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The reaction mechanism of phenylethanolamine N-methyltransferase: A density functional theory study
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
Department of Medicinal Chemistry, University of Michigan, Ann Arbor.
Department of Medicinal Chemistry, University of Michigan, Ann Arbor.
KTH, School of Biotechnology (BIO), Theoretical Chemistry.
2009 (English)In: Biochimica et Biophysica Acta - Proteins and Proteomics, ISSN 1570-9639, E-ISSN 1878-1454, Vol. 1794, no 12, 1831-1837 p.Article in journal (Refereed) Published
Abstract [en]

Hybrid density functional theory methods were used to investigate the reaction mechanism of human phenylethanolamine N-methyltransferase (hPNMT). This enzyme catalyzes the S-adenosyl-L-methionine-dependent conversion of norepinephrine to epinephrine, which constitutes the terminal step in the catecholamine biosynthesis. Several models of the active site were constructed based on the X-ray structure. Geometries of the stationary points along the reaction path were optimized and the reaction barrier and energy were calculated and compared to the experimental values. The calculations demonstrate that the reaction takes place via an S(N)2 mechanism with methyl transfer being rate-limiting, a suggestion supported by mutagenesis studies. Optimal agreement with experimental data is reached using a model in which both active site glutamates; are protonated. Overall, the mechanism of hPNMT is more similar to those of catechol O-methyltransferase and glycine N-methyltransferase than to that of guanidinoacetate N-methyltransferase in which methyl transfer is coupled to proton transfer.

Place, publisher, year, edition, pages
2009. Vol. 1794, no 12, 1831-1837 p.
Keyword [en]
Quantum chemistry, Enzyme mechanism, Methyl transfer, Mutagenesis, pK(a)
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-24818DOI: 10.1016/j.bbapap.2009.08.022ISI: 000271293700013Scopus ID: 2-s2.0-73049101676OAI: oai:DiVA.org:kth-24818DiVA: diva2:353456
Note
QC 20100927. Uppdaterad från manuskript till artikel (20100927).Available from: 2010-09-27 Created: 2010-09-27 Last updated: 2017-12-12Bibliographically 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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