Abnormal or deficient cysteine dioxygenase (CDO, EC 1.13.11.20) activity has been claimed to be seen in individuals with a variety of diseases, both non-neurological and neurological. Low CDO activity may result in problems, either because of insufficient supply of sulfate (or taurine) as products of cysteine catabolism that are needed for a variety of purposes including phase II conjugation reactions or because of accumulation of cysteine or toxic metabolites. We have identified CDO as the major hepatic enzyme involved in regulation of cysteine catabolism. The regulatory response is robust, with CDO activity being barely detectable in liver of animals fed low protein diets and increasing up to 170-fold in rats fed diets containing high levels of protein or sulfur amino acids. The long-term objective is to further elucidate the molecular mechanisms involved in the regulation of CDO and to understand the possible contribution of genetic or other impairments in CDO in the etiology of diseases such as rheumatoid arthritis. Proposed studies include (1) the characterization of the two CDO isoforms; (2) studies of CDO expression and regulation by cysteine in nonhepatic tissues (brain, kidney, and lung) as a step in understanding the relation of cysteine metabolism to the development and progression of certain neurological and nonneurological diseases associated with aging; (3) assessment of the mechanism by which CDO levels are increased -- an increased rate of mRNA translation or an increased stability of CDO protein in the presence of cysteine, and, if appropriate, examination of the possible formation of an alternatively processed mRNA transcript for CDO; and (4) assessment of the relationship of tissue cysteine concentration to CDO levels in intact rats. Experiments will involve dietary treatments of rats and assessment of the effects of diet on CDO expression in various tissues, studies of the molecular mechanisms involved in regulation of CDO abundance, and characterization of CDO protein and CDO mRNA isolated from these rats or from hepatocytes in primary culture.
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