Nutritional Regulation of Cysteine Dioxygenase

Cornell University, Ithaca NY

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Abstract

DESCRIPTION (provided by applicant): Cysteine catabolism is dependent upon two unique enzymes that are the only known mammalian thiol dioxygenases-enzymes adding molecular oxygen to a sulfhydryl group to form a sulfinic acid. These two unique enzymes are cysteine dioxygenase (CDO), encoded by CDO1, and cysteamine dioxygenase (ADO, 2-aminoethanethiol dioxygenase), which we recently showed to be encoded by human gene C10orf22. The clinical literature and, more recently, the study of CDO polymorphisms in disease and control populations, have shown a strong association of impaired metabolism of cysteine to sulfate and taurine and/or CDO loss-of-function mutations with a variety of autoimmune and neurodegenerative diseases. CDO is one of the most highly regulated metabolic enzymes responding to diet that is known, and this robust regulation of CDO activity suggests that cysteine homeostasis is very important to the living organism. Our long-term goals are integrate molecular and organismal studies (a) to further elucidate the structure-function relations in CDO and ADO to provide insights into thiol chemistry and regulation of these enzymes and (b) to further elucidate the roles of CDO and ADO in intermediary metabolism and regulation of physiological function in healthy individuals as well as the possible roles and contributions of CDO deficiency to autoimmune and/or neurodegenerative diseases. Our specific aims related are (1) to define the catalytic mechanism of CDO through structural and spectroscopic studies of complexes of wild type and mutant enzymes in complex with substrates, products and substrate analogs; (2) to crystallize and solve the structure of wild type ADO, and carry out studies to characterize its catalytic mechanism; (3) to characterize the phenotype of CDO-knockout or CDO-deficient mice, including those with tissue- specific CDO gene disruption; (4) to determine whether adverse effects of CDO gene disruption are affected by dietary manipulations (e.g., reduced by restricted cysteine, supplemental taurine, or supplemental sulfate, or amplified by diets containing excess sulfur amino acids, low taurine, or low sulfate); (5) to assess the functional contribution of CDO expressed in specific cell types or tissues to cysteine metabolism and regulation of cysteine levels; (6) to determine whether specific mechanisms that might contribute to the development or progression or severity of autoimmune and/or neurodegenerative disease -- including reduced taurine mediated antioxidation, reduced expression of the complement regulatory protein DAF, reduced capacity for sulfation of glycosaminoglycans, and increased production of H2S -- are altered in the CDO knockout mouse model; and (7) to assess the role of ADO in cysteamine metabolism and in the biosynthesis of hypotaurine/taurine by generating and studying an ADO knockout mouse model.