This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed XAS experiments are part of a project aimed at characterizing the reaction mechanisms of two members of the nonheme Fe(II) dioxygenase family of enzymes, AlkB homologue 2 (ABH2, in collaboration with Prof. Max Costa, NYU School of Medicine) and cysteine dioxygenase (CDO). Specifically, we seek to use XAS to elucidate the mechanism by which Ni(II) ions inhibit AlkB and thus produce hypermethylated DNA, which in turn can cause cancer and lead to genetic defects. Second, we seek to understand the role played by cysteine and cysteamine in the redox chemistry of CDO. In the case of ABH2, XAS will provide some of the information regarding the sequential reaction mechanism (binding of a-ketoglutarate, not binding but change the iron geometry upon substrate binding, and oxygen activation) which in comparison with similar data from the Ni(II) complex will lead to a detailed understanding of the reaction mechanism and the mechanism by which Ni(II) inhibits the enzyme. In the case of CDO, the roles of cysteine and cysteamine as reductants and/or ligands will be addressed. By comparing and contrasting the mechanisms of these enzymes, we hope to further the understanding of how nature tunes the active sites of non-heme Fe(II) enzymes in order to catalyze the wide variety of different reactions that is a feature of this enzyme family.
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