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Reaction Mechanism of the Dinuclear Zinc Enzyme N-Acyl-l-homoserine Lactone Hydrolase: A Quantum Chemical Study
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2009 (English)In: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 48, no 4, 1442-1448 p.Article in journal (Refereed) Published
Abstract [en]

N-acyl-L-homosedne lactone hydrolase (AHL lactonase) is a dinuclear zinc enzyme responsible for the hydrolytic ring opening of AHLs, disrupting quorum sensing in bacteria. The reaction mechanism is investigated using hybrid density functional theory. A model of the active site is designed on the basis of the X-ray crystal structure, and stationary points along the reaction pathway are optimized and analyzed. Two possible mechanisms based on two different substrate orientations are considered. The calculations give support to a reaction mechanism that involves two major chemical steps: nucleophilic attack on the substrate carbonyl carbon by the bridging hydroxide and ring opening by direct ester C-O bond cleavage, The roles of the two zinc ions are analyzed. Zn1 is demonstrated to stabilize the charge of the tetrahedral intermediate, thereby facilitating the nucleophilic attack, while Zn2 stabilizes the charge of the alkoxide resulting from the ring opening, thereby lowering the barrier for the C-O bond cleavage.

Place, publisher, year, edition, pages
2009. Vol. 48, no 4, 1442-1448 p.
National Category
Chemical Sciences
URN: urn:nbn:se:su:diva-43034DOI: 10.1021/ic801531nOAI: diva2:353200
Available from: 2010-09-24 Created: 2010-09-24 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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