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Methyl transfer in glycine N-methyltransferase. A theoretical study
Polina Velichkova1, Fahmi Himo
1Theoretical Chemistry, Department of Biotechnology, Royal Institute of Technology, Albanova University Center, SE-106 91 Stockholm, Sweden.
The Journal of Physical Chemistry. B
|July 21, 2006
Summary
Density functional theory calculations reveal the methyl transfer step in glycine N-methyltransferase (GNMT) is thermodynamically plausible. Hydrogen bonds to the glycine substrate
Area of Science:
- Biochemistry
- Computational Chemistry
- Enzymology
Background:
- Glycine N-methyltransferase (GNMT) is crucial for methylation processes.
- The enzyme utilizes S-adenosyl-L-methionine (SAM) to methylate glycine into sarcosine.
- Understanding the methyl transfer mechanism is key to enzyme function.
Purpose of the Study:
- To investigate the mechanism of the methyl transfer step in GNMT.
- To assess the thermodynamic plausibility of the proposed S(N)2 reaction pathway.
- To explore the role of active site interactions, specifically hydrogen bonds, on the reaction barrier.
Main Methods:
- Density functional theory (DFT) calculations were employed.
- The hybrid functional B3LYP was utilized for the computations.
- Quantum chemical models of varying sizes, up to 98 atoms, were constructed based on X-ray crystal structures.
Main Results:
- The methyl transfer step via an S(N)2 mechanism is thermodynamically plausible.
- Hydrogen bonds to the glycine substrate's amino group reduce the reaction barrier.
- Hydrogen bonds to the carboxylate group increase the reaction barrier.
Conclusions:
- The study supports a single-step S(N)2 mechanism for methyl transfer in GNMT.
- Active site hydrogen bonding significantly influences the enzyme's catalytic efficiency.
- Computational insights provide a deeper understanding of GNMT's enzymatic activity.
