Studies toward the development of monoamine oxidase B specific inhibitors

Emory University, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): Monoamine oxidases A and B (MAO A and MAO B) are outer mitochondria bound flavoproteins responsible for the oxidative metabolism of biogenic amine neurotransmitters as well as dietary amines which prevent the latter from behaving as false neurotransmitters. Catalysis is accomplished through amine oxidation to the corresponding aldehyde. These two enzymes differ in their substrate specificities, however MAO A and MAO B share about 72% sequence identity. Because the catalytic function of the two isoforms are similar in nature, the structure of the substrate cavity is responsible for the observed specificity. As a result of the determination of a high resolution crystal structure of MAO B, a gating residue has been identified that is unique to MAO B revealing a potential mechanism for MAO B substrate selection. This finding is of particular interest due to the development of selective inhibitors for MAO B as a target for drug therapy for prevention of neurodegenerative disorders. Specifically, the two most common neurodegenerative disorders in the western world are Alzheimer's disease and Parkinson's disease. The pathological hallmarks of these diseases are the loss of neurons in either the cortex and hippocampus (Alzheimer's disease) or the substantia nigra (Parkinson's disease). It is known that the age-related increase in MAO B levels in neuronal tissue together with the catalytic production of hydrogen peroxide (leading to reactive oxygen species) contributes to cellular apoptosis and subsequent neurodegeneration. Therefore, the purpose of this project is to explore the structure/function relationships of MAO B by identifying amino acid residues responsible for its substrate specificity and designing specific inhibitors that target the enzyme as neuroprotecting agents. The project goal will be realized though: Specific Aim 1. the determination of the role of the lle-199 residue unique to MAO B;Specific Aim 2. the elucidation of the mechanism of inhibition of MAO B with a nanomolar inhibitor, mofegiline (MDL 72.974A). PUBLIC HEALTH RELEVANCE The goal of this project is to explore the structure/function relationship of the enzyme, monoamine oxidase B, by identifying amino acid residues responsible for substrate specificity and designing inhibitors that target these amino acid residues for their applications as neuroprotecting agents for the treatment of Parkinson's disease and Alzheimer's disease.