Multifunctional biocatalyst for conjugate reduction and reductive amination

Thomas W. Thorpe, James R. Marshall, Vanessa Harawa, Rebecca E. Ruscoe, Anibal Cuetos, James D. Finnigan, Antonio Angelastro, Rachel S. Heath, Fabio Parmeggiani, Simon J. Charnock, Roger M. Howard, Rajesh Kumar, David S. B. Daniels, Gideon Grogan and Nicholas J. Turner ()
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Thomas W. Thorpe: University of Manchester, Manchester Institute of Biotechnology
James R. Marshall: University of Manchester, Manchester Institute of Biotechnology
Vanessa Harawa: University of Manchester, Manchester Institute of Biotechnology
Rebecca E. Ruscoe: University of Manchester, Manchester Institute of Biotechnology
Anibal Cuetos: University of York
James D. Finnigan: Prozomix
Antonio Angelastro: University of Manchester, Manchester Institute of Biotechnology
Rachel S. Heath: University of Manchester, Manchester Institute of Biotechnology
Fabio Parmeggiani: University of Manchester, Manchester Institute of Biotechnology
Simon J. Charnock: Prozomix
Roger M. Howard: Pfizer Worldwide Research and Development
Rajesh Kumar: Pfizer Worldwide Research and Development
David S. B. Daniels: Pfizer Worldwide Research and Development
Gideon Grogan: University of York
Nicholas J. Turner: University of Manchester, Manchester Institute of Biotechnology

Nature, 2022, vol. 604, issue 7904, 86-91

Abstract: Abstract Chiral amine diastereomers are ubiquitous in pharmaceuticals and agrochemicals1, yet their preparation often relies on low-efficiency multi-step synthesis2. These valuable compounds must be manufactured asymmetrically, as their biochemical properties can differ based on the chirality of the molecule. Herein we characterize a multifunctional biocatalyst for amine synthesis, which operates using a mechanism that is, to our knowledge, previously unreported. 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 bearing 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.

Date: 2022
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DOI: 10.1038/s41586-022-04458-x

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