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Computational Tale of Two Enzymes: Glycerol Dehydration With or Without B12

  • Borislav Kovačević
    Borislav Kovačević
    Department of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia
  • Danijela Barić
    Danijela Barić
    Department of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia
  • Darko Babić
    Darko Babić
    Department of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia
    More by Darko Babić
  • Luka Bilić
    Luka Bilić
    Department of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia
    More by Luka Bilić
  • Marko Hanževački
    Marko Hanževački
    Department of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia
  • Gregory M. Sandala
    Gregory M. Sandala
    Department of Chemistry and Biochemistry, Mount Allison University, Sackville, New Brunswick E4L 1G8, Canada
  • Leo Radom
    Leo Radom
    School of Chemistry, University of Sydney, Sydney, NSW 2006, Australia
    More by Leo Radom
  • , and 
  • David M. Smith*
    David M. Smith
    Department of Physical Chemistry, Ruđer Bošković Institute, 10000 Zagreb, Croatia
    *[email protected]
Cite this: J. Am. Chem. Soc. 2018, 140, 27, 8487–8496
Publication Date (Web):June 12, 2018
https://doi.org/10.1021/jacs.8b03109
Copyright © 2018 American Chemical Society

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    Abstract

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    We present a series of QM/MM calculations aimed at understanding the mechanism of the biological dehydration of glycerol. Strikingly and unusually, this process is catalyzed by two different radical enzymes, one of which is a coenzyme-B12-dependent enzyme and the other which is a coenzyme-B12-independent enzyme. We show that glycerol dehydration in the presence of the coenzyme-B12-dependent enzyme proceeds via a 1,2-OH shift, which benefits from a significant catalytic reduction in the barrier. In contrast, the same reaction in the presence of the coenzyme-B12-independent enzyme is unlikely to involve the 1,2-OH shift; instead, a strong preference for direct loss of water from a radical intermediate is indicated. We show that this preference, and ultimately the evolution of such enzymes, is strongly linked with the reactivities of the species responsible for abstracting a hydrogen atom from the substrate. It appears that the hydrogen-reabstraction step involving the product-related radical is fundamental to the mechanistic preference. The unconventional 1,2-OH shift seems to be required to generate a product-related radical of sufficient reactivity to cleave the relatively inactive C–H bond arising from the B12 cofactor. In the absence of B12, it is the relatively weak S–H bond of a cysteine residue that must be homolyzed. Such a transformation is much less demanding, and its inclusion apparently enables a simpler overall dehydration mechanism.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b03109.

    • Model systems and optimized QM/MM geometries of reactants, intermediates, transition structures, and products (Figures S1 to S6); bond dissociation enthalpies, pK of histidine, energy and mean absolute deviation, energy profiles, and coordinates of molecules (Tables S1 to S9); and complete citations for refs (54,57,and58) (PDF)

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    15. Yaoyang Li, Yadi Yao, Lu Yu, Changlin Tian, Min Dong. Mechanistic investigation of B12-independent glycerol dehydratase and its activating enzyme GD-AE. Chemical Communications 2022, 58 (16) , 2738-2741. https://doi.org/10.1039/D1CC06991H
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    25. Benjamin J Levin, Emily P Balskus. Discovering radical-dependent enzymes in the human gut microbiota. Current Opinion in Chemical Biology 2018, 47 , 86-93. https://doi.org/10.1016/j.cbpa.2018.09.011

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