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To PLP or Not to PLP: Stereodivergent Transaminase-Catalyzed Reactions Directed by Kinetic and Thermodynamic Control
Madeline J Fitzgerald1, Xiaoyan Li2, Dawei Peng3,4
1Department of Chemistry, University of California, Berkeley, California 94720-1460, United States.
The Journal of Organic Chemistry
|September 1, 2025
Summary
A single transaminase enzyme can produce either cis or trans cyclohexylamines with high selectivity. Controlling reaction conditions or using a PLP cofactor precursor directs the stereochemical outcome, enabling efficient biocatalysis.
Area of Science:
- Organic Chemistry
- Biocatalysis
- Enzyme Engineering
Background:
- Selective catalysis is crucial in organic synthesis.
- Reactions with distinct kinetic and thermodynamic products offer potential for divergent outcomes using a single catalyst.
Purpose of the Study:
- To develop a biocatalytic method for stereodivergent synthesis of cyclohexylamines.
- To investigate the role of reaction conditions and cofactor supplementation in controlling stereochemical outcomes.
Main Methods:
- Utilized *E. coli* cells expressing a specific transaminase (WT-Vf-ATA).
- Manipulated reaction conditions and PLP (pyridoxal-5'-phosphate) cofactor supplementation.
- Employed a modified cell preparation including a PLP metabolic precursor.
Main Results:
- Achieved high diastereoselectivity (>10:1 dr) for both cis and trans cyclohexylamines from 4-methylcyclohexanone.
- Demonstrated stereodivergence across a range of substrates.
- Enabled enantiomeric and diastereomerically enriched amine production from racemic ketones via dynamic kinetic resolution.
- Identified PLP cofactor availability as a key factor in directing stereochemical outcome.
Conclusions:
- A single transaminase can catalyze stereodivergent synthesis of cyclohexylamines.
- PLP cofactor availability is a critical factor for optimizing transaminase activity and stereoselectivity.
- This work provides a simple yet powerful method for stereodivergent biocatalysis.
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