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Quantum Chemical Modeling of the Dehalogenation Reaction of Haloalcohol Dehalogenase
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
2008 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 4, no 7, 1129-1137 p.Article in journal (Refereed) Published
Abstract [en]

The dehalogenation reaction of haloalcohol dehalogenase HheC from Agrobacterium radiobacter AD1 was investigated theoretically using hybrid density functional theory methods. HheC catalyzes the enantioselective conversion of halohydrins into their corresponding epoxides. The reaction is proposed to be mediated by a catalytic Ser132-Tyr145-Arg149 triad, and a distinct halide binding site is suggested to facilitate halide displacement by stabilizing the free ion. We investigated the HheC-mediated dehalogenation of (R)-2-chloro-1-phenylethanol using three quantum chemical models of various sizes. The calculated barriers and reaction energies give support to the suggested reaction mechanism. The dehalogenation occurs in a single concerted step, in which Tyr145 abstracts a proton from the halohydrin substrate and the substrate oxyanion displaces the chloride ion, forming the epoxide. Characterization of the involved stationary points is provided. Furthermore, by using three different models of the halide binding site, we are able to assess the adopted modeling methodology.

Place, publisher, year, edition, pages
2008. Vol. 4, no 7, 1129-1137 p.
Keyword [en]
DENSITY-FUNCTIONAL THERMOCHEMISTRY; HYDROGEN-HALIDE-LYASE; HALOALKANE DEHALOGENASE; HALOHYDRIN DEHALOGENASE; REACTION-MECHANISM; AGROBACTERIUM-RADIOBACTER; MOLECULAR-ENERGIES; S(N)2 DISPLACEMENT; EPOXIDE HYDROLASE; METHYL TRANSFER
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-8106DOI: 10.1021/ct8000443ISI: 000257502800012OAI: oai:DiVA.org:kth-8106DiVA: diva2:13337
Note
QC 20100811. Uppdaterad från submitted till published (20100811).Available from: 2008-03-18 Created: 2008-03-18 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Nitrile Hydratases and Epoxide-Transforming Enzymes: Quantum Chemical Modeling of Reaction Mechanisms and Selectivities
Open this publication in new window or tab >>Nitrile Hydratases and Epoxide-Transforming Enzymes: Quantum Chemical Modeling of Reaction Mechanisms and Selectivities
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Quantum chemical studies of enzymatic reactions are able to provide detailed insight into mechanisms and catalytic strategies. The energetic feasibility of proposed mechanisms can be established, and new possible reaction pathways can be put forward. The role of the involved active site residues can be analyzed in detail and the origins for experimentally observed selectivities can be investigated. Density functional theory (DFT), in particular the hybrid functional B3LYP, is the method of choice in this kind of studies.

In this thesis, the reaction mechanisms of several enzymes have been explored using the B3LYP functional. The studied enzymes include limonene epoxide hydrolase (LEH), soluble epoxide hydrolase (sEH), haloalcohol dehalogenase (HheC), and nitrile hydratase (NHase). Transition states and intermediates along various reaction pathways were optimized and evaluated.

For the three epoxide-transforming enzymes, the role of the proposed catalytic residues could be confirmed. Analysis of in silico mutations helped to quantify the effect of various functional groups on the barriers and regioselectivities of epoxide opening. A detailed analysis of the factors governing the enzymatic regioselectivities is given.

For nitrile hydratase, various putative first- and second-shell mechanisms have been studied. Active site models based on both the Co(III)-NHase and the Fe(III)-NHase were employed. The studied mechanisms include general base-catalyzed reaction pathways with water as nucleophile as well as two pathways involving cysteine-sulfenate as nucleophile. Several computed mechanisms exhibit similar barriers, making it difficult to pinpoint the true NHase mechanism.

Place, publisher, year, edition, pages
Stockholm: KTH, 2008. x, 74 p.
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2008:1
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-4668 (URN)978-91-7178-885-6 (ISBN)
Public defence
2008-04-04, FB52, AlbaNova, Roslagstullsbacken 21, Stockholm, 10:30
Opponent
Supervisors
Note
QC 20100811Available from: 2008-03-18 Created: 2008-03-18 Last updated: 2010-08-11Bibliographically approved

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