Phenylethanolamine N-methyltransferase has β-carboline 2N-methyltransferase activity: hypothetical relevance to Parkinson’s disease
| Autor: | Debra A. Gearhart, Michael A. Collins, Edward J. Neafsey |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Methyltransferase
medicine.disease_cause Substrate Specificity Pathogenesis Cellular and Molecular Neuroscience chemistry.chemical_compound medicine Humans Enzyme Inhibitors chemistry.chemical_classification Toxin Chemistry Phenylethanolamine N-Methyltransferase Parkinson Disease Methyltransferases Cell Biology Methylation Benzazepines Molecular biology Phenylethanolamine N-methyltransferase Phenylethanolamine medicine.anatomical_structure Enzyme Biochemistry Adrenal Medulla Adrenal medulla |
| Zdroj: | Neurochemistry International. 40:611-620 |
| ISSN: | 0197-0186 |
| DOI: | 10.1016/s0197-0186(01)00115-2 |
| Popis: | Mammalian brain has a β-carboline 2 N -methyltransferase activity that converts β-carbolines, such as norharman and harman, into 2 N -methylated β-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 β-carboline 2 N -methylation activity was previously unknown. We report pharmacological and biochemical evidence that phenylethanolamine N -methyltransferase (EC 2.1.1.28) has β-carboline 2 N -methyltransferase activity. Specifically, purified phenylethanolamine N -methyltransferase (PNMT) catalyzes the 2 N -methylation (21.1 pmol/h per unit PNMT) of 9-methylnorharman, but not the 9 N -methylation of 2-methylnorharmanium cation. LY134046, a selective inhibitor of phenylethanolamine N -methyltransferase, inhibits (IC 50 1.9 μM) the 2 N -methylation of 9-methylnorharman, a substrate for β-carboline 2 N -methyltransferase. Substrates of phenylethanolamine N -methyltransferase also inhibit β-carboline 2 N -methyltransferase activity in a concentration-dependent manner. β-Carboline 2 N -methyltransferase activity (43.7 pmol/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 β-carbolinium cations in the pathogenesis of idiopathic Parkinson’s disease. Presuming that phenylethanolamine N -methyltransferase activity forms toxic 2 N -methylated β-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 2 N -methylated β-carbolinium cations. |
| Databáze: | OpenAIRE |
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