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RetroBioCat as a computer-aided synthesis planning tool for biocatalytic reactions and cascades

Nature Catalysis volume 4, pages 98–104 (2021)Cite this article

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Abstract

As the enzyme toolbox for biocatalysis has expanded, so has the potential for the construction of powerful enzymatic cascades for efficient and selective synthesis of target molecules. Additionally, recent advances in computer-aided synthesis planning are revolutionizing synthesis design in both synthetic biology and organic chemistry. However, the potential for biocatalysis is not well captured by tools currently available in either field. Here we present RetroBioCat, an intuitive and accessible tool for computer-aided design of biocatalytic cascades, freely available at retrobiocat.com. Our approach uses a set of expertly encoded reaction rules encompassing the enzyme toolbox for biocatalysis, and a system for identifying literature precedent for enzymes with the correct substrate specificity where this is available. Applying these rules for automated biocatalytic retrosynthesis, we show our tool to be capable of identifying promising biocatalytic pathways to target molecules, validated using a test set of recent cascades described in the literature.

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Fig. 1: An overview of the requirements for a biocatalysis CASP tool.
Fig. 2: Critical components of RetroBioCat.
Fig. 3: Human-led exploration of a network of potential biotransformations using network explorer.
Fig. 4: An example selection of some of the biocatalytic cascades identified in the literature and used as a test set for pathway explorer.

Data availability

Other than literature precedent data, which can currently only be accessed at https://retrobiocat.com pending future publications, the database files for RetroBiocat at the time of publication are available at https://doi.org/10.6084/m9.figshare.12696482.v4. The 52 pathway test set is available, along with the source code at https://doi.org/10.6084/m9.figshare.12698072.v7 or https://github.com/willfinnigan/retrobiocat.

Code availability

RetroBioCat is freely available as a web application at https://retrobiocat.com. We have also made the source code freely available under the MIT license, available at https://github.com/willfinnigan/retrobiocat, or specifically for the version described here, at https://doi.org/10.6084/m9.figshare.12698072.v7.

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Acknowledgements

We acknowledge financial support from the European Research Council (788231-ProgrES-ERC-2017-ADG to S.L.F.; BIO-HBORROW: grant no. 742987 to N.J.T.). We also thank all the beta-testers of RetroBioCat, particularly S. Cosgrove and R. Speight.

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Authors and Affiliations

  1. Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, Manchester, UK

    William Finnigan, Lorna J. Hepworth, Sabine L. Flitsch & Nicholas J. Turner

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  1. William Finnigan
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Contributions

W.F., L.J.H., S.L.F. and N.J.T. planned the work. Code for RetroBioCat written by W.F. Pathway test set generated by L.J.H. Initial draft of the manuscript written by W.F., with subsequent contributions from L.J.H., S.L.F. and N.J.T. All authors have given approval to the final version of the manuscript.

Corresponding authors

Correspondence to Sabine L. Flitsch or Nicholas J. Turner.

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The authors declare no competing interests.

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Peer review information Nature Catalysis thanks Connor Coley, Nicolas Moitessier, Dörte Rother and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 An example generated using Network Explorer to illustrate changes in molecular complexity.

Arrows and reactions are coloured by the change in molecular complexity, determined using the SC-Score. Green indicates a negative change in molecule complexity, which in most cases corresponds to a synthetically useful transformation. Red indicates a positive change in molecular complexity. Colours are determined relative to the other transformations leading to a specific molecule. Some reactions have been removed for clarity. Pathway published in reference68.

Extended Data Fig. 2 Rankings for pathways 12 to 20 of the test-set for Pathway explorer.

A continuation of Fig. 4, showing rankings for pathways 12 to 20 by RetroBioCat using a maximum of 4 steps and either the default scoring weights, or default weights but with the weight for number of steps with literature precedent set to zero, are shown. Pathways are marked as identified even where RetroBioCat suggests additional steps. * indicates pathways where the data from the relevant paper has not been added to the database of literature precedent reactions in RetroBioCat. TPL: tyrosine phenol lyase, AAD: amino acid deaminase, AADH: amino acid dehydrogenase, TDL: thiamine-dependent lyase, TA: transaminase, PSase: Pictet-Spenglerase, PAL: phenylalanine ammonia lyase, P450: cytochrome P450, ADH: alcohol dehydrogenase, CumDO: cumene dioxygenase, ERED: ene reductase, BVMO: Baeyer-Villiger monooxygenase, SMO: styrene monooxygenase, AlDH: aldehyde dehydrogenase, AlOx: alcohol oxidase.

Extended Data Fig. 3 Rankings for pathways 21 to 30 of the test-set for Pathway explorer.

A continuation of Fig. 4, showing rankings for pathways 21 to 30 by RetroBioCat using a maximum of 4 steps and either the default scoring weights, or default weights but with the weight for number of steps with literature precedent set to zero, are shown. Pathways are marked as identified even where RetroBioCat suggests additional steps. * indicates pathways where the data from the relevant paper has not been added to the database of literature precedent reactions in RetroBioCat. TDL: thiamine-dependent lyase, ADH: alcohol dehydrogenase, PAL: phenylalanine ammonia lyase, CAR: carboxylic acid reductase, ERED: ene reductase, IRED: imine reductase, AmOx: amine oxidase, P450: cytochrome P450, ATP: adenosine triphosphate, NADP: nicotinamide adenine dinucleotide phosphate.

Extended Data Fig. 4 Rankings for pathways 31 to 40 of the test-set for Pathway explorer.

A continuation of Fig. 4, showing rankings for pathways 31 to 40 by RetroBioCat using a maximum of 4 steps and either the default scoring weights, or default weights but with the weight for number of steps with literature precedent set to zero, are shown. Pathways are marked as identified even where RetroBioCat suggests additional steps. * indicates pathways where the data from the relevant paper has not been added to the database of literature precedent reactions in RetroBioCat. ADH: alcohol dehydrogenase, BVMO: Baeyer-Villiger monooxygenase, SMO: styrene monooxygenase, EH: epoxide hydrolase, AmDH: amine dehydrogenase, CAR: carboxylic acid reductase, TA: transaminase, AlOx: alcohol oxidase, ERED: ene reductase, TrpS: tryptophan synthase, XOR: xanthine oxidoreductase, AAD: amino acid deaminase, ATP: adenosine triphosphate, NADP: nicotinamide adenine dinucleotide phosphate, BNA: 1-benzyl-1,4-dihydropyridine-3-carboxamide.

Extended Data Fig. 5 Rankings for pathways 41 to 52 of the test-set for Pathway explorer.

A continuation of Fig. 4, showing rankings for pathways 41 to 52 by RetroBioCat using a maximum of 4 steps and either the default scoring weights, or default weights but with the weight for number of steps with literature precedent set to zero, are shown. Pathways are marked as identified even where RetroBioCat suggests additional steps. * indicates pathways where the data from the relevant paper has not been added to the database of literature precedent reactions in RetroBioCat. TA: transaminase, IRED: imine reductase, PAL: phenylalanine ammonia lyase, DC: decarboxylase, AmDH: amine dehydrogenase, TPL: tyrosine phenol lyase, AAD: amino acid deaminase, TAM: tyrosine aminomutase, TDL: thiamine-dependent lyase, ADH: alcohol dehydrogenase, AlOx: alcohol oxidase, EH: epoxide hydrolase, CAR: carboxylic acid reductase, ATP: adenosine triphosphate, NADP: nicotinamide adenine dinucleotide phosphate.

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Finnigan, W., Hepworth, L.J., Flitsch, S.L. et al. RetroBioCat as a computer-aided synthesis planning tool for biocatalytic reactions and cascades. Nat Catal 4, 98–104 (2021). https://doi.org/10.1038/s41929-020-00556-z

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