Investigation of FAD Chemical Models to Study the Monoamine Oxidase Catalyzed Oxidation of Cyclic Tertiary-Allylamines

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Virginia Tech

Flavin adenine dinucleotide (FAD) is a coenzyme that participates in the redox process of flavoenzymes. Attempts to characterize the catalytic pathways of these enzymes have relied in part on the use of FAD chemical models. The efforts described in this dissertation focus on the chemical model approach to investigate the mechanism of the monoamine oxidase (MAO) catalyzed oxidation of the cyclic tertiary allylamine 1-methyl-4-(2-methyl-1H-pyrrol-2-yl)-1,2,3,6-tetrahydropyridine (TMMP), which is a close analog of the parkinsonian-inducing designer drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MAO-B catalyzes the conversion of MPTP and its derivatives into active neurotoxins in the brain that subsequently mediate neurogenerative processes that mimic the events leading to idiopathic Parkinson's disease. Monoamine oxidase inhibitors are currently used to treat early stages of Parkinson's disease. Two FAD chemical models are examined in this project: 5-ethyl-3-methyllumiflavinium perchlorate (5Et3MLF+ClO4-) and 3-methyllumiflavin (3MLF). The flavinium salt 5Et3MLF+ClO4- is an activated form of 3MLF.

These FAD chemical models have been used to examine the MAO catalyzed oxidation. MAO-B is expressed in the brain and is known to be involved in the conversion of TMMP into the neurotoxic metabolite 1-methyl-4-phenyl pyridnium (MMP+). MAO-B is responsible for the alpha-carbon oxidation of TMMP to yield 1-methyl-4-(2-methylpyrrol-2-yl)-2,3-dihydropyridinium (DHP+), which then undergoes a second 2-electron oxidation to MMP+. Previous findings demonstrated that 3MLF and 5Et3MLF+ClO4- promoted the oxidation reaction of primary and secondary amines but not tertiary amines. However, the cyclic tertiary allylamine TMMP has not been examined experimentally. Therefore, the alpha-carbon oxidation of TMMP in the presence of the FAD chemical models is reported in this dissertation. The effect of dioxygen and water on the activity of these FAD models is also investigated.

single electron transfer, FAD chemical model, monoamine oxidase, cyclic tertiary-allylamine, Parkinson's disease