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

Kovačević, Borislav; Borislav, Kovačević; Babić, Darko; Bilić, Luka; Hanževački, Marko; Sandala, Gregory M.; Radom, Leo; Smith, David M. (2018) Computational Tale of Two Enzymes: Glycerol Dehydration With or Without B12. Journal of the American Chemical Society, 140 (27). pp. 8487-8496. ISSN 0002-7863

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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.

Item Type: Article
Additional Information: This work was financially supported by the Croatian Science Foundation project CompSoLS-MolFlex (IP-11-2013-8238). The computational resources were provided by the University Computing Centre (SRCE), the University of Zagreb, and the Croatian National Grid Infrastructure (CRO-NGI).
Uncontrolled Keywords: B12 dependent GDH. B12 independent GDH; QM/MM; mechanism of catalysis
Subjects: NATURAL SCIENCES > Chemistry > Theoretical Chemistry
Divisions: Division of Physical Chemistry
Project titleProject leaderProject codeProject type
Računalna rješenja u bioznanostima: Značaj savitljivosti molekula-CompSoLS-MolFlexDavid SmithIP-2013-11-8238HRZZ
Depositing User: Borislav Kovačević
Date Deposited: 25 Nov 2019 07:41
DOI: 10.1021/jacs.8b03109

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