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Quantum Chemical Modeling of Asymmetric Enzymatic Reactions
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. (Fahmi Himo)
2015 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Stockholm: Department of Organic Chemistry, Stockholm University , 2015. , s. 55
Emneord [en]
biocatalysis, enantioselectivity, density functional theory, B3LYP, enzyme, hydrolysis, decarboxylation
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
URN: urn:nbn:se:su:diva-116694ISBN: 978-91-7649-181-2 (tryckt)OAI: oai:DiVA.org:su-116694DiVA, id: diva2:807334
Disputas
2015-06-02, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 14:00 (engelsk)
Opponent
Veileder
Merknad

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript.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

 

Tilgjengelig fra: 2015-05-11 Laget: 2015-04-23 Sist oppdatert: 2022-03-01bibliografisk kontrollert
Delarbeid
1. Quantum Chemistry as a Tool in Asymmetric Biocatalysis: Limonene Epoxide Hydrolase Test Case
Åpne denne publikasjonen i ny fane eller vindu >>Quantum Chemistry as a Tool in Asymmetric Biocatalysis: Limonene Epoxide Hydrolase Test Case
2013 (engelsk)Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 52, nr 17, s. 4563-4567Artikkel i tidsskrift (Fagfellevurdert) Published
Emneord
biocatalysis, enantioselectivity, enzymes, quantum chemistry, transition states
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-90395 (URN)10.1002/anie.201300594 (DOI)000318043600008 ()
Forskningsfinansiär
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Merknad

AuthorCount:2;

Tilgjengelig fra: 2013-06-03 Laget: 2013-06-03 Sist oppdatert: 2022-02-24bibliografisk kontrollert
2. Theoretical Study of Reaction Mechanism and Stereoselectivity of Arylmalonate Decarboxylase
Åpne denne publikasjonen i ny fane eller vindu >>Theoretical Study of Reaction Mechanism and Stereoselectivity of Arylmalonate Decarboxylase
2014 (engelsk)Inngår i: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 4, nr 11, s. 4153-4160Artikkel i tidsskrift (Fagfellevurdert) 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.

Emneord
DFT, biocatalysis, enzymology, active site, enantioselectivity, transition state
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-116689 (URN)10.1021/cs5009738 (DOI)000344639300042 ()
Forskningsfinansiär
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Tilgjengelig fra: 2015-04-23 Laget: 2015-04-23 Sist oppdatert: 2022-02-23bibliografisk kontrollert
3. Quantum Chemical Modeling of Enantioconvergency in Soluble Epoxide Hydrolase
Åpne denne publikasjonen i ny fane eller vindu >>Quantum Chemical Modeling of Enantioconvergency in Soluble Epoxide Hydrolase
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-116692 (URN)
Tilgjengelig fra: 2015-04-23 Laget: 2015-04-23 Sist oppdatert: 2022-02-23bibliografisk kontrollert
4. Theoretical Study of the Reaction Mechanism of Phenolic Acid Decarboxylase
Åpne denne publikasjonen i ny fane eller vindu >>Theoretical Study of the Reaction Mechanism of Phenolic Acid Decarboxylase
(engelsk)Manuskript (preprint) (Annet vitenskapelig)
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
urn:nbn:se:su:diva-116690 (URN)
Tilgjengelig fra: 2015-04-23 Laget: 2015-04-23 Sist oppdatert: 2022-02-23bibliografisk kontrollert

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