Zugl.: Kiel, Univ., Diss., 2007

Thesis (M.S.)--University of Kentucky, 2008. / Title from document title page (viewed on February 2, 2009). Document formatted into pages; contains: ix, 146 p. : ill. (some col.). Includes abstract and vita. Includes bibliographical references (p. 138-145).

Thesis (Ph. D.)--University of Virginia, 1997. / Spine title: Role of Tryptophan in cytochrome b₅. Includes bibliographical references (187-196). Also available online through Digital Dissertations.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1951. / Parts I.B., C., D., F., and II. A. reprinted from Journal of biological chemistry: Part I.B.: vol. 185, no. 2 (Aug. 1950), p. 741-747 ; Part I.C.: vol. 187, no. 2 (Dec. 1950), p. 597-604 ; Part I.D.: vol. 189, no. 2 (Apr. 1951), p. 659-663 ; Part I.F.: vol. 189, no. 1 (Mar. 1951), p. 361-369 ; Part II. A.: vol. 185, no. 2 (Aug. 1950), p. 887-893. Remainder typescript. Vita. Includes bibliographical references.

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The amino acid, tryptophan, obtained through dietary means, is metabolised by the enzymes tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and tryptophan hydroxylase. All the enzymes have an effect on circulating tryptophan levels, especially TDO, since it is the major site of tryptophan catabolism in the liver and results in the production of kynurenine metabolites, viz. kynurenine, kynurenic acid, 3-hydroxyanthranilic acid and quinolinic acid. Extrahepatically, IDO is responsible for the synthesis of the kynurenine metabolites. Tryptophan 2,3-dioxygenase and IDO activity is increased by hormones or substrates such as tryptophan, and inflammation, in the case of IDO. Tryptophan availability for serotonin (5-HT) synthesis by the enzyme tryptophan hydroxylase is primarily dependent on TDO activity. A study was attempted in order to ascertain whether any of the endogenous metabolites of the kynurenine and serotonergic pathways would be able to inhibit TDO activity. Results showed that although the kynurenines had no effect, the indoleamines, except for the indoleacetic acids, were able to reduce TDO activity. 6-Methoxy-2-benzoxazolinone (6-MBOA), a structural analogue to melatonin, was the most potent inhibitor with a reduction in activity of 55 % compared with the control. The pineal gland in the rat brain has been shown to have the highest IDO activity. With induction, the kynurenine metabolite concentrations of kynurenic acid and quinolinic acid are increased. The effects of both compounds were determined on the serotonergic pathway. Although kynurenic acid produced no significant effect, quinolinic acid significantly reduced N-acetylserotonin and melatonin synthesis at concentrations of lOJLM and 100 JLM respectively. Many authors have implicated oxygen derived species as causative agents in the important neurodegenerative disorders such as Parkinson's and Huntington's disease. Increased radical generation and lipid peroxidation have been suggested to be responsible for the toxic destruction of neurons, especially in the brain because of its high lipid content and oxygen demand. The brain is therefore vulnerable to oxidative attack. During inflammatory diseases, IDO is induced with a resultant increase in kynurenines. This study was also an attempt at determining the effect of kynurenines on lipid peroxidation. All metabolites of the kynurenine pathway were able to induce lipid peroxidation significantly. The antioxidative potential of various tryptophan analogues, viz. serotonin, melatonin and 6-methoxy-2-benzoxazolinone, was determined using quinolinic acid-induced lipid peroxidation. Serotonin, melatonin and 6-MBOA were able to significantly reduce quinolinic acid-induced lipid peroxidation.

In the model cruciferous plant, Arabidopsis thaliana, tryptophan (Trp) is a focal point for growth and defense as it is used for the production of secondary metabolites including the growth hormone indole-3-acetic acid (IAA, or auxin), and two classes of defense compounds: indole glucosinolates (IGs) and camalexin. Trp metabolism in plants is of general importance to agriculture because animals (including humans) cannot synthesize Trp and must obtain it from their diet. Questions remain about the synthesis and regulation of Trp and how it relates to secondary metabolism in Arabidopsis. In this thesis it is shown that IGs are a sink for Trp metabolism because auxotrophic mutants deficient in Trp production are suppressed in combination with the IG-deficient cyp79B2 cyp79B3 mutant and enhanced in combination with IG overproducing mutant, atr1D. Because Trp auxotrophic mutants were found to produce IGs, the four predicted Arabidopsis Trp Synthase Beta genes (TSB1, TSB2, TSB3 and TSBt2) were examined for their role in Trp primary and secondary metabolism. It was determined that members of this gene family, while being redundant for enzyme activity, may have unique functions in channeling Trp to different secondary endpoints. tsb1 tsb2 plants display a healthier phenotype and produce lower IG levels than the single tsb1 mutants, in contrast to tsb1 tsbt2 plants, which have elevated IG production and an enhanced auxotrophic phenotype. tsb2 tsbt2 plants are indiscernible from WT. Gene expression in Trp biosynthetic pathway steps, IG biosynthesis genes, and regulatory TFs is dysregulated in these mutants. In a second part of this thesis, transcriptional regulation of IG synthesis was examined with respect to tissue specificity and stress. In collaboration with Judith Bender's laboratory at Brown University, the function of a subfamily of three Myb transcription factors that have been implicated in regulating IG biosynthesis genes was studied. Using combinations of Myb knockout mutants and GUS reporter plants, tissue specific roles for MYB34 and MYB51 in root and shoot tissues, respectively, were found. In addition, roles were discovered for MYB34 in mediating anti-herbivory signals, and for both MYB51 and MYB122 in regulating defense against microbial pathogens.

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Doctor of Philosophy / Department of Diagnostic Medicine/Pathobiology / Steven S. Dritz / A total of 8 experiments and a meta-analysis were performed with the overarching goal to improve amino acid and energy utilization in swine diets. The first experiment used a total of 255 nursery pigs to evaluate the optimum dietary standardized ileal digestible (SID) tryptophan to lysine (Trp:Lys) ratio. Four experiments also were conducted using 6,668 finishing pigs to determine the effects of SID Trp:Lys ratio in diets containing dried distillers grains with solubles (DDGS) on growth performance and carcass characteristics. A subsequent experiment evaluated the interaction between Trp and large neutral amino acids (Trp:LNAA) on growth performance of early and late-finishing pigs. Lastly, data from 41 trials and 2 validation trials were used to develop a regression equations to predict ADG or gain to feed (G:F) as influenced by BW and net energy (NE) content in growing-finishing pigs. In Exp. 1, the growth performance and economics indicated the optimum SID Trp concentration for 6-to 10-kg nursery pigs at 20.3% of Lys. In Exp. 2, 3, and 4, there were no differences in growth performance due to SID Trp:Lys ratio; however, increasing the SID Trp:Lys ratio suggested an opportunity to improve carcass yield and lean in pigs fed high levels of DDGS. Experiment 5 indicated an optimum SID Trp:Lys ratio of 20% for 71- to 127-kg pigs fed high level of DDGS. In Exp. 6, growth performance was unaffected by dietary treatment suggesting that 16.5% SID Trp:Lys was adequate to prevent a negative impact on growth when SID Trp:LNAA was as low as 3.0% in finishing period. Overall, the experiments suggested a higher optimum SID Trp:Lys ratio than is currently standard practice. The regression analysis from the meta-analysis showed that increasing dietary NE improved ADG and G:F. However, the magnitude of improvement will be minimized if the SID Lys concentration is limiting. The validation experiments indicated that the prediction equations provided a good estimation of growth rate and feed efficiency of growing-finishing pigs fed different levels of dietary NE except for pigs fed the diet with DDGS. These predictions of growth performance can then be used to model economic value of different dietary energy strategies.