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Methyl transfer in glycine N-methyltransferase: a theoretical study
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
2005 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 109, no 16, 8216-8219 p.Article in journal (Refereed) Published
Abstract [en]

Density functional theory calculations using the hybrid functional B3LYP have been performed to study the methyl transfer step in glycine N-methyltransferase (GNMT). This enzyme catalyzes the S-adenosyl-l-methionine (SAM)-dependent methylation of glycine to form sarcosine. The starting point for the calculations is the recent X-ray crystal structure of GNMT complexed with SAM and acetate. Several quantum chemical models with different sizes, employing up to 98 atoms, were used. The calculations demonstrate that the suggested mechanism, where the methyl group is transferred in a single SN2 step, is thermodynamically plausible. By adding or eliminating various groups at the active site, it was furthermore demonstrated that hydrogen bonds to the amino group of the glycine substrate lower the reaction barrier, while hydrogen bonds to the carboxylate group raise the barrier.

Place, publisher, year, edition, pages
2005. Vol. 109, no 16, 8216-8219 p.
Keyword [en]
Carboxylation; Catalysis; Crystal structure; Functions; Molecular structure; Permittivity; X ray crystallography; Acetate molecules; Glycine; Methyl carbon; Methyl transfer
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-5570DOI: 10.1021/jp0443254ISI: 000228603700084Scopus ID: 2-s2.0-18444364203OAI: oai:DiVA.org:kth-5570DiVA: diva2:9979
Note
QC 20100727Available from: 2008-12-04 Created: 2008-12-04 Last updated: 2017-11-21Bibliographically 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
2. Modeling of methyl transfer reactions in S-Adenosyl-L-Methionine dependent enzymes
Open this publication in new window or tab >>Modeling of methyl transfer reactions in S-Adenosyl-L-Methionine dependent enzymes
2006 (English)Licentiate thesis, comprehensive summary (Other scientific)
Abstract [en]

A very important trend for studying biomolecules is computational chemistry. In particular, nowadays it is possible to use theoretical methods to figure out the catalytic mechanism of enzyme reactions. Quantum chemistry has become a powerful tool to achieve a description of biological processes in enzymes active sites and to model reaction mechanisms.

The present thesis uses Density Functional Theory (DFT) to investigate catalytic mechanism of methyltransferase enzymes. Two enzymes were studied – Glycine N-MethylTransferase (GNMT) and Guanidinoacetate Methyltransferase (GAMT). Different models of the enzyme active sites, consisting of 20 to 100 atoms, are employed. The computed energetics are compared and are used to judge the feasibility of the reaction mechanisms under investigation.

For the GNMT enzyme, the methyl transfer reaction was found to follow an SN2 reaction mechanism. The calculations demonstrate that the mechanism is thermodynamically reasonable. Based on the calculations it was concluded that hydrogen bonds to the amino group of the glycine substrate lower the reaction barrier, while hydrogen bonds to carboxylate group raise the barrier.

In the GAMT enzyme the methyl transfer reaction was found to follow a concerted asynchronous mechanism which includes transfer of a methyl group accompanied by a proton transfer taking place simultaneously in the same kinetic step. The calculated barrier agrees well with the experimental rate constant. i

Place, publisher, year, edition, pages
Stockholm: Bioteknologi, 2006. iii, 30 p.
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-3910 (URN)91-7178-289-3 (ISBN)
Presentation
2006-04-07, Sal FA32, AlbaNova, Stockholm, 09:00
Opponent
Supervisors
Note
QC 20101124Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2010-11-24Bibliographically approved

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