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A Reductive Aminase Switches to Imine Reductase Mode for a Bulky Amine Substrate
Amelia K Gilio1, Thomas W Thorpe2, Alex Heyam1
1Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K.
ACS Catalysis
|February 13, 2023
Summary
Imine reductases (IREDs) catalyze reductive amination reactions. A study on IR77 identified a mutant, IR77-A208N, with enhanced stability and activity for coupling larger amines, achieving up to 93% yield.
Area of Science:
- Biocatalysis
- Enzymology
- Organic Chemistry
Background:
- Imine reductases (IREDs) catalyze reductive amination (RedAm), but struggle with larger amines.
- Pharmaceutical synthesis requires efficient coupling of ketones with diverse, often bulky, amines.
Purpose of the Study:
- To characterize the IR77 enzyme from Ensifer adhaerens for reductive amination with larger amines.
- To engineer an improved IRED variant for enhanced activity and stability.
Main Methods:
- Enzyme characterization and structure determination of IR77.
- Structure-guided mutagenesis and directed evolution to create IR77 variants.
- Biochemical assays, X-ray crystallography, and nano differential scanning fluorimetry for analysis.
Main Results:
- IR77 demonstrated activity with larger bicyclic amines, though likely via ex situ imine formation.
- A mutant, IR77-A208N, showed improved activity and stability.
- Preparative scale reactions with IR77-A208N yielded up to 93% of secondary amine products.
Conclusions:
- Engineered IR77-A208N is a robust biocatalyst for reductive amination with challenging amines.
- This work expands the scope of enzymatic reductive amination for pharmaceutical intermediate synthesis.
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