As the principle enzyme in metabolism of the amine neurotransmitters in the brain, mitochondrial monoamine oxidase (MAO) has been implicated in numerous behavioral disorders. Definitive evidence for abnormalities in its function in relation to particular disease states is, however, yet to be established. This proposal addresses two important biochemical aspects of the problem including mechanisms of in vivo regulation of the enzyme in relation to other aspects of amine neurotransmitter function and the structural basis of differentiation between the A and B multiple forms of MAO which have different amine substrate specificities and tissue distribution. Specific lines of experimentation relative to these goals are as follows: 1) Investigation of the mechanism and in vivo significance of inhibition of the B form of MAO by the lipid, phosphatidylserine (PS) by measurement of effects on enzyme kinetic and thermodynamic parameters, studies of in situ MAO-PS binding, use of spin label spectroscopic probes to monitor changes in active site conformation and membrane fluidity, modification of inhibitor structure and addition of agents to modulate PS biosynthesis. 2) The mechanism of activation of MAO A by the lipid phosphatidylinositol will be studied using similar protocols to those for PS inhibition of the B form. 3) Effects of systematic perturbations of mitochondrial membrane fluidity on MAO A and B activity will be determined by incorporation of synthetic analogs of the major structural lipids, phosphatidylcholine and phosphatidylethanolamine with varying acyl group unsaturation and chain length. 4) Kinase mediated phosphorylation of MAO as another potential mode of regulation will be investigated in whole cell preparations. 5) Acrylamide gel electrophoresis of radiolabeled MAO after treatment with crosslinking agents will be used to study subunit structure of the enzyme. 6) Monoclonal antibodies from hybridomas raised against MAO A will be characterized as to antigenic specificity and immunoglobin type and used in investigations of the peptide structure of this form and for preparation of histochemical stains to determine its distribution in brain tissue. Results from these studies will be of importance in establishing a molecular basis for abnormalities in MAO function and in the rational design of drugs to treat disorders in which it has been implicated. Additionally, they will add to our knowledge in the more general problems of the structural features of enzyme-membrane interactions and mechanisms of regulation of amine neurotransmitter metabolism.
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