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A QM/MM Investigation of the Catalytic Mechanism of Coenzyme B12-Independent Glycerol Dehydratase

The coenzyme B12-independent glycerol dehydratase (GDH) catalyzes the dehydration of glycerol (1) to give the 3-hydroxy-propanal (2). This reaction is analogous to those catalyzed by the coenzyme B12-dependent enzymes GDH and diol dehydratase in that the mechanism proceeds via radical intermediates. In the present system, however, a thiyl radical, derived from an active site cysteine residue, is utilized to initiate substrate catalysis via an initial H-atom abstraction. Recently, GDH has been characterized by biochemical and crystallographic methods[1, 2], though an extensive mechanistic analysis of the conversion of 1 to 2 has yet to be performed. We seek to address this issue in the present work. To do so, QM/MM calculations have been performed in order to characterize distinct pathways for the dehydratation reaction of 1 to 2. The key step in this reaction is believed to be a 1, 2-hydroxyl migration, generating a 1, 1-diol which can then eliminate water either before or after the final H-atom abstraction. Interestingly, we have found that the 1, 2-hydroxyl migration does not occur in B12-independent GDH. Instead, water is lost directly from the reactant radical, giving the aldehyde radical, which then abstracts an H-atom from the sulfur to form the product aldehyde.

B12-independent dehydration; glycerol; QM/MM calculations

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