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Theoretical study of the methyl transfer in guanidinoacetate methyltransferase
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
2006 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 110, no 1, 16-19 p.Article in journal (Refereed) Published
Abstract [en]

The reaction mechanism of the guanidinoacetate methyltransferase (GAMT) enzyme has been investigated by means of density functional theory using the B3LYP hybrid functional. GAMT catalyzes the S-adenosyl-l-methionine (SAM)-dependent methylation of guanidinoacetate (GAA) to form creatine. A quantum chemical model was built on the basis of the recent crystal structure of GAMT complexed with S-adenosylhomocysteine (SAH) and GAA. The methyl group transfer from SAM to NE of GAA is shown to occur concertedly with a proton transfer from NE to the neighboring OD1 of Asp134. Good agreement is found between the calculated barrier and the experimental rate.

Place, publisher, year, edition, pages
2006. Vol. 110, no 1, 16-19 p.
Keyword [en]
Catalysis; Crystal structure; Enzymes; Hybrid computers; Probability density function; Propylene; Structural analysis; Creatine; Guanidinoacetate methyltransferase; Methylation; S-adenosylhomocysteine (SAH)
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-5571DOI: 10.1021/jp055120dISI: 000234520700006OAI: oai:DiVA.org:kth-5571DiVA: diva2:9980
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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