期刊
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
卷 539, 期 1, 页码 1-8出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2013.08.019
关键词
Mechanism; Inhibition; Ordered sequential; Epinephrine; Adrenaline; AdoMet
资金
- National Institutes of Health [NIH HL 34193]
Phenylethanolamine N-methyltransferase (PNMT) catalyzes the conversion of norepinephrine (noradrenaline) to epinephrine (adrenaline) while, concomitantly, S-adenosyl-L-methionine (AdoMet) is converted to S-adenosyl-L-homocysteine. This reaction represents the terminal step in catecholamine biosynthesis and inhibitors of PNMT have been investigated, inter alia, as potential antihypertensive agents. At various times the kinetic mechanism of PNMT has been reported to operate by a random mechanism, an ordered mechanism in which norepinephrine binds first, and an ordered mechanism in which AdoMet binds first. Here we report the results of initial velocity studies on human PNMT in the absence and presence of product and dead end inhibitors. These, coupled with isothermal titration calorimetry and fluorescence binding experiments, clearly shown that hPNMT operates by an ordered sequential mechanism in which AdoMet binds first. Although the log V pH-profile was not well defined, plots of log V/K versus pH for AdoMet and phenylethanolamine, as well as the pK(i) versus pH for the inhibitor, SK&F 29661, were all bell-shaped indicating that a protonated and an unprotonated group are required for catalysis. (C) 2013 Elsevier Inc. All rights reserved.
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