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A redox-mediated Kemp eliminase

Author

Listed:
  • Aitao Li

    (Max-Planck-Institut für Kohlenforschung
    Philipps-Universität Marburg)

  • Binju Wang

    (Institute of Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem)

  • Adriana Ilie

    (Max-Planck-Institut für Kohlenforschung
    Philipps-Universität Marburg)

  • Kshatresh D. Dubey

    (Institute of Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem)

  • Gert Bange

    (Philipps-Universität Marburg)

  • Ivan V. Korendovych

    (Syracuse University)

  • Sason Shaik

    (Institute of Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem)

  • Manfred T. Reetz

    (Max-Planck-Institut für Kohlenforschung
    Philipps-Universität Marburg)

Abstract

The acid/base-catalysed Kemp elimination of 5-nitro-benzisoxazole forming 2-cyano-4-nitrophenol has long served as a design platform of enzymes with non-natural reactions, providing new mechanistic insights in protein science. Here we describe an alternative concept based on redox catalysis by P450-BM3, leading to the same Kemp product via a fundamentally different mechanism. QM/MM computations show that it involves coordination of the substrate’s N-atom to haem-Fe(II) with electron transfer and concomitant N–O heterolysis liberating an intermediate having a nitrogen radical moiety Fe(III)–N· and a phenoxyl anion. Product formation occurs by bond rotation and H-transfer. Two rationally chosen point mutations cause a notable increase in activity. The results shed light on the prevailing mechanistic uncertainties in human P450-catalysed metabolism of the immunomodulatory drug leflunomide, which likewise undergoes redox-mediated Kemp elimination by P450-BM3. Other isoxazole-based pharmaceuticals are probably also metabolized by a redox mechanism. Our work provides a basis for designing future artificial enzymes.

Suggested Citation

  • Aitao Li & Binju Wang & Adriana Ilie & Kshatresh D. Dubey & Gert Bange & Ivan V. Korendovych & Sason Shaik & Manfred T. Reetz, 2017. "A redox-mediated Kemp eliminase," Nature Communications, Nature, vol. 8(1), pages 1-8, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14876
    DOI: 10.1038/ncomms14876
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    1. Ekta Shandilya & Bhargav Rallabandi & Subhabrata Maiti, 2024. "In situ enzymatic control of colloidal phoresis and catalysis through hydrolysis of ATP," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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