Monoamines oxidase (MAO) is one of the enzymes responsible for the catabolism of various biogenic individuals that the concentration of various biogenic amines is diminished. Consequently, compounds that inhibit Or inactivate MAO A, the isozyme that selectively degrades norepinephrine and serotonin, exhibit antidepressant activity. Because of the importance Of maintaining a high concentration of dopamine in the brains of those afflicted with Parkinson disease, compounds that inactivate MAO B, the isozyme that degrades dopamine, are used in the treatment of Parkinson's disease.
The specific aims for this project period are (i) to design new inactivators for MAO and elucidate the inactivation mechanisms of these compounds; (2) to further investigate the mechanism of MAO; and (3) to identify, at least, some of the residues in the active site of MAO. The new inactivators include 4-methylthiobenzyl amine, 4-substituted-dihydropyridines, N-(2- methylenecyclopropyl)benzylamine, and a series of new heterocyclic potential inactivators of MAO. Mechanistic information will be obtained with the use of pyridine N-oxides as potential intramolecular radical traps, and by investigating the possible involvement of an active site disulfide in MAO-catalyzed oxidations. Active site structural information will be obtained by several approaches: with NMR studies of the active site labeled with 1-phenylcyclopropylamine and tranylcypromine; with classical peptide mapping following inactivation by several mechanism-based inactivators; with polymer-supported enzyme inactivation to obtain active site residue information more efficiently; with biotin- inactivator enzyme inactivation, again to gain active site residue information more quickly; by investigating the structure of the modified flavin using NMR and mass spectral techniques after inactivation of a new fungal monoamine oxidase, MAO N; by utilizing the structural information from MAO N to elucidate the modified flavin structures after inactivation of MAO B; and with an attempted crystal structure of MAO B. We also will investigate the stereoselectivity of ring cleavage of 1-phenylcyclobutylamine and determine the potential stereoselectivity of MAO-catalyzed oxidations in organic solvents and the use of MAO in catalyzing the oxidation of hydrophobic molecules in organic solvents.
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