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dc.contributor.authorNg, Sze-fong
dc.date.accessioned2018-07-12T18:29:14Z
dc.date.available2018-07-12T18:29:14Z
dc.date.issued1988
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 50-02, Section: B, page: 5480.;Advisors: Sasha Englard.
dc.identifier.urihttps://yulib002.mc.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:8909485
dc.identifier.urihttps://hdl.handle.net/20.500.12202/3248
dc.description.abstractA. Studies were carried out using the isolated rat liver perfusion technique to determine whether livers obtained from starved animals would exhibit an increased capacity for the de novo synthesis of carnitine. For the perfused rat liver, carnitine and its metabolites can be conveniently measured in both the liver and the perfusate after the administration of asialofetuin containing residues of (methyl-{dollar}\sp3{dollar}H) 6-N-trimethyl-L-lysine ( (methyl-{dollar}\sp3{dollar}H) Lys(Me{dollar}\sb3{dollar})). This modified glycoprotein, following uptake via receptor-mediated endocytosis, is degraded intracellularly, causing the release of labeled free Lys(Me{dollar}\sb3{dollar}) residues. Using this technique, we obtained data indicating that livers from fasting animals have a higher capacity for the synthesis of carnitine from intracellularly released Lys(Me{dollar}\sb3{dollar}). In contrast, livers obtained from clofibrate-treated animals, in which plasma ketone body levels are low and hepatic carnitine levels are 5-8 fold higher than in untreated animals, showed significantly depressed rates of synthesis of carnitine. The mechanism responsible for the production of elevated hepatic carnitine levels during fasting therefore appears to be different from that operating in liver from rat treated with clofibrate.;B. {dollar}\gamma{dollar}-Butyrobetaine hydroxylase, an {dollar}\alpha{dollar}-ketoglutarate-dependent dioxygenase, catalyzes the terminal step in carnitine biosynthesis. The binding sites for {dollar}\alpha{dollar}-ketoglutarate and ascorbate, obtained from Pseudomonas sp AK1, were characterized by determining the inhibitory capacity of a series of related, systematically modified aliphatic and aromatic compounds. Pyridine dicarboxylates were identified as competitive inhibitors of the enzyme with respect to {dollar}\alpha{dollar}-ketoglutarate, while dihydroxybenzoates were found to be competitive inhibitors of the hydroxylase with respect to both {dollar}\alpha{dollar}-ketoglutarate and ascorbate. Since the most potent competitive antagonists in the two classes of inhibitors were those compounds that displayed structural subdomains for bidentate interaction with the active site iron atom, these findings strongly suggest that chelation to the iron atom at the catalytic center of {dollar}\gamma{dollar}-butyrobetaine hydroxylase is necessary for both {dollar}\alpha{dollar}-ketoglutarate and ascorbate utilization. Comparisons were made between the Ki values obtained in our studies with {dollar}\gamma{dollar}-butyrobetaine hydroxylase with the Ki values obtained for the same compounds with prolyl and lysyl hydroxylases. Critical differences in the relative spatial orientations of the {dollar}\alpha{dollar}-ketoglutarate binding sites among these {dollar}\alpha{dollar}-ketoglutarate-dependent dioxygenases were revealed.
dc.publisherProQuest Dissertations & Theses
dc.subjectBiochemistry.
dc.titleMetabolic and enzymological studies of biosynthesis in carnitine
dc.typeDissertation


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