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Updated: Aug 7, 2025

A Microwave-Assisted Direct Heteroarylation of Ketones Using Transition Metal Catalysis

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Published on: February 16, 2020

Computationally Supported Inversion of Ketoreductase Stereoselectivity.

Estela Delgado-Arciniega¹, Hein J Wijma¹, Chantal Hummel¹

¹Biotransformation and Biocatalysis, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands.

Chembiochem : a European Journal of Chemical Biology

|March 14, 2023

Summary

This summary is machine-generated.

Computational enzyme redesign successfully inverted the enantioselectivity of an alcohol dehydrogenase. This method efficiently predicts enzyme variants for asymmetric synthesis, minimizing experimental screening.

Keywords:

MD simulations alcohol dehydrogenase biocatalysis computational design ketoreductase

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Area of Science:

Biocatalysis
Enzyme Engineering
Computational Chemistry

Background:

Directed evolution and rational design are standard enzyme redesign methods.
Computational enzyme redesign offers potential for predicting desired mutant properties with less screening.
Alcohol dehydrogenases (ADHs) are crucial biocatalysts in asymmetric synthesis.

Purpose of the Study:

To computationally redesign a thermostable alcohol dehydrogenase from Thermus thermophilus.
To invert the enantioselectivity of the enzyme for asymmetric ketone reduction.
To demonstrate the utility of computational methods in controlling enzyme stereoselectivity.

Main Methods:

Utilized an adapted CASCO workflow incorporating Rosetta for enzyme design.
Employed molecular dynamics simulations and Boltzmann weighing of binding energies for variant ranking.
Applied a linear interaction energy approach to correct for binding modes.

Main Results:

Predicted four variants with inverted enantioselectivity, each with 6-8 mutations.
Observed only modest reductions in kcat/KM values (2- to 7-fold).
Laboratory testing confirmed inverted enantioselectivity in three variants, yielding (R)-alcohols with up to 99% enantiomeric excess.

Conclusions:

Computational enzyme redesign can effectively control ketoreductase stereoselectivity.
The developed method enables prediction of enzyme variants with inverted enantioselectivity.
This approach facilitates asymmetric transformations with minimal experimental effort.