Monoamine oxidases A and B are localized in the outer mitochondrial membrane. Each enzyme contains an 8 alpha-S- cysteinyl FAD coenzyme and catlyzes the oxidative deamination of biogenic amines such as serotonin and dopamine which function as neurotransmitters and also functio in regulation of renal sodium reabsorption. This project seeks to achieve an understanding of their detailed catalytic mechanisms; particularly the mode of C-H bond cleavage and to use structure-functon studies to elucidate the factors important in substrate specificities for their respective catalytic sites. Using a novel yeast expression system for the human liver enzymes, the influence of riboflavin analougue structure on; a) the covalent flavin binding to the enzymes and b) the function of the coenzyme in catalysis will be investigated. Mechanistic approaches including stopped flow kinetic studies, kinetic isotope effect studies, and the influence of magnetic field on the kinetic properties will be employed to distinguish among three proposed catalytic mechanisms in the literature as well as to test whether MAO A and MAO B function via similar catalytic mechanisms. The results from these studies should provide new insights into the structures of the active sites of these two pharmacologically import enzymes which may lead to the development of improved specific inhibitors which may be useful in the clinical treatment of disorders such as depression and to potentiate L-DOPA therapy of patients with Parkinson's Disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Physical Biochemistry Study Section (PB)
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Preusch, Peter C
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Emory University
Schools of Medicine
United States
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Edmondson, Dale E (2014) Hydrogen peroxide produced by mitochondrial monoamine oxidase catalysis: biological implications. Curr Pharm Des 20:155-60
Martinoli, Christian; Dudek, Hanna M; Orru, Roberto et al. (2013) Beyond the Protein Matrix: Probing Cofactor Variants in a Baeyer-Villiger Oxygenation Reaction. ACS Catal 3:3058-3062
Orru, R; Aldeco, M; Edmondson, D E (2013) Do MAO A and MAO B utilize the same mechanism for the C-H bond cleavage step in catalysis? Evidence suggesting differing mechanisms. J Neural Transm (Vienna) 120:847-51
Binda, Claudia; Aldeco, Milagros; Mattevi, Andrea et al. (2011) Interactions of monoamine oxidases with the antiepileptic drug zonisamide: specificity of inhibition and structure of the human monoamine oxidase B complex. J Med Chem 54:909-12
Wang, Jin; Edmondson, Dale E (2011) ²H kinetic isotope effects and pH dependence of catalysis as mechanistic probes of rat monoamine oxidase A: comparisons with the human enzyme. Biochemistry 50:7710-7
Aldeco, Milagros; Arslan, Betul Kacar; Edmondson, Dale E (2011) Catalytic and inhibitor binding properties of zebrafish monoamine oxidase (zMAO): comparisons with human MAO A and MAO B. Comp Biochem Physiol B Biochem Mol Biol 159:78-83
Milczek, Erika M; Binda, Claudia; Rovida, Stefano et al. (2011) The 'gating' residues Ile199 and Tyr326 in human monoamine oxidase B function in substrate and inhibitor recognition. FEBS J 278:4860-9
Wang, Jin; Edmondson, Dale E (2011) Topological probes of monoamine oxidases A and B in rat liver mitochondria: inhibition by TEMPO-substituted pargyline analogues and inactivation by proteolysis. Biochemistry 50:2499-505
Binda, Claudia; Mattevi, Andrea; Edmondson, Dale E (2011) Structural properties of human monoamine oxidases A and B. Int Rev Neurobiol 100:1-11
Binda, Claudia; Aldeco, Milagros; Geldenhuys, Werner J et al. (2011) Molecular Insights into Human Monoamine Oxidase B Inhibition by the Glitazone Anti-Diabetes Drugs. ACS Med Chem Lett 3:39-42

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