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Nickel superoxide dismutase reaction mechanism studied by hybrid density functional methods
Stockholm University, Faculty of Science, Department of Physics.
Stockholm University, Faculty of Science, Department of Physics.
2006 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 128, no 23, 7466-7475 p.Article in journal (Refereed) Published
Abstract [en]

The reaction mechanism for the disproportionation of the toxic superoxide radical to molecular oxygen and hydrogen peroxide by the nickel-dependent superoxide dismutase (NiSOD) has been studied using the B3LYP hybrid DFT method. Based on the recent X-ray structures of the enzyme in the resting oxidized Ni(III) and X-ray-reduced Ni(II) states, the model investigated includes the backbone spacer of six residues (sequence numbers 1−6) as a structural framework. The side chains of residues His1, Cys2, and Cys6, which are essential for nickel binding and catalysis, were modeled explicitly. The catalytic cycle consists of two half-reactions, each initiated by the successive substrate approach to the metal center. The two protons necessary for the dismutation are postulated to be delivered concertedly with the superoxide radical anions. The first (reductive) phase involves Ni(III) reduction to Ni(II), and the second (oxidative) phase involves the metal reoxidation back to its resting state. The Cys2 thiolate sulfur serves as a transient protonation site in the interim between the two half-reactions, allowing for the dioxygen and hydrogen peroxide molecules to be released in the reductive and oxidative phases, respectively. The His1 side chain nitrogen and backbone amides of the active site channel are shown to be less favorable transient proton locations, as compared to the Cys2 sulfur. Comparisons are made to the Cu- and Zn-dependent SOD, studied previously using similar models.

Place, publisher, year, edition, pages
2006. Vol. 128, no 23, 7466-7475 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:su:diva-23847DOI: 10.1021/ja053665fOAI: oai:DiVA.org:su-23847DiVA: diva2:194873
Note
Part of urn:nbn:se:su:diva-513Available from: 2005-05-05 Created: 2005-05-05 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Theoretical Modeling of Enzyme Catalysis with Focus on Radical Chemistry
Open this publication in new window or tab >>Theoretical Modeling of Enzyme Catalysis with Focus on Radical Chemistry
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hybrid density functional theory (DFT) B3LYP method is applied to study the four diverse enzyme systems: zinc-containing peptidases (thermolysin and stromelysin), methyl-coenzyme M reductase, ribonucleotide reductases (classes I and III), and superoxide dismutases (Cu,Zn- and Ni-dependent enzymes). Powerfull tools of modern quantum chemistry are used to address the questions of biological pathways at their molecular level, proposing a novel mechanism for methane production by methyl-coenzyme M reductase and providing additional insights into hydrolysis by zinc peptidases, substrate conversion by ribonucleotide reductases, and biological superoxide dismutation. Catalysis by these enzymes, with the exception of zinc peptidases, involves radical chemistry.

Place, publisher, year, edition, pages
Stockholm: Fysikum, 2005. 104 p.
Keyword
density functional theory, enzyme catalysis, radical chemistry, zinc-containing peptidase, methyl-coenzyme M reductase, ribonucleotide reductase, superoxide dismutase
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:su:diva-513 (URN)91-7155-018-6 (ISBN)
Public defence
2005-05-26, sal FA32, AlbaNova universitetscentrum, Roslagstullsbacken 21, Stockholm, 10:00
Opponent
Supervisors
Available from: 2005-05-05 Created: 2005-05-05Bibliographically approved

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