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Density functional theory study of the reaction mechanism of the DNA repairing enzyme alkylguanine alkyltransferase
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
2008 (English)In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 463, no 1-3, 214-218 p.Article in journal (Refereed) Published
Abstract [en]

The reaction mechanism of human O6-alkylguanine-DNA alkyltransferase (AGT) is studied using density functional theory. AGT repairs alkylated DNA by directly removing the alkyl group from the O6 position of the guanine. A quantum chemical model of the active site was devised based on the recent crystal structure of the AGT–DNA complex. The potential energy curve is calculated and the stationary points are characterized. It is concluded that the previously proposed reaction mechanism is energetically plausible. In this mechanism, His146 first acts as a water-mediated general base to activate Cys145, which then performs a nucleophilic attack to dealkylate the guanine base.

Place, publisher, year, edition, pages
2008. Vol. 463, no 1-3, 214-218 p.
Keyword [en]
alkylguanine alkyltransferase
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-9699DOI: 10.1016/j.cplett.2008.08.043ISI: 000259150400042Scopus ID: 2-s2.0-51349146401OAI: oai:DiVA.org:kth-9699DiVA: diva2:127000
Note
QC 20100727Available from: 2008-12-04 Created: 2008-11-27 Last updated: 2010-09-27Bibliographically approved
In thesis
1. Quantum Chemical Modeling of Enzymatic Methyl Transfer Reactions
Open this publication in new window or tab >>Quantum Chemical Modeling of Enzymatic Methyl Transfer Reactions
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, quantum chemistry, in particular the B3LYP density functional method, is used to investigate a number of methyl transfer enzymes. Quantum chemical methodology is today a very important tool in the elucidation of properties and reaction mechanisms of enzyme active sites. The enzymes considered in this thesis are the S-adenosyl L-methionine-dependent enzymes - glycine N-methyltransferase, guanidinoacetate methyltransferase, phenylethanolamine N-methyltransferase, and histone lysine methyltransferase. In addition, the reaction mechanism of the DNA repairing enzyme O6-methylguanine methyltransferase is studied. Active site models of varying sizes were designed and stationary points along the reaction paths were optimized and characterized. Potential energy surfaces for the reactions were calculated and the feasibility of the suggested reaction mechanisms was able to be judged. By systematically increasing the size of the models, deeper insight into the details of the reactions was obtained, the roles of the various active site residues could be analyzed, and, very importantly, the adopted modeling strategy was evaluated.

Place, publisher, year, edition, pages
Stockholm: KTH, 2008. ix, 51 p.
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2008:26
Keyword
reaction mechanism
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-9695 (URN)978-91-7415-171-8 (ISBN)
Public defence
2008-12-18, FB53, AlbaNova, Roslagstullsbacken 21, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20100927Available from: 2008-12-04 Created: 2008-11-27 Last updated: 2010-09-27Bibliographically approved

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