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Multistep enzyme cascades as a route towards green and sustainable pharmaceutical syntheses

Nature Chemistry volume 14, pages 489–499 (2022)Cite this article

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Abstract

Enzyme cascades are a powerful technology to develop environmentally friendly and cost-effective synthetic processes to manufacture drugs, as they couple different biotransformations in sequential reactions to synthesize the product. These biocatalytic tools can address two key parameters for the pharmaceutical industry: an improved selectivity of synthetic reactions and a reduction of potential hazards by using biocompatible catalysts, which can be produced from sustainable sources, which are biodegradable and, generally, non-toxic. Here we outline a broad variety of enzyme cascades used either in vivo (whole cells) or in vitro (purified enzymes) to specifically target pharmaceutically relevant molecules, from simple building blocks to complex drugs. We also discuss the advantages and requirements of multistep enzyme cascades and their combination with chemical catalysts through a series of reported examples. Finally, we examine the efficiency of enzyme cascades and how they can be further improved by enzyme engineering, process intensification in flow reactors and/or enzyme immobilization to meet all the industrial requirements.

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Fig. 1: Classification of enzyme cascades.
Fig. 2: Enzyme cascades that involve TAs for the synthesis of pharmaceutical building blocks.
Fig. 3: Parallel enzymatic cascades for the synthesis of pharmaceutical building blocks.
Fig. 4: Enzyme cascades for the synthesis of simple drugs.
Fig. 5: (Chemo)enzymatic synthesis of complex drugs.
Fig. 6: Strategies to improve pharmaceutical syntheses by enzyme cascades for integration at the industrial scale.

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Article 24 June 2021

Elizabeth L. Bell, William Finnigan, … Sabine L. Flitsch

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Acknowledgements

We thank SNSF (200021_192274, F.P.) and the University of Bern ‘SELF’ Postdoctoral Fellowship (SELF19-03 BIORPHANDRUG, A.I.B.-M.) for financial support.

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  1. Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland

    Ana I. Benítez-Mateos, David Roura Padrosa & Francesca Paradisi

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F.P. conceived the article and A.I.B.-M., D.R.P. and F.P. contributed to the discussions and wrote the manuscript. A.I.B.-M. and D.R.P. made equal contributions to the manuscript.

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Correspondence to Francesca Paradisi.

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Benítez-Mateos, A.I., Roura Padrosa, D. & Paradisi, F. Multistep enzyme cascades as a route towards green and sustainable pharmaceutical syntheses. Nat. Chem. 14, 489–499 (2022). https://doi.org/10.1038/s41557-022-00931-2

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