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Dipeptide hydrolysis by the dinuclear zinc enzyme human renal dipeptidase: Mechanistic insights from DFT calculations
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2010 (English)In: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 104, no 1, 37-46 p.Article in journal (Refereed) Published
Abstract [en]

The reaction mechanism of the dinuclear zinc enzyme human renal dipeptidase is investigated using hybrid density functional theory. This enzyme catalyzes the hydrolysis of dipeptides and beta-lactam antibiotics. Two different protonation states in which the important active site residue Asp288 is either neutral or ionized were considered. In both cases, the bridging hydroxide is shown to be capable of performing the nucleophilic attack on the substrate carbonyl carbon from its bridging position, resulting in the formation of a tetrahedral intermediate. This step is followed by protonation of the dipeptide nitrogen, coupled with C-N bond cleavage. The calculations establish that both cases have quite feasible energy barriers. When the Asp288 is neutral, the hydrolytic reaction occurs with a large exothermicity. However, the reaction becomes very close to thermoneutral with an ionized Asp288. The two zinc ions are shown to play different roles in the reaction. Zn1 binds the amino group of the substrate, and Zn2 interacts with the carboxylate group of the substrate, helping in orienting it for the nucleophilic attack. In addition, Zn2 stabilizes the oxyanion of the tetrahedral intermediate, thereby facilitating the nucleophilic attack

Place, publisher, year, edition, pages
2010. Vol. 104, no 1, 37-46 p.
Keyword [en]
Dipeptidase; Dinuclear zinc enzymes; Reaction mechanism; Density functional theory
National Category
Chemical Sciences
URN: urn:nbn:se:su:diva-43035DOI: 10.1016/j.jinorgbio.2009.09.025ISI: 000272417300005OAI: diva2:353203
Available from: 2010-09-24 Created: 2010-09-24 Last updated: 2011-11-23Bibliographically 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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