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Balancing Specificity and Promiscuity in Enzyme Evolution: Multidimensional Activity Transitions in the Alkaline Phosphatase Superfamily

  • Bert van Loo
    Bert van Loo
    Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom
    More by Bert van Loo
  • Christopher D. Bayer
    Christopher D. Bayer
    Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom
  • Gerhard Fischer
    Gerhard Fischer
    Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom
  • Stefanie Jonas
    Stefanie Jonas
    Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom
  • Eugene Valkov
    Eugene Valkov
    Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom
  • Mark F. Mohamed
    Mark F. Mohamed
    Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom
  • Anastassia Vorobieva
    Anastassia Vorobieva
    Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom
  • Celine Dutruel
    Celine Dutruel
    Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom
  • Marko Hyvönen*
    Marko Hyvönen
    Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom
    *[email protected]
  • , and 
  • Florian Hollfelder*
    Florian Hollfelder
    Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom
    *[email protected]
Cite this: J. Am. Chem. Soc. 2019, 141, 1, 370–387
Publication Date (Web):November 30, 2018
https://doi.org/10.1021/jacs.8b10290
Copyright © 2018 American Chemical Society
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Abstract

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Highly proficient, promiscuous enzymes can be springboards for functional evolution, able to avoid loss of function during adaptation by their capacity to promote multiple reactions. We employ a systematic comparative study of structure, sequence, and substrate specificity to track the evolution of specificity and reactivity between promiscuous members of clades of the alkaline phosphatase (AP) superfamily. Construction of a phylogenetic tree of protein sequences maps out the likely transition zone between arylsulfatases (ASs) and phosphonate monoester hydrolases (PMHs). Kinetic analysis shows that all enzymes characterized have four chemically distinct phospho- and sulfoesterase activities, with rate accelerations ranging from 1011- to 1017-fold for their primary and 109- to 1012-fold for their promiscuous reactions, suggesting that catalytic promiscuity is widespread in the AP-superfamily. This functional characterization and crystallography reveal a novel class of ASs that is so similar in sequence to known PMHs that it had not been recognized as having diverged in function. Based on analysis of snapshots of catalytic promiscuity “in transition”, we develop possible models that would allow functional evolution and determine scenarios for trade-off between multiple activities. For the new ASs, we observe largely invariant substrate specificity that would facilitate the transition from ASs to PMHs via trade-off-free molecular exaptation, that is, evolution without initial loss of primary activity and specificity toward the original substrate. This ability to bypass low activity generalists provides a molecular solution to avoid adaptive conflict.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b10290.

  • Full synthetic procedures, additional information on other experimental procedures, protein purification, detailed kinetic measurements (Michaelis–Menten parameters, pH-rate profiles), X-ray crystallography processing statistics, additional figures with details on structural comparison, and full description of sequence data and structural data used for phylogenetic analysis (PDF)

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Cited By


This article is cited by 18 publications.

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  8. Patrick C. F. Buchholz, Bert van Loo, Bernard D. G. Eenink, Erich Bornberg-Bauer, Jürgen Pleiss. Ancestral sequences of a large promiscuous enzyme family correspond to bridges in sequence space in a network representation. Journal of The Royal Society Interface 2021, 18 (184) https://doi.org/10.1098/rsif.2021.0389
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  12. David Kerk, Mario E. Valdés-Tresanco, Ryan Toth, Sergei Yu. Noskov, Kenneth K.-S. Ng, Greg B. Moorhead. Origin of the Phosphoprotein Phosphatase (PPP) sequence family in Bacteria: Critical ancestral sequence changes, radiation patterns and substrate binding features. BBA Advances 2021, 1 , 100005. https://doi.org/10.1016/j.bbadva.2021.100005
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  17. Shelley D Copley. The physical basis and practical consequences of biological promiscuity. Physical Biology 2020, 17 (5) , 051001. https://doi.org/10.1088/1478-3975/ab8697
  18. William M. Atkins. Mechanisms of promiscuity among drug metabolizing enzymes and drug transporters. The FEBS Journal 2020, 287 (7) , 1306-1322. https://doi.org/10.1111/febs.15116

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