Humans coordinate their movement and behavior through chemical signalling systems. The most advanced of these is the central nervous system (CNS) which utilizes a spectrum of biogenic amines, such as serotonin, noradrenaline, and dopamine, as specific neurotransmitters. Neurotransmitter level in the brain high highly regulated, mainly through three routes: by their synthesis, transport and ultimately, degradation. Monoamine oxidases (MAOs) are the key enzymes in the human brain that provide the catabolic regulation of the signaling amines. MAOs hold a powerful attraction for biochemists, pharmacologists and neurologists. Conventional treatment of numerous human neurological disorders such as mental depression, parkinsonism, and Alzheimer's disease is based on using specific inhibitors of MAOs. Little is known, though, about the molecular mechanism of catalysis by MAOs, or the structural determinants definition the substrate and the inhibitor specificity of these enzymes. The goal of this proposal is to create a structural basis for understanding of the molecular mechanism of monoamine oxidases; to define the structural determinants of the substrate and inhibitor specificity of human MAO and B types using MAON, a homolog that is closely related to human MAO A and B.
