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Protein S-nitrosylation: Methods of Detection and RegulationForrester, Michael T. January 2009 (has links)
<p>Protein S-nitrosylation--the post-translational modification of cysteine thiols into S-nitrosothiols--is a principle mechanism of nitric oxide-based signaling. Studies have demonstrated myriad roles for S-nitrosylation in organisms from bacteria to humans, and recent efforts have greatly advanced our scientific understanding of how this redox-based modification is dynamically regulated during physiological and pathophysiological conditions. This doctoral thesis is focused on the 1) analysis of existing methodologies for the detection of protein S-nitrosylation; 2) development of new methodologies for the detection of protein S-nitrosylation and 3) discovery of novel enzymatic mechanisms by which S-nitrosylation is regulated in vivo. The specificity of the biotin switch technique, the mainstay assay for detecting S-nitrosylation, was rigorously assessed and validated. This study was paramount as a response to several published (though poorly grounded) criticisms of the biotin switch technique. Separately presented is a unique resin-based assay for proteomic analysis of S-nitrosylation (dubbed "SNO-RAC"), which is combined with mass spectrometric tools to identify sites of S-nitrosylation in several cellular models (e.g. E. coli, mammalian cells). Other data presented herein demonstrate that the thioredoxin system is regulated, in a negative feedback manner, to control S-nitrosylation and prevent nitrosative stress. This system involves nitric oxide-dependent suppression of an established thioredoxin inhibitor, the thioredoxin interacting protein (Txnip). This, in turn, affords thioredoxin an optimal environment to drive protein denitrosylation and prevent nitrosative stress secondary to endogenous nitric oxide production.</p> / Dissertation
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Structural Biochemistry and Inhibition of CaaX Protein Prenyltransferases From Human PathogensHast, Michael Alan January 2010 (has links)
<p>Protein prenylation is a post-translational lipid modification required for proper function by over 100 proteins in the eukaryotic cell. Proteins that receive this modification mediate a wide variety of functions in the cell, including critical signal transduction events. A family of structurally-related protein prenyltransferase enzymes carry out this reaction: protein farnesyltransferase (FTase), protein geranylgeranyltransferase-I (GGTase-I) and Rab geranylgeranyltransferase (GGTase-II or Rab GGTase). The focus of this dissertation will be on CaaX protein prenyltransferases, FTase and GGTase-I, which recognize a defined C-terminal motif on substrate proteins: cysteine (C), followed by two generally aliphatic amino acids (aa) and a variable (X) residue. </p><p>Protein farnesyltransferase (FTase) catalyzes the addition of a 15-carbon isoprenoid lipid to certain CaaX proteins, while protein geranylgeranyltransferase-I catalyzes the addition of a 20-carbon lipid. FTase and GGTase-I have been shown to be important drug targets in the fight against cancer, as many of the prenylated signal transduction proteins play significant roles in oncogenesis. More recently, protein prenyltransferases have been identified in human pathogens, and these orthologs also show promise as drug targets for treating infectious diseases. The research in this dissertation seeks to understand the structural biochemistry and mechanisms inhibition of protein prenyltransferase orthologs from human pathogens. </p><p>Molecular cloning techniques, biochemical assays, and macromolecular X-ray crystallography are employed to express recombinant proteins and study their structure and function. In this work I present the first X-ray structures of non-mammalian protein prenyltransferases, including the FTases from <italic>Cryptococcus neoformans</italic>, <italic>Aspergillus fumigatus</italic>, and <italic>Candida albicans </italic>; as well as the GGTase-I from <italic>Candida albicans</italic>. These structures reveal regions of the active sites that diverge sufficiently from mammalian orthologs that selective inhibitors to treat infectious diseases may be developed. In addition, I present the crystal structures of a novel series of FTase inhibitors bound to both mammalian FTase and <italic>C. neoformans</italic> FTase. The structures of these ethylenediamine-scaffold inhibitors reveal dominant determinants of inhibitor binding, as well as ways that the inhibitors could be modified to bind the FTases from multiple human pathogens. Taken together, the data presented in this dissertation advance our understanding of the structural biology of protein prenyltransferases across multiple species, and these data can be exploited to develop novel treatments for infectious diseases.</p> / Dissertation
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Defining multiple registers within a highly segmented coiled coil of the Escherichia coli Structural Maintenance of Chromosomes (SMC) protein MukBWeitzel, Christopher S. January 2009 (has links)
Thesis (Ph. D.)--Indiana University, Dept. of Chemistry, 2009. / Title from PDF t.p. (viewed Feb. 10, 2010). Source: Dissertation Abstracts International, Volume: 70-05, Section: B, page: 2913. Adviser: Martha G. Oakley.
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EFFECTS OF POLYHALOGENATED AROMATIC HYDROCARBONS ON VITAMIN A CATABOLISM AND THE REGULATION OF VITAMIN A HOMEOSTASIS IN RATS (HYDROCARBONS)BANK, PAULA ANN. January 1989 (has links)
Thesis (Ph. D.)--University OF MICHIGAN. / CO-CHAIRMEN: MAIJA H. ZILE; ROLF HARTUNG.
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MECHANISTIC STUDY OF CHOLESTEROL MONOHYDRATE DISSOLUTION IN AQUEOUS BILE SALT-LECITHIN SYSTEMSSU, CHING-CHIANG. January 1982 (has links)
Thesis (Ph. D.)--University OF MICHIGAN.
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ISOLATION AND CHARACTERIZATION OF A PLASMID COINTEGRATE FROM SALMONELLA TYPHIMURIUMMANIS, JACK JAY. January 1975 (has links)
Thesis (Ph. D.)--University OF MICHIGAN.
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CYSTEINE-SPECIFIC CLEAVAGE OF PROTEINS VIA BISALKYLATING QUINONEDIIMIDESHOLMES, THOMAS JAMES, JR. January 1975 (has links)
Thesis (Ph. D.)--University OF MICHIGAN.
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BIOCHEMICAL TOXICOLOGY OF HUMAN PLACENTAL HIGH AFFINITY CALCIUM-STIMULATED ATPASE AND CALCIUM TRANSPORT (UPTAKE, DDT, DOT)TREINEN, KIMBERLEY ANNE. January 1986 (has links)
Thesis (Ph. D.)--University OF MICHIGAN.
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EFFECT OF TUMOR PROMOTING PHORBOL ESTER, 12-O-TETRADECANOYLPHORBOL-13-ACETATE, ON TERMINAL DIFFERENTIATION OF RAT KERATINOCYTE IN CULTURE (TPA)KIM, HEE-JOONG. January 1985 (has links)
Thesis (Ph. D.)--University OF MICHIGAN.
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PARTIAL PURIFICATION AND CHARACTERIZATION OF A PEROXIDASE FROM NEONATAL RAT SKINSTROHM, BRADFORD HARRY. January 1987 (has links)
Thesis (Ph. D.)--University OF MICHIGAN. / CO-CHAIRMEN: ARUN P. KULKARNI; ROLF HARTUNG.
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