期刊
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
卷 1794, 期 12, 页码 1831-1837出版社
ELSEVIER
DOI: 10.1016/j.bbapap.2009.08.022
关键词
Quantum chemistry; Enzyme mechanism; Methyl transfer; Mutagenesis; pK(a)
资金
- The Swedish Research Council
- The Wenner-Gren Foundations
- The Carl Trygger Foundation
- The Magn Bergvall Foundation
- National Institutes of Health [RO1 HL34193]
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. (C) 2009 Elsevier B.V. All rights reserved.
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