Multifunctional biocatalyst for conjugate reduction and reductive amination

Thomas Thorpe; James Marshall; Vanessa Harawa; Rebecca Ruscoe; Anibal Cuetos; James Finnigan; Antonio Angelastro; Rachel Heath; Fabio Parmeggianni; S.J. Charnock; Roger Howard; Rajesh Kumar; David  Daniels; Gideon James Grogan; Nicholas Turner

doi:10.1038/s41586-022-04458-x

Multifunctional biocatalyst for conjugate reduction and reductive amination

Thomas Thorpe, James Marshall, Vanessa Harawa, Rebecca Ruscoe, Anibal Cuetos, James Finnigan, Antonio Angelastro, Rachel Heath, Fabio Parmeggianni, S.J. Charnock, Roger Howard, Rajesh Kumar, David Daniels, Gideon James Grogan, Nicholas Turner

Chemistry

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

Abstract

Chiral amine diastereomers are ubiquitous in pharmaceuticals and agrochemicals,1 yet their preparation often relies on low-efficiency multi-step synthesis.2 These valuable compounds must be manufactured asymmetrically, as their biochemical properties can differ based on the chirality of the molecule. Herein, we report the discovery and characterisation of a multi-functional biocatalyst for amine synthesis, which operates using a previously unreported mechanism. This enzyme (EneIRED), identified within a metagenomic imine reductase (IRED) collection3 and originating from an unclassified Pseudomonas species, possesses an unusual active site architecture that facilitates amine-activated conjugate alkene reduction followed by reductive amination. This enzyme can couple a broad selection of α,β-unsaturated carbonyls with amines for the efficient preparation of chiral amine diastereomers baring up to three stereocentres. Mechanistic and structural studies have been carried out to delineate the order of individual steps catalysed by EneIRED which have led to a proposal for the overall catalytic cycle. This work shows that the IRED family can serve as a platform for facilitating the discovery of further enzymatic activities for application in synthetic biology and organic synthesis.

Original language	English
Pages (from-to)	86-91
Journal	Nature
Volume	604
Early online date	6 Apr 2022
DOIs	https://doi.org/10.1038/s41586-022-04458-x
Publication status	Published - 2022

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Cite this

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title = "Multifunctional biocatalyst for conjugate reduction and reductive amination",

abstract = "Chiral amine diastereomers are ubiquitous in pharmaceuticals and agrochemicals,1 yet their preparation often relies on low-efficiency multi-step synthesis.2 These valuable compounds must be manufactured asymmetrically, as their biochemical properties can differ based on the chirality of the molecule. Herein, we report the discovery and characterisation of a multi-functional biocatalyst for amine synthesis, which operates using a previously unreported mechanism. This enzyme (EneIRED), identified within a metagenomic imine reductase (IRED) collection3 and originating from an unclassified Pseudomonas species, possesses an unusual active site architecture that facilitates amine-activated conjugate alkene reduction followed by reductive amination. This enzyme can couple a broad selection of α,β-unsaturated carbonyls with amines for the efficient preparation of chiral amine diastereomers baring up to three stereocentres. Mechanistic and structural studies have been carried out to delineate the order of individual steps catalysed by EneIRED which have led to a proposal for the overall catalytic cycle. This work shows that the IRED family can serve as a platform for facilitating the discovery of further enzymatic activities for application in synthetic biology and organic synthesis.",

author = "Thomas Thorpe and James Marshall and Vanessa Harawa and Rebecca Ruscoe and Anibal Cuetos and James Finnigan and Antonio Angelastro and Rachel Heath and Fabio Parmeggianni and S.J. Charnock and Roger Howard and Rajesh Kumar and David Daniels and Grogan, {Gideon James} and Nicholas Turner",

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T1 - Multifunctional biocatalyst for conjugate reduction and reductive amination

AU - Thorpe, Thomas

AU - Marshall, James

AU - Harawa, Vanessa

AU - Ruscoe, Rebecca

AU - Cuetos, Anibal

AU - Finnigan, James

AU - Angelastro, Antonio

AU - Heath, Rachel

AU - Parmeggianni, Fabio

AU - Charnock, S.J.

AU - Howard, Roger

AU - Kumar, Rajesh

AU - Daniels, David

AU - Grogan, Gideon James

AU - Turner, Nicholas

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 - 2022

Y1 - 2022

N2 - Chiral amine diastereomers are ubiquitous in pharmaceuticals and agrochemicals,1 yet their preparation often relies on low-efficiency multi-step synthesis.2 These valuable compounds must be manufactured asymmetrically, as their biochemical properties can differ based on the chirality of the molecule. Herein, we report the discovery and characterisation of a multi-functional biocatalyst for amine synthesis, which operates using a previously unreported mechanism. This enzyme (EneIRED), identified within a metagenomic imine reductase (IRED) collection3 and originating from an unclassified Pseudomonas species, possesses an unusual active site architecture that facilitates amine-activated conjugate alkene reduction followed by reductive amination. This enzyme can couple a broad selection of α,β-unsaturated carbonyls with amines for the efficient preparation of chiral amine diastereomers baring up to three stereocentres. Mechanistic and structural studies have been carried out to delineate the order of individual steps catalysed by EneIRED which have led to a proposal for the overall catalytic cycle. This work shows that the IRED family can serve as a platform for facilitating the discovery of further enzymatic activities for application in synthetic biology and organic synthesis.

AB - Chiral amine diastereomers are ubiquitous in pharmaceuticals and agrochemicals,1 yet their preparation often relies on low-efficiency multi-step synthesis.2 These valuable compounds must be manufactured asymmetrically, as their biochemical properties can differ based on the chirality of the molecule. Herein, we report the discovery and characterisation of a multi-functional biocatalyst for amine synthesis, which operates using a previously unreported mechanism. This enzyme (EneIRED), identified within a metagenomic imine reductase (IRED) collection3 and originating from an unclassified Pseudomonas species, possesses an unusual active site architecture that facilitates amine-activated conjugate alkene reduction followed by reductive amination. This enzyme can couple a broad selection of α,β-unsaturated carbonyls with amines for the efficient preparation of chiral amine diastereomers baring up to three stereocentres. Mechanistic and structural studies have been carried out to delineate the order of individual steps catalysed by EneIRED which have led to a proposal for the overall catalytic cycle. This work shows that the IRED family can serve as a platform for facilitating the discovery of further enzymatic activities for application in synthetic biology and organic synthesis.

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