engleski

Modeling the Reactions Catalyzed by Coenzyme B12 Dependent Enzymes

Understanding the factors responsible for efficient catalysis is of utmost importance in our quest to harness the tremendous power that enzymes possess. Computational chemistry has emerged as an important adjunct to experimental chemistry and biochemistry in this regard, because it provides detailed insights into the relationship between structure and function in a systematic and straightforward manner. This Account highlights our recent high-level theoretical investigations towards this end, which have involved the radical-based reactions catalyzed by coenzyme B12 (AdoCbl)-dependent enzymes. In addition to their fundamental position in biology, these enzymes represent a valuable framework within which to understand nature's method of efficiently handling high-energy species to execute very specific reactions. The AdoCbl-mediated reactions are characterized by the interchange of a hydrogen atom and a functional group on adjacent carbon atoms. Our calculations are consistent with the main role of AdoCbl being to provide a source of radicals, and thus to move the 1, 2-rearrangements onto the radical potential energy surface. Next, our calculations indicate that the radical rearrangement step is facilitated by partial proton transfer involving the substrate. Specifically, we observe that the energy requirements for radical rearrangement are reduced dramatically with appropriate partial protonation or partial deprotonation or sometimes (synergistically) both. Such interactions are particularly relevant to enzyme catalysis, because it is likely that the local amino acid environment in the active site of an enzyme can function in this capacity through hydrogen bonding. Finally, our calculations indicate that the intervention of a very stable radical along the reaction pathway may inactivate the enzyme, indicating that sustained catalysis depends on a delicate energy balance. Our studies demonstrate that a small model approach of the type that we employ can provide important and revealing insights into the mechanism of action of AdoCbl-dependent enzymes.

Coenzyme B12; ab initio calculations

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