Multifunctional biocatalyst for conjugate reduction and reductive amination

TY - JOUR

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.

U2 - 10.1038/s41586-022-04458-x

DO - 10.1038/s41586-022-04458-x

M3 - Article

SN - 0028-0836

VL - 604

SP - 86

EP - 91

JO - Nature

JF - Nature

ER -