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Insights from Quantum Chemical Calculations into Active Site Structure and Reaction Mechanism of Manganese-Dependent Dinitrogenase Reductase-Activating Glycohydrolase
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
(English)Manuscript (preprint) (Other academic)
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-141319OAI: oai:DiVA.org:su-141319DiVA: diva2:1086636
Available from: 2017-04-03 Created: 2017-04-03 Last updated: 2017-04-03Bibliographically approved
In thesis
1. Quantum Chemical Studies of Enzymatic Reaction Mechanisms
Open this publication in new window or tab >>Quantum Chemical Studies of Enzymatic Reaction Mechanisms
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Computer modeling of enzymes is a valuable complement to experiments. Quantum chemical studies of enzymatic reactions can provide a detailed description of the reaction mechanism and elucidate the roles of various residues in the active site. Different reaction pathways can be analyzed, and their feasibility be established based on calculated energy barriers.

In the present thesis, density functional theory has been used to study the active sites and reaction mechanisms of three different enzymes, cytosine deaminase (CDA) from Escherichia coli, ω-transaminase from Chromobacterium violaceum (Cv-ωTA) and dinitrogenase reductase-activating glycohydrolase (DraG) from Rhodospirillum rubrum. The cluster approach has been employed to design models of the active sites based on available crystal structures. The geometries and energies of transition states and intermediates along various reaction pathways have been calculated, and used to construct the energy graphs of the reactions.

In the study of CDA (Paper I), two different tautomers of a histidine residue were considered. The obtained reaction mechanism was found to support the main features of the previously proposed mechanism. The sequence of the events was established, and the residues needed for the proton transfer steps were elucidated.

In the study of Cv-ωTA (Paper II and Paper III), two active site models were employed to study the conversion of two different substrates, a hydrophobic amine and an amino acid. Differences and similarities in the reaction mechanisms of the two substrates were established, and the role of an arginine residue in the dual substrate recognition was confirmed.

In the study of DraG (Paper IV), two different substrate-binding modes and two different protonation states of an aspartate residue were considered. The coordination of the first-shell ligands and the substrate to the two manganese ions in the active site was characterized, and a possible proton donor in the first step of the proposed reaction mechanism was identified.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2017. 64 p.
Keyword
density functional theory, B3LYP, enzyme, cluster approach, mechanism, zinc, manganese, cytosine deaminase, ω-transaminase, dinitrogenase reductase-activating glycohydrolase, dual substrate recognition
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-141321 (URN)978-91-7649-764-7 (ISBN)978-91-7649-765-4 (ISBN)
Public defence
2017-05-23, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 14:00 (English)
Opponent
Supervisors
Note

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

Available from: 2017-04-27 Created: 2017-04-03 Last updated: 2017-04-27Bibliographically approved

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