Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 58-71).

Catechol-O-methyltransferase (COMT) metabolizes catechols, notably dopamine. The COMT Val158Met polymorphism influences its enzyme activity, and multiple neural correlates of this genotype on dopaminergic phenotypes have been reported, particularly with regards to working memory. COMT activity can also be regulated pharmacologically by COMT inhibitors. The ‘inverted-U’ relationship between dopamine signalling and cognitive performance predicts that the effects of COMT inhibition will differ according to COMT genotype. The goal of this thesis was to better understand COMT’s impact on brain function and behaviour. Here, 33 subjects homozygous for COMT Val158 (‘Val homozygotes’) and 34 homozygous for COMT Met158 (‘Met homozygotes’) were randomly assigned, double-blind, to a single dose of the brain-penetrant COMT inhibitor tolcapone (200mg) or placebo. They completed the N-back task of working memory, an emotional face processing task, and a gambling task, in a magnetoencephalography (MEG) scanner, allowing both behavioural performance and neural activity to be investigated. The data presented in this thesis confirm that COMT activity influences performance on, and neural activity during, the N-back task, in a way consistent with the inverted-U model of dopamine function. The effect on risky decision making is novel, and indicates that COMT plays roles in domains beyond working memory, and that such domains may also follow an inverted-U. Neural activity during the faces task and the gambling task also show COMT-modulated differences. The behavioural results show that the direction of effect of a drug can be influenced by sequence variation in its target gene. They are of translational relevance, since COMT inhibitors are used in the adjunctive treatment of Parkinson’s disease and are under evaluation in schizophrenia and other disorders. The MEG data show that for the three tasks, there are effects of Val158Met genotype, of tolcapone, and their interaction, on neural activity (for example, the P300 during N-back), revealing a complex temporal and spatial pattern which sheds some light on the neural processing underlying these tasks and their previously reported fMRI correlates.

The antibiotic fungal metabolite sinefungin is a potent inhibitor of S-adenosylmethionine-acceptor methyltransferases. Its effect on insect metabolism and especially on corpora allata farnesoic acid methyltransferase, which catalyzes the penultimate step of juvenile hormone biosynthesis, was investigated in Locusta migratoria. Injection of sinefungin results in a delay of imaginal molt and in suppression of ovary development. Isolated corpora allata are unable to synthesize juvenile hormone III in the presence of more than 1.0 mM sinefungin. In a cell-free system containing the S-adenosylmethionine-dependent farnesoic acid methyltransferase from corpora allata sinefungin is a competitive inhibitor of the synthesis of methylfarnesoate with Ki of 1 μM.

No description available.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 183-205).

Juvenile hormones (JHs) are key regulators of both metamorphosis and adult reproductive processes. The role of two key enzymes in the biosynthetic pathway of JH were examined: Farnesoic Acid O-Methyltransferase (FAMeT) and Juvenile Hormone Acid Methyltransferase (JHAMT). In crustaceans, FAMeT has been found to methylate farnesoic acid (FA), producing methyl farnesoate (MF) prior to epoxidation at the penultimate stage of JH biosynthesis. JHAMT was discovered more recently in the silkworm Bombyx mori and converts epoxidated FA (JHacids) to active JH through methylation using S-adenosyl-L-methionine (SAM). The aim of the proposed research is to examine the influence of a) decreasing the amount of FAMeT produced using an enhancer trapping P-element and b) increasing the levels of JHAMT and FAMeT in specific tissues using GAL4 overexpression techniques. Immunohistochemical analysis was used to confirm the presence of FAMeT in the CA of D. melanogaster ring glands. Analysis of MF, JHIII and JHB3 release in wild type and mutant stocks in the presence and absence of Drome AST (PISCF-type) suggest that Drosophila FAMeT has little if any effect on the sesquiterpenoid biosynthesis. Drome-AST appears to have a select effect on JHB3 biosynthesis and not MF or JHIII. Analysis of JHB3 release from larval and adult flies ubiquitously overexpressing JHAMT showed a significant increase when compared to wildtype (p<0.01 and p<0.0001 respectively). No significant difference was seen in JHB3 release in flies ubiquitously overexpressing FAMeT. A significant increase in hatching success was seen in flies overexpressing FAMeT in the larval ring gland and oocytes (p<0.05) whereas no significant decrease was seen in JHAMT-overexpressing flies during development. A significant extension of lifespan was also seen when FAMeT was overexpressed in the border and follicle cells of the oocyte (p<0.0001). The direct role of JHAMT in JHB3 synthesis has been demonstrated. The involvement of FAMeT and JHAMT in development and longevity may require other interacting proteins to elicit an effect, which is a limiting factor in overexpression experiments of the two enzymes. Additionally, this is the first example of AST action within D. melanogaster. / Thesis (Master, Biology) -- Queen's University, 2007-09-27 20:08:23.69

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第18336号 / 農博第2061号 / 新制||農||1023(附属図書館) / 学位論文||H26||N4843(農学部図書室) / 31194 / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 梅澤 俊明, 教授 矢﨑 一史, 教授 三上 文三 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(生命科学) / 甲第20780号 / 生博第386号 / 新制||生||51(附属図書館) / 京都大学大学院生命科学研究科統合生命科学専攻 / (主査)教授 佐藤 文彦, 教授 河内 孝之, 教授 福澤 秀哉 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM