Bioactivation of Azaheterocyclic Amines via S-Adenosyl-L-Methionine-Dependent N-Methyltransferases

  • Kazuo Matsubara
Chapter

Abstract

In this chapter, I focus on the N-methyltransferases capable of catalyzing S-adenosyl-l-methionine (SAM)-dependent methylation of azaheterocyclic amines, and on their substrates underlying neurodegenerative disease. Epidemiological studies indicate that idiopathic Parkinson’s disease is associated with certain environmental factors, such as early exposure to rural life (Rajput et al., 1987; Koller et al., 1990; Morano et al., 1994), drinking water from rural wells (Rajput et al., 1987; Morano et al., 1994), and exposure to certain pesticides (Semchuk et al., 1993; Fleming et al., 1994; Seidler et al., 1996), wood preservatives (Seidler et al., 1996) and industrial toxicants (Tanner and Langston, 1990). The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) opened the possibility that Parkinson’s disease may be initiated or precipitated by environmental or endogenous toxins with a structure similar to MPTP, acting in genetically-predisposed individuals. Since several N-methylated azaheterocyclic amines are known to be toxic, the question is whether azaheterocyclics can be bioactivated by N-methyltransferases in vivo and in vitro. In particular, indoleamine-related β-carbolines (βCs), catecholamine-derived tetrahydroisoquinolines (6,7-DHTIQs) and phenethylamine-derived tetrahydroisoquinolines (TIQs) are of interest as endogenous MPTP-like toxins or protoxins. These substances are N-methylated directly or following oxidation to quaternary amines, structurally related to 1-methyl-4-phenylpyridinium (MPP+).

Keywords

Nicotinic Acid Biogenic Amine Methyl Donor Parkinsonian Patient Heterocyclic Amine 
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© Springer Science+Business Media New York 1998

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  • Kazuo Matsubara

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