IBN-9511156 O'Donnell, Janis Catecholamines are one of the basic groups of messenger molecules in the central nervous system and are intimately involved in transmitting information about the environment to the appropriate brain regions in all animals. The enzyme regulating catecholamine biosynthesis is tyrosine hydroxylase. An essential cofactor required by tyrosine hydroxylase is tetrahydrobiopterin. If tetrahydrobiopterin levels are compromised, then catecholamine biosynthesis is similarly compromised pointing to the reliance of tyrosine hydroxylase on this cofactor. Dr. O'Donnell has been instrumental in identifying the enzyme responsible for the production of tetrahydrobiopterin. This enzyme is GTP cyclohydrolase. In the experiments supported by this award, Dr. O'Donnell will examine the physical interaction of tyrosine hydroxylase with GTP cyclohydrolase to better understand the integral dependence of one enzyme on the other. The structures present in GTP cyclohydrolase that physically interact with tyrosine hydroxylase will be examined using sophisticated molecular techniques to alter the structure of the cyclohydrolase enzyme. Further investigations will map the location of GTP cyclohydrolase and tyrosine hydoxylase in neurons to establish whether they exist as a complex or as individual molecules. In addition, by genetic screening procedures, the genes encoding these enzymes will be studied to determine if they are controlled by similar regulatory elements providing for coregulation at the gene and protein level in controlling the production of the essential cofactor, tetrahydrobiopterin. Catecholamines are crucial elements in normal functioning of the central nervous system and understanding the regulation of catecholamine biosynthesis is critical for future understanding of neurological disorders, such as Parkinson's disease.
