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Quantum Chemical Modeling of Asymmetric Enzymatic Reactions
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Fahmi Himo)
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Computational methods are very useful tools in the study of enzymatic reactions, as they can provide a detailed understanding of reaction mechanisms and the sources of various selectivities. In this thesis, density functional theory has been employed to examine four different enzymes of potential importance for biocatalytic applications. The enzymes considered are limonene epoxide hydrolase, soluble epoxide hydrolase, arylmalonate decarboxylase and phenolic acid decarboxylase. Besides the reaction mechanisms, the enantioselectivities in three of these enzymes have also been investigated in detail. In all studies, quite large quantum chemical cluster models of the active sites have been used. In particular, the models have to account for the chiral environment of the active site in order to reproduce and rationalize the experimentally observed selectivities.

For both epoxide hydrolases, the calculated enantioselectivities are in good agreement with experiments. In addition, explanations for the change in stereochemical outcome for the mutants of limonene epoxide hydrolase, and for the observed enantioconvergency in the soluble epoxide hydrolase are presented.

The reaction mechanisms of the two decarboxylases are found to involve the formation of an enediolate- or a quinone methide intermediate, supporting thus the main features of the proposed mechanisms in both cases. For arylmalonate decarboxylase, an explanation for the observed enantioselectivity is also presented.

In addition to the obtained chemical insights, the results presented in this thesis demonstrate that the quantum chemical cluster approach is indeed a valuable tool in the field of asymmetric biocatalysis.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2015. , 55 p.
Keyword [en]
biocatalysis, enantioselectivity, density functional theory, B3LYP, enzyme, hydrolysis, decarboxylation
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-116694ISBN: 978-91-7649-181-2 (print)OAI: oai:DiVA.org:su-116694DiVA: diva2:807334
Public defence
2015-06-02, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 14:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.

 

Available from: 2015-05-11 Created: 2015-04-23 Last updated: 2015-06-11Bibliographically approved
List of papers
1. Quantum Chemistry as a Tool in Asymmetric Biocatalysis: Limonene Epoxide Hydrolase Test Case
Open this publication in new window or tab >>Quantum Chemistry as a Tool in Asymmetric Biocatalysis: Limonene Epoxide Hydrolase Test Case
2013 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 52, no 17, 4563-4567 p.Article in journal (Refereed) Published
Keyword
biocatalysis, enantioselectivity, enzymes, quantum chemistry, transition states
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-90395 (URN)10.1002/anie.201300594 (DOI)000318043600008 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Note

AuthorCount:2;

Available from: 2013-06-03 Created: 2013-06-03 Last updated: 2017-12-06Bibliographically approved
2. Theoretical Study of Reaction Mechanism and Stereoselectivity of Arylmalonate Decarboxylase
Open this publication in new window or tab >>Theoretical Study of Reaction Mechanism and Stereoselectivity of Arylmalonate Decarboxylase
2014 (English)In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 4, no 11, 4153-4160 p.Article in journal (Refereed) Published
Abstract [en]

The reaction mechanism of arylmalonate decarboxylase is investigated using density functional theory calculations. This enzyme catalyzes the asymmetric decarboxylation of prochiral disubstituted malonic acids to yield the corresponding enantiopure carboxylic acids. The quantum chemical cluster approach is employed, and two different models of the active site are designed: a small one to study the mechanism and characterize the stationary points and a large one to study the enantioselectivity. The reactions of both α-methyl-α-phenylmalonate and α-methyl-α-vinylmalonate are considered, and different substrate binding modes are assessed. The calculations overall give strong support to the suggested mechanism in which decarboxylation of the substrate first takes place, followed by a stereoselective protonation by a cysteine residue. The enediolate intermediate and the transition states are stabilized by a number of hydrogen bonds that make up the dioxyanion hole, resulting in feasible energy barriers. It is further demonstrated that the enantioselectivity in the case of α-methyl-α-phenylmalonate substrate is dictated already in the substrate binding, because only one binding mode is energetically accessible, whereas in the case of the smaller α-methyl-α-vinylmalonate substrate, both the binding and the following transition states contribute to the enantioselectivity.

Keyword
DFT, biocatalysis, enzymology, active site, enantioselectivity, transition state
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-116689 (URN)10.1021/cs5009738 (DOI)000344639300042 ()
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2015-04-23 Created: 2015-04-23 Last updated: 2017-12-04Bibliographically approved
3. Quantum Chemical Modeling of Enantioconvergency in Soluble Epoxide Hydrolase
Open this publication in new window or tab >>Quantum Chemical Modeling of Enantioconvergency in Soluble Epoxide Hydrolase
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-116692 (URN)
Available from: 2015-04-23 Created: 2015-04-23 Last updated: 2016-01-29Bibliographically approved
4. Theoretical Study of the Reaction Mechanism of Phenolic Acid Decarboxylase
Open this publication in new window or tab >>Theoretical Study of the Reaction Mechanism of Phenolic Acid Decarboxylase
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-116690 (URN)
Available from: 2015-04-23 Created: 2015-04-23 Last updated: 2016-01-29Bibliographically approved

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