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Ni Z, Stine AE, Tyo KEJ, et al. Curating a comprehensive set of enzymatic reaction rules for efficient novel biosynthetic pathway design. Metab Eng. 2021;65:79-87doi: 10.1016/j.ymben.2021.02.006.
Ni, Z., Stine, A. E., Tyo, K. E. J., & Broadbelt, L. J. (2021). Curating a comprehensive set of enzymatic reaction rules for efficient novel biosynthetic pathway design. Metabolic engineering, 6579-87. https://doi.org/10.1016/j.ymben.2021.02.006
Ni, Zhuofu, et al. "Curating a comprehensive set of enzymatic reaction rules for efficient novel biosynthetic pathway design." Metabolic engineering vol. 65 (2021): 79-87. doi: https://doi.org/10.1016/j.ymben.2021.02.006
Ni Z, Stine AE, Tyo KEJ, Broadbelt LJ. Curating a comprehensive set of enzymatic reaction rules for efficient novel biosynthetic pathway design. Metab Eng. 2021 May;65:79-87. doi: 10.1016/j.ymben.2021.02.006. Epub 2021 Mar 01. PMID: 33662575.
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Metab Eng. 2021 May;65:79-87. doi: 10.1016/j.ymben.2021.02.006. Epub 2021 Mar 01.

Curating a comprehensive set of enzymatic reaction rules for efficient novel biosynthetic pathway design.

Metabolic engineering

Zhuofu Ni, Andrew E Stine, Keith E J Tyo, Linda J Broadbelt

Affiliations

  1. Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, 60208, USA.
  2. Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, 60208, USA. Electronic address: [email protected].

PMID: 33662575 DOI: 10.1016/j.ymben.2021.02.006

Abstract

Enzyme substrate promiscuity has significant implications for metabolic engineering. The ability to predict the space of possible enzymatic side reactions is crucial for elucidating underground metabolic networks in microorganisms, as well as harnessing novel biosynthetic capabilities of enzymes to produce desired chemicals. Reaction rule-based cheminformatics platforms have been implemented to computationally enumerate possible promiscuous reactions, relying on existing knowledge of enzymatic transformations to inform novel reactions. However, past versions of curated reaction rules have been limited by a lack of comprehensiveness in representing all possible transformations, as well as the need to prune rules to enhance computational efficiency in pathway expansion. To this end, we curated a set of 1224 most generalized reaction rules, automatically abstracted from atom-mapped MetaCyc reactions and verified to uniquely cover all common enzymatic transformations. We developed a framework to systematically identify and correct redundancies and errors in the curation process, resulting in a minimal, yet comprehensive, rule set. These reaction rules were capable of reproducing more than 85% of all reactions in the KEGG and BRENDA databases, for which a large fraction of reactions is not present in MetaCyc. Our rules exceed all previously published rule sets for which reproduction was possible in this coverage analysis, which allows for the exploration of a larger space of known enzymatic transformations. By leveraging the entire knowledge of possible metabolic reactions through generalized enzymatic reaction rules, we are able to better utilize underground metabolic pathways and accelerate novel biosynthetic pathway design to enable bioproduction towards a wider range of new molecules.

Copyright © 2021 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Keywords: Cheminformatics; Enzyme promiscuity; Novel pathway design; Reaction network generation

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