Phenylethanolamine N-methyltransferase has beta-carboline 2N-methyltransferase activity: hypothetical relevance to Parkinson's disease.
Mammalian brain has a beta-carboline 2N-methyltransferase activity that converts beta-carbolines, such as norharman and harman, into 2N-methylated beta-carbolinium cations, which are structural and functional analogs of the Parkinsonian-inducing toxin 1-methyl-4-phenylpyridinium cation (MPP+). The identity and physiological function of this beta-carboline 2N-methylation activity was previously unknown. We report pharmacological and biochemical evidence that phenylethanolamine N-methyltransferase (EC 2.1.1.28) has beta-carboline 2N-methyltransferase activity. Specifically, purified phenylethanolamine N-methyltransferase (PNMT) catalyzes the 2N-methylation (21.1 pmol/h per unit PNMT) of 9-methylnorharman, but not the 9N-methylation of 2-methylnorharmanium cation. LY134046, a selective inhibitor of phenylethanolamine N-methyltransferase, inhibits (IC50 1.9 microM) the 2N-methylation of 9-methylnorharman, a substrate for beta-carboline 2N-methyltransferase. Substrates of phenylethanolamine N-methyltransferase also inhibit beta-carboline 2N-methyltransferase activity in a concentration-dependent manner. beta-Carboline 2N-methyltransferase activity (43.7pmol/h/mg protein) is present in human adrenal medulla, a tissue with high phenylethanolamine N-methyltransferase activity. We are investigating the potential role of N-methylated beta-carbolinium cations in the pathogenesis of idiopathic Parkinson's disease. Presuming that phenylethanolamine N-methyltransferase activity forms toxic 2N-methylated beta-carbolinium cations, we propose a novel hypothesis regarding Parkinson's disease-a hypothesis that includes a role for phenylethanolamine N-methyltransferase-catalyzed formation of MPP+ -like 2N-methylated beta-carbolinium cations.
Gearhart
Debra A
DA
Department of Cellular Biology and Anatomy, Veterans Affairs Medical Center, Medical College of Georgia, Augusta 30912-2000, USA. dgearhar@mail.mcg.edu
Neafsey
Edward J
EJ
Collins
Michael A
MA
D000313:Adrenal Medulla / Q000201:enzymology; D001552:Benzazepines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology*; D010625:Phenylethanolamine N-Methyltransferase / Q000378:metabolism*; D013379:Substrate Specificity
D001552:Benzazepines; D004791:Enzyme Inhibitors; C028625:LY 134046; D008780:Methyltransferases; C105799:beta-carboline-2-N-methyltransferase; D010625:Phenylethanolamine N-Methyltransferase