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Modeling of methyl transfer reactions in S-Adenosyl-L-Methionine dependent enzymes
KTH, School of Biotechnology (BIO).
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: urn:nbn:se:kth:diva-3910ISBN: 91-7178-289-3 (print)OAI: oai:DiVA.org:kth-3910DiVA: diva2:9981
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
List of papers
1. Methyl transfer in glycine N-methyltransferase: a theoretical study
Open this publication in new window or tab >>Methyl transfer in glycine N-methyltransferase: a theoretical study
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.

Keyword
Carboxylation; Catalysis; Crystal structure; Functions; Molecular structure; Permittivity; X ray crystallography; Acetate molecules; Glycine; Methyl carbon; Methyl transfer
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-5570 (URN)10.1021/jp0443254 (DOI)000228603700084 ()2-s2.0-18444364203 (Scopus ID)
Note
QC 20100727Available from: 2008-12-04 Created: 2008-12-04 Last updated: 2017-11-21Bibliographically approved
2. Theoretical study of the methyl transfer in guanidinoacetate methyltransferase
Open this publication in new window or tab >>Theoretical study of the methyl transfer in guanidinoacetate methyltransferase
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.

Keyword
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:nbn:se:kth:diva-5571 (URN)10.1021/jp055120d (DOI)000234520700006 ()
Note
QC 20100727Available from: 2008-12-04 Created: 2008-12-04 Last updated: 2017-11-21Bibliographically approved

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