Cofactor-Dependent Amine Oxidations

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DESCRIPTION (provided by applicant): The copper-containing amine oxidases (CAOs) comprise a ubiquitous class of enzymes in all living organisms. In plants and mammals, CAOs play important roles in metabolizing biogenic amines involved in growth, cell division, differentiation, and the stress response, as well as in metabolism of xenobiotic amines, in some cases with cytotoxic consequences. All CAOs utilize a quinone cofactor derived postranslationally from an active site tyrosine residue to mediate a transaminative conversion of primary amines to aldehydes, distinct from the mechanism utilized by the flavin- dependent amine oxidases and those heme enzymes that metabolize amines. Studies using cofactor models in the past grant periods have inspired the discovery of new types of enzyme activated mechanisms of inhibition, and these studies, along with development of other traditional inactivation strategies, have resulted in highly promising degrees of inhibition selectivity. Important information on the nature of quinone cofactor biogenesis was also revealed. In the next grant period, an increased focus on selectivity should provide candidate inhibitors that are selective for individual CAOs, particularly the plasma monoamine and diamine oxidases, the soluble and tissue-bound semicarbazide-sensitive amine oxidases, and lysyl oxidase. These enzymes are important targets for inhibitor development on account of the emerging recognition of their key physiological roles in aspects of fibrosis in arthritis and atherosclerosis, in late-stage complications of diabetes and cardiovascular disease, and in adipose tissue physiology. Cases of highly selective enzyme inactivation will be subjected to spectroscopic and protein digestion/mass spectroscopic studies to reveal the structural nature of selectivity. Continued model studies are planned to clarify mechanistic aspects of cofactor operation (topaquinone or lysine tyrosyiquinone) important to the design of additional selective inactivators, and of cofactor biogenesis that are still unclear.