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No description available.

Skeletal mineralisation is dependent on the generation of inorganic phosphate (Pi), which has traditionally been attributed to tissue non-specific alkaline phosphatase (TNAP). However, evidence exists to suggest the presence of other Pi generating phosphatases in bone. The most compelling being that initial bone mineralisation events in newborn TNAP knockout mice appear to be normal, although abnormalities of the skeleton and dentition appear later. PHOSPHO1 is a phosphatase, which belongs to the haloacid dehalogenase (HAD) superfamily of magnesium-dependent hydrolyases. The work of this thesis has shown that PHOSPHO1 is able to catalyse the hydrolysis of phosphoethanolamine (PEA) and phosphocholine (PCho), which displays favourable kinetics under optimal conditions indicating that these reactions would occur <i>in vivo</i>. Site directed mutagenesis of active site residues, along with molecular modelling, confirm this enzyme as a member of the HAD superfamily as well as implicating residues in substrate specific interactions. PHOSPHO1 protein is localised to the mineralising sites of the skeleton and cells of bone and cartilage in the mouse model. Further to this PHOSPHO1 is present in an active state within matrix vesicles, the epicentre of mineral formation. Modulation of PHOSPHO1 activity through siRNA gene knockdown studies and specific PHOSPHO1 inhibitors leads to a decrease in the mineralization potential of cells and matrix vesicles respectively. These data further support the hypothesis that PHOSPHO1 plays a central role in matrix mineralization, and indicates that the function of PHOSPHO1 is to sequester Pi from PEA and PCho contained within the glycerolipid membrane of matrix vesicles.

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No description available.

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Selenium has been shown to be essential for several animal species and, although essentiality has not been proven for Man, there are several lines of reasoning to suggest it. The recent discovery that selenium is an essential constituent of the enzyme glutathione peroxidase, which is found in the tissues of many animal species and has also been demonstrated in human erythrocytes, suggests that selenium may also be an essential element for Man. In addition, some of the urinary metabolites of selenium produced by man are the same as those produced by the rat, and the proven essentiality of selenium for the rat indicates that the same may be true for man. In the work described in this thesis, the effects of alterations in the dietary levels of selenium and vitamin E on the metabolic route for the detoxification of acute levels of selenium. have been examined in the rat. In addition, the activity of dietary conditions, and correlation between enzyme activity and the concentration of selenium in liver was studied. All experimental methods and enzymic assays have been described in detail. -. The effect of silver,. which causes selenium deficiency symptoms in vitamin E-deficient rats, onglutathione peroxidase activity and concentration of liver selenium was investigated. in an attempt to explain gross, physical manifestations by changes in parameters of selenium metabolism. In the presence of toxic levels of dietary selenium, the effect of silver on selenium detoxification was investigated. Finally, the short-term uptake of 75Se in various tissues of rats given vitamin E, selenium and toxic metals such as mercury, cadmium and silver, was measured and compared with control rats in order to begin to explore the nature of these elements with selenium and vitamin E.

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