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Catalytically Promiscuous PLP-Dependent Aminotransferases Are Biocatalysts for C-C Bond Formation
Alexander T Kim1,2, James R Howard2, Andrés G Cuba Cáceres1,2
1†Life Sciences Institute, ‡Program in Chemical Biology, §Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
ACS Central Science
|July 25, 2026
Summary
Pyridoxal-5'-phosphate (PLP)-dependent enzymes, specifically aminotransferases, were engineered to form carbon-carbon bonds, a novel biocatalytic function. This discovery expands the toolkit for synthesizing complex molecules using readily available enzymes.
Area of Science:
- Biocatalysis and Enzyme Engineering
- Organic Synthesis
- Drug Discovery
Background:
- Pyridoxal-5 andomIndex'-phosphate (PLP)-dependent enzymes are crucial for amino acid functionalization but often exhibit limited substrate specificity.
- Catalytic promiscuity in PLP-dependent enzymes offers potential for discovering new biocatalytic activities.
- Access to noncanonical amino acids is vital for natural product synthesis and drug discovery.
Purpose of the Study:
- To explore the potential of PLP-dependent enzymes, particularly aminotransferases, for catalyzing carbon-carbon (C-C) bond formation.
- To identify novel biocatalysts for accessing nucleophilic intermediates essential in synthesis.
- To investigate cofactor-centric strategies for expanding biocatalytic reaction scope.
Main Methods:
- Utilized a cofactor-centric approach focusing on PLP-dependent enzymes not previously known for C-C bond formation.
- Investigated the activity of aminotransferases Aro8 and TyrB in mediating C-C bond formation.
- Assessed the impact of adding a sacrificial ketoacid on the non-native C-C bond forming activity.
- Analyzed the conformational dynamics of Aro8 and TyrB and their effect on reaction diastereoselectivity.
Main Results:
- Demonstrated that aminotransferases Aro8 and TyrB can mediate C-C bond formation, a previously unreported activity for this enzyme class.
- Showed that the addition of a sacrificial ketoacid enhances this novel C-C bond forming function.
- Observed distinct conformational dynamics between Aro8 and TyrB, influencing the diastereoselectivity of the C-C bond formation.
- Identified aminotransferases as a promising, yet untapped, resource for biocatalytic C-C bond formation.
Conclusions:
- Aminotransferases possess an unexploited capability for catalyzing C-C bond formation.
- Cofactor-guided reaction discovery is a valuable strategy for uncovering new biocatalytic transformations.
- Engineered PLP-dependent enzymes offer new avenues for the synthesis of valuable noncanonical amino acids and complex molecules.
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