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    • Albert Einstein College of Medicine: Doctoral Dissertations
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    • Albert Einstein College of Medicine: Doctoral Dissertations
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    Structural and functional studies of indoleamine 2,3-dioxygenase activity and regulation

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    Date
    2009
    Author
    Samelson-Jones, Benjamin Jacob
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    Abstract
    The heme-enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes the initial and rate-determining step of tryptophan catabolism. The activity of IDO inhibits cell proliferation. Most notably, IDO activity has been demonstrated to inhibit immune-cell proliferation, which allows the immune system to tolerate foreign antigens. This thesis characterizes several structure-function relationships that underlie IDO activity and regulation.;Nitric oxide (NO) is an important regulator of IDO, inhibiting IDO expression and activity as well as promoting the degradation of IDO protein. Data in this thesis convincingly shows that the NO-bound IDO is situated in a unique protein environment and adopts an out-of-plane deformed geometry that is sensitive to tryptophan binding. The proximal heme iron-histidine bond is surprisingly fragile, and is prone to rupture in the presence of NO under mildly acidic conditions. The conformational changes associated with the formation of the 5-coordinate species suggest a molecular mechanism for NO-induced IDO degradation, as well a model for temporal regulation between IDO and iNOS in the immune response.;Previous descriptions of the ferric enzyme have been contradictory. Data in this thesis show that ferric IDO is distally coordinated by an endogenous histidine at cryogenic temperatures. Further, a novel IDO conformation is reported in which an endogenous cysteine is axially coordinated to the ferric iron under mild denaturant conditions. These data suggest that the molecular mechanisms for the inactivation of IDO may be due to the conformational changes associated with the coordination of the heme iron with endogenous low-spin ligands.;The catalytic cycle of IDO was also studied. Activation entropies and enthalpies as well as optical absorption spectra of the ternary complex are reported.;Enantiomer-specific interactions of tryptophan binding were investigated in order to better understand the substrate-enzyme interactions required for catalysis, as well as to improve the design and specificity of IDO inhibitors. The first clear spectroscopic changes due to D-Trp binding are reported, which suggest that bound D-Trp forms hydrogen-bonds with heme ligands, but, unlike bound L-Trp, does not induce protein conformational changes. The binding of a series of tryptophan-derivatives to IDO was used to elucidate these observed differences between L- and D-Trp binding to IDO. The results suggest that inhibitors that mimic the alpha-amino group and alpha-carboxylic acid group of L-Trp will bind best to IDO.
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    https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3357323
    https://hdl.handle.net/20.500.12202/1046
    Citation
    Source: Dissertation Abstracts International, Volume: 70-04, Section: B, page: 2133.;Advisors: Syun-Ru Yeh.
    *This is constructed from limited available data and may be imprecise.
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