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Theoretical study of the RNA hydrolysis mechanism of the dinuclear zinc enzyme RNase Z
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2009 (English)In: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-0682, Vol. 2009, no 20, 2967-2972 p.Article in journal (Refereed) Published
Abstract [en]

RNase Z is a dinuclear zinc enzyme that catalyzes the removal of the tRNA 3'-end trailer. Density functional theory is used to investigate the phosphodiester hydrolysis mechanism of this enzyme with a model of the active site constructed on the basis of the crystal structure. The calculations imply that the reaction proceeds through two steps. The first step is a nucleophihc attack by a bridging hydroxide coupled with protonation of the leaving group by a Glu-His diad. Subsequently, a water molecule activated by the same Glu-His diad makes a reverse attack, regenerating the bridging hydroxide. The second step is calculated to be the rate-limiting step with a barrier of 18 kcal/mol, in good agreement with experimental kinetic studies. Both zinc ions participate in substrate binding and orientation, facilitating nucleophilic attack. In addition, they act as electrophilic catalysts to stabilize the pentacoordinate trigonal-bipyramidal transition states.

Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA , 2009. Vol. 2009, no 20, 2967-2972 p.
Keyword [en]
Enzyme catalysis; Metalloenzymes; Dinuclear zinc enzymes; Density functional calculations; Hydrolysis; Reaction mechanisms; Zinc
National Category
Other Basic Medicine
URN: urn:nbn:se:su:diva-31365DOI: 10.1002/ejic.200900202ISI: 000268290000010OAI: diva2:276197
Available from: 2009-11-11 Created: 2009-11-11 Last updated: 2010-10-01Bibliographically approved
In thesis
1. Quantum Chemical Cluster Modeling of Enzymatic Reactions
Open this publication in new window or tab >>Quantum Chemical Cluster Modeling of Enzymatic Reactions
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The Quantum chemical cluster approach has been shown to be quite powerful and efficient in the modeling of enzyme active sites and reaction mechanisms. In this thesis, the reaction mechanisms of several enzymes have been investigated using the hybrid density functional B3LYP. The enzymes studied include four dinuclear zinc enzymes, namely dihydroorotase, N-acyl-homoserine lactone hydrolase, RNase Z, and human renal dipeptidase, two trinuclear zinc enzymes, namely phospholipase C and nuclease P1, two tungstoenzymes, namely formaldehyde ferredoxin oxidoreductase and acetylene hydratase, aspartate α-decarboxylase, and mycolic acid cyclopropane synthase. The potential energy profiles for various mechanistic scenarios have been calculated and analyzed. The role of the metal ions as well as important active site residues has been discussed.

  In the cluster approach, the effects of the parts of the enzyme that are not explicitly included in the model are taken into account using implicit solvation methods.

  For all six zinc-dependent enzymes studied, the di-zinc bridging hydroxide has been shown to be capable of performing nucleophilic attack on the substrate. In addition, one, two, or even all three zinc ions participate in the stabilization of the negative charge in the transition states and intermediates, thereby lowering the barriers.

  For the two tungstoenzymes, several different mechanistic scenarios have been considered to identify the energetically most feasible one. For both enzymes, new mechanisms are proposed.

  Finally, the mechanism of mycolic acid cyclopropane synthase has been shown to be a direct methyl transfer to the substrate double bond, followed by proton transfer to the bicarbonate.

  From the studies of these enzymes, we demonstrate that density functional calculations are able to solve mechanistic problems related to enzymatic reactions, and a wealth of new insight can be obtained.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2010. 76 p.
cluster approach, density functional theory, B3LYP, enzyme, mechanism, dinuclear, trinuclear, zinc, tungsten, hydrolysis, decarboxylation, formaldehyde oxidation, hydration, methyl transfer
National Category
Theoretical Chemistry
Research subject
Organic Chemistry
urn:nbn:se:su:diva-43026 (URN)978-91-7447-129-8 (ISBN)
Public defence
2010-10-27, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Available from: 2010-10-05 Created: 2010-09-24 Last updated: 2010-10-07Bibliographically approved

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Liao, Rong-ZhenHimo, Fahmi
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