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Theoretical Insights into the enzymatic reaction mechanisms of dehydratases and dehalogenases

Theoretical Insights into the enzymatic reaction mechanisms of dehydratases and dehalogenases

Datum: 13. Juli 2017 16:00

Ort: Allmandring 3, Seminarraum 1.079

Veranstalter: ICP

Theoretical Insights into the enzymatic reaction mechanisms of dehydratases and dehalogenases

Sebastián Miranda-Rojas, Universidad Andrés Bello, Santiago Chile

Enzymes are macromolecular systems capable of performing fascinating chemical transformations that otherwise would be difficult or even impossible. These molecular machines are the main responsible of life, and their continuous understanding has leaded towards the design of new promising devises in fields such as remediation, chemical catalysis, energy conversion, biosensors among others.

We propose to uncover the main factors that govern the mechanisms by which two very different enzymes are able to perform difficult chemical transformations. 

The first case corresponds to fluoroacetate dehalogenase (FAcD), an enzyme capable of removing a fluorine atom from fluoroacetate (FAc). This represents a challenging process as the carbon fluorine (C-F) bond is the strongest carbon-halogen bond found in nature. To achieve this task, it proceeds by an initial concerted nucleophilic substitution (SN 2) reaction that eliminates the fluorine atom as fluoride, followed by a hydrolysis reaction to release the product.

The understanding of the first elementary step of this reaction provides useful insights for the design of new methods for the remediation of sewage water by eliminating the fluorinated compounds. The reaction mechanism was analyzed in terms of structural and electronic processes aiming to define the role of the catalytic site. Together with this, we shed light into the nature of the selectivity mechanism towards fluoroacetate over chloroacetate.

The second case of study corresponds to (R)-2-Hydroxyisocaproyl-CoA dehydratase, a radical enzyme that uses an iron-sulfur cluster as a cofactor. This enzyme catalyzes an atypical dehydration that could be useful to obtain very difficult molecular targets associated to the pharmaceutical industry, that otherwise would need several steps in their synthesis, increasing the costs of the process. This particular enzyme catalyzes the transformation of hydroxyisocaproyl-CoA to isocaprenoyl-CoA. The first step of the reaction involves an electron transfer towards the substrate, which initiates the transformation through radical intermediates.

We aim to present a complete machanistic proposal for this complex chemical transformation, exploring the role that these radical intermediates have in the catalysis, which at this date is not fully understood.

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