Author
Listed:
- 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
Politecnico di Milano)
- 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)
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.
Suggested Citation
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. , 2022.
"Multifunctional biocatalyst for conjugate reduction and reductive amination,"
Nature, Nature, vol. 604(7904), pages 86-91, April.
Handle:
RePEc:nat:nature:v:604:y:2022:i:7904:d:10.1038_s41586-022-04458-x
DOI: 10.1038/s41586-022-04458-x
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