The pathological neurodegenerative hallmark of Parkinson’s Disease (PD) is the selective loss of nigrostriatal neurons and the resulting depletion of the catecholaminyl neurotransmitter dopamine. The flavoenzyme monoamine oxidase-B (MAO-B) catalyzes the a-carbon oxidation of multiple aminyl neurotransmitters, including dopamine. MAO-B also catalyzes the oxidative bioactivation of the nigrostriatal neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP (1)] in humans and susceptible animal models. This transformation leads to the dihydropyridiniumyl intermediate 2+ that undergoes a second 2-electron oxidation to the ultimate neurotoxin, the pyridiniumyl metabolite 3+. Past studies have not provided a definitive mechanistic pathway to account for the conversion of 1 to 2+. The aim of the present study was to examine the corresponding MAO-B catalyzed a-carbon oxidation of the MPTP analog 1-methyl-4-(1-methyl-1H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (4) using 5-ethyl-3-methyllumiflavinium perchlorate (4), a chemical model for the MAO-B cofactor FAD and an efficient oxidant for the conversion of 5 to the corresponding dihydropyridiniumyl product 6+. Evidence will be presented to document the role of dioxygen on this reaction. Also, the fate of the flaviniumyl species 4 will be considered.

Mechanistic studies on the monoamine oxidase-B catalyzed oxidation of a cyclic tertiary allylamine analog of MPTP using a flavin chemical model

255th National Meeting (2018)

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