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Diminishing returns and tradeoffs constrain the laboratory optimization of an enzyme

Author

Listed:
  • Nobuhiko Tokuriki

    (Michael Smith Laboratories, University of British Columbia
    University of Cambridge
    Weizmann Institute of Science)

  • Colin J. Jackson

    (Research School of Chemistry, Australian National University
    Institut de Biologie Structurale)

  • Livnat Afriat-Jurnou

    (Weizmann Institute of Science)

  • Kirsten T. Wyganowski

    (Michael Smith Laboratories, University of British Columbia)

  • Renmei Tang

    (Michael Smith Laboratories, University of British Columbia)

  • Dan S. Tawfik

    (Weizmann Institute of Science)

Abstract

Optimization processes, such as evolution, are constrained by diminishing returns—the closer the optimum, the smaller the benefit per mutation, and by tradeoffs—improvement of one property at the cost of others. However, the magnitude and molecular basis of these parameters, and their effect on evolutionary transitions, remain unknown. Here we pursue a complete functional transition of an enzyme with a >109-fold change in the enzyme’s selectivity using laboratory evolution. We observed strong diminishing returns, with the initial mutations conferring >25-fold higher improvements than later ones, and asymmetric tradeoffs whereby the gain/loss ratio of the new/old activity decreased 400-fold from the beginning of the trajectory to its end. We describe the molecular basis for these phenomena and suggest they have an important role in shaping natural proteins. These findings also suggest that the catalytic efficiency and specificity of many natural enzymes may be far from their optimum.

Suggested Citation

  • Nobuhiko Tokuriki & Colin J. Jackson & Livnat Afriat-Jurnou & Kirsten T. Wyganowski & Renmei Tang & Dan S. Tawfik, 2012. "Diminishing returns and tradeoffs constrain the laboratory optimization of an enzyme," Nature Communications, Nature, vol. 3(1), pages 1-10, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2246
    DOI: 10.1038/ncomms2246
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    Cited by:

    1. Dan Kozome & Adnan Sljoka & Paola Laurino, 2024. "Remote loop evolution reveals a complex biological function for chitinase enzymes beyond the active site," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Karol Buda & Charlotte M. Miton & Nobuhiko Tokuriki, 2023. "Pervasive epistasis exposes intramolecular networks in adaptive enzyme evolution," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Enrico Orsi & Lennart Schada von Borzyskowski & Stephan Noack & Pablo I. Nikel & Steffen N. Lindner, 2024. "Automated in vivo enzyme engineering accelerates biocatalyst optimization," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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