Research Project
7499542
[unreadable] DESCRIPTION (provided by applicant): Copper-containing amine oxidases and lysyl oxidases are widely distributed in nature and are involved in the metabolism of biogenic primary amines, in the maturation of connective tissue, and numerous other physiological processes. The human vascular adhesion protein (hVAP-1) is an amine oxidase, and its oxidase activity is directly involved in cellular adhesion. Multiple "lysyl oxidase like" (LOXL) proteins have been recognized in mammals, and these proteins may substitute for lysyl oxidase, but may also have roles in multiple cellular processes, including differentiation, proliferation, and motility. It appears that recently recognized biogenic amines and several pharmaceutical compounds may be metabolized by or inhibit amine oxidases. A multidisciplinary approach emphasizing spectroscopy, kinetics, site directed mutagenesis, and crystallography is proposed to elucidate the chemical and biological principles that define key structure- function relationships in amine oxidases and lysyl oxidases. A major goal is to determine the structures of key amine oxidases, including a lysyl oxidase, and of amine oxidase and lysyl oxidase complexes with inhibitors and substrate analogues. Other major goals are to define the active-site structures, catalytic mechanisms, and the molecular bases for substrate specificity and selective inhibition in amine oxidases, including hVAP-1 and LOXLs. Experiments designed to resolve outstanding mechanistic questions in the biogenesis of TPQ and LTQ are also proposed. In addition, the structure and biogenesis of a related enzyme, galactose oxidase, will be examined. Combining structural and mechanistic data will permit a detailed understanding of the structure and function of these important enzymes to be developed. [unreadable] [unreadable] [unreadable]
