Our research group is interested in determining the molecular properties of certain proteins in the nervous system and applying the results of these studies to Parkinson's Disease, Alzheimer's Disease and aging. In particular, our work focuses on the characterization of monoamine oxidase A and B (MAO A and B), enzymes that play a vital role in the metabolism of biogenic amines in the CNS and in peripheral tissues. MAO B is believed to be linked to idiopathic Parkinson's disease, and both enzymes have been implicated in other neurologic and psychiatric disorders.
Our past work has resulted in the isolation and sequencing of the cDNA clones that encode the human MAO A and B enzymes. Comparison of their deduced amino acid sequences shows that they have a high degree of sequence identity (70%), but different amino acid residues occur at the same position thrughout the polypeptide chains, indicating that these two enzymes are derived from separate genes.
Site-directed mutagenesis studies permit us to examine these molecules at the molecular level to determine what motifs and which amino acid residues are essential for catalytic activity. Mutant cDNAs are expressed in COS cells, and MAO A and B enzymatic activities and FAD non-covalent and covalent binding to these variant proteins are measured. Expression of mutant cDNAs have helped identify six regions and several critical amino acid residues in MAO that play a role in function. These results, along with information on the tertiary structures of MAO A and B, will permit us to design new drugs for the treatment of neurological and psychiatric disorders.
