

Abstract

Bibliographical note

Access to Document

Other files and links

Profiles

Gideon James Grogan

Cite this