Novel Catalases and their Products

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DESCRIPTION (provided by applicant): The long-term objective of this application is to elucidate the roles of a novel group of proteins related in sequence and structure to catalase and to define the biochemistry and chemistry of their reactions and novel products. Catalase is renowned for its key role in the oxidative defense of all aerobic organisms. One can anticipate selective reactions of these new catalase relatives with potential oxidative metabolism and/or functioning in the disposition of natural peroxides. The prototypical enzyme of this proposal is an allene oxide synthase, an enzyme that catalyzes a cytochrome P450-type of reaction yet which exhibits distinct sequence homology to catalase. In Aim 1, a newly available X-ray crystal structure of the catalase-related AOS will be used to reveal the mechanistic basis of catalysis and the comparisons and contrasts with human catalase. The goal is to provide an understanding of the ability to catalyze P450-type chemistry within the catalase fold. Aim 2 will focus on analysis of the catalytic activities of other novel enzyme candidates that have similar sequence characteristics defined as retention of the heme-binding features of a catalase within an unusually short polypeptide for catalases of only ~40kD. These enzymes occur in organisms that include bacteria of importance for their pathogenicity and a crop blight fungus characterized as a major threat to the world's food supply. Allene oxides are of major importance in biotechnology and their cyclopentenone derivatives are also studied for their potent antineoplastic effects. Aim 3 will seek to establish the structure and precise stereochemistry of natural allene oxides and especially structural issues pertinent to their cyclizations. This is of fundamental interest in understanding the nature of allene oxide synthase reactions as well as the chemistry of cyclopentenone synthesis. The results of this study will provide new insights and a new way of thinking about the enzymatic capabilities of a long-recognized protein family with established roles as a sentinel at the forefront of oxidative defense.