A density functional theory study on the role of His-107 in arylamine N-acetyltransferase 2 acetylation

Biophysical Chemistry
Qing-An QiaoZhongxi Yu

Abstract

Arylamine N-acetyltransferases (NATs, EC 2.3.1.5) catalyze an acetyl group transfer from acetyl coenzyme A (AcCoA) to primary arylamines, and are responsible for the biotransformation and metabolism of drugs, carcinogens, etc. Structure analysis revealed that His-107 was likely the residue accountable for mediating acetyl transfer. We have examined the full catalytic mechanism of this system by means of DFT method. The results indicate that if the acetyl group directly transferred from the donor, p-nitrophenyl acetate, to the acceptor, cysteine, the high activation energy will be a great hindrance. These energies have dropped a little in a range of 20-25 kJ/mol when His-107 is assisting the transfer process. However, when protonated His-107 is mediating the reaction, the activation energies have dropped about 70-85 kJ/mol. Our calculations strongly support an enzymatic acetylation mechanism that experiences a thiolate-imidazolium pair, which have verified the presumption from experiments.

References

Jun 22, 2000·Pharmacogenetics·D W HeinE Sim
Jul 6, 2000·Nature Structural Biology·J C SinclairM E Noble
Mar 10, 2001·Trends in Pharmacological Sciences·A UptonE Sim
Oct 18, 2001·Journal of the American Chemical Society·F Himo, P E Siegbahn
May 5, 2005·Proceedings of the National Academy of Sciences of the United States of America·Richard A Friesner
Aug 17, 2005·Biochemistry·Haiqing WangCarston R Wagner

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Citations

Apr 13, 2007·Expert Opinion on Drug Metabolism & Toxicology·Edith SimElizabeth Fullam
Feb 14, 2014·The Journal of Physical Chemistry. B·Xinlei ZhangCheng Luo

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