The importance of catalytic promiscuity for enzyme design and evolution

Reuben B. Leveson-Gower, Clemens Mayer*, Gerard Roelfes

*Corresponding author for this work

Research output: Contribution to journalReview articleAcademicpeer-review

36 Citations (Scopus)

Abstract

The ability of one enzyme to catalyse multiple, mechanistically distinct transformations likely played a crucial role in organisms' abilities to adapt to changing external stimuli in the past and can still be observed in extant enzymes. Given the importance of catalytic promiscuity in nature, enzyme designers have recently begun to create catalytically promiscuous enzymes in order to expand the canon of transformations catalysed by proteins. This article aims to both critically review different strategies for the design of enzymes that display catalytic promiscuity for new-to-nature reactions and highlight the successes of subsequent directed-evolution efforts to fine-tune these novel reactivities. For the former, we put a particular emphasis on the creation, stabilization and repurposing of reaction intermediates, which are key for unlocking new activities in an existing or designed active site. For the directed evolution of the resulting catalysts, we contrast approaches for enzyme design that make use of components found in nature and those that achieve new reactivities by incorporating synthetic components. Following the critical analysis of selected examples that are now available, we close this Review by providing a set of considerations and design principles for enzyme engineers, which will guide the future generation of efficient artificial enzymes for synthetically useful, abiotic transformations.

Original languageEnglish
Pages (from-to)687-705
Number of pages19
JournalNature reviews chemistry
Volume3
Issue number12
DOIs
Publication statusPublished - Dec-2019

Keywords

  • ARTIFICIAL TRANSFER HYDROGENASES
  • SUBSTITUTED CARBONIC-ANHYDRASE
  • MICHAEL-TYPE ADDITIONS
  • DIRECTED EVOLUTION
  • ACTIVE-SITE
  • ATOM-TRANSFER
  • TRANSCRIPTIONAL REPRESSOR
  • COMPUTATIONAL DESIGN
  • DIVERGENT EVOLUTION
  • CARBENE TRANSFER

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