Thesis (Ph. D.)--University of Missouri--Columbia, 2000. / Typescript. Vita. Includes bibliographical references (leaves 189-204). Also available on the Internet.

A diverse array of proteins has evolved to detect and affect carbohydrate structures, thereby performing critical roles in important biological events. Carbohydrate recognition usually employs a high degree of precision, as discriminating between two carbohydrate structures can depend on a single hydrogen bond or the configuration of a hydroxyl group. My work has focused on the molecular recognition of carbohydrate antigens by two biologically important classes of carbohydrate-binding proteins: antibodies and lectins. Single crystal x-ray diffraction has been employed to study the IgG2a antibody LPT3-1 and the lectins Griffonia simplicifolia 1-A4 (GSI-A4) and Lathyrus odoratus lectin (LOdL). LPT3-1 targets the conserved inner core structure of lipooligosaccharide from Neisseria meningitidis, the leading cause of meningitis and septicaemia. Structural characterization of LPT3-1 with an inner core fragment demonstrates how this antibody achieves selective cross-reactivity to variants of the inner core and provides insight that could support the development of a broadly protective N. meningitidis vaccine. Legume lectin GSI-A4 displays specificity towards the terminal galactose and N-acetyl-D-galactosamine of carbohydrates, yet the closely related lectin GSI-B4 will only recognize a terminal galactose. The structures of GSI-A4 co-crystallized with two different carbohydrates reveals the mechanism by which GSI-A4 displays this cross-reactivity, which allows for specific recognition of two important tumour-associated carbohydrate antigens. LOdL is a member of the Mannose/Glucose legume lectin family that can recognize an array of clinically significant antigens including abnormal glycosylation patterns on gp120 of HIV. Characterization of LOdL in complex with glucose at high resolution provides a putative primary sequence and molecular level insight into the molecular recognition displayed by this lectin. Structural data indicates LOdL is cross-reactive with the related glucose epimer mannose, and would display a similar if not identical affinity for glucose and mannose, enabling cross-reactivity with oligosaccharides displaying a terminal mannose. The similarity in sequence and primary recognition between LOdL and Pisum sativum lectin (PSL) suggests that LOdL also shares oligosaccharide specificity with PSL and similarly could demonstrate anti-HIV activity. Overall, the structural characterization of these three carbohydrate-binding proteins reveals mechanisms by which antibodies and lectins can employ selective cross-reactivity to discriminate among clinically-relevant carbohydrate structures. / Graduate / mj3parker@gmail.com

published_or_final_version / Physiology / Master / Master of Philosophy

published_or_final_version / Physiology / Master / Master of Philosophy

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4 pp. / discontinued 3/4/11 / Carbohydrate is the main fuel for the body's muscles and brain. Adequate carbohydrate intake is important for supplying fuel in an athlete's diet.

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A series of novel triphenylstannyl-C, (triphenylstannyl)methyl- O- and (tributylstannyl)methyl-O- substituted pentofuranose compounds have been synthesised. Two methods were employed: (i) the reaction of triphenyltinlithium with derivatised and protected (or partially protected) carbohydrates, and (ii) the reactions of carbohydrate alkoxides with (iodomethyl)triphenyltin and (iodomethyl)tributylin. The solution structures of the triorganotin-carbohydrate compounds were investigated by 1H, 13C and 119Sn NMR spectroscopy. In solution all of the triorganotin-carbohydrates were shown to contain four-co-ordinate tin atoms. The solid-state structures were investigated by a combination of solid-state NMR spectroscopy and single-crystal X-ray diffraction. There were no major conformational changes between the two phases for any of the compounds. The molecular structures of methyl 5-deoxy-2,3- O-isopropylidine-5-triphenylstannyl-beta-D-ribofuranoside and 5-deoxy-1,1- O-isopropylidine-5-triphenylstannyl-alpha-D-xylofuranose were determined. Two different molecular conformations were identified for the former compound, and hydrogen-bonding between adjacent molecules was shown to be present in the latter case. The reactions of the triorganotin-carbohydrate compounds with iodine and bromine were studied. The results indicated that the rate of cleavage of butyl-tin bonds was much slower than the cleavage of phenyl-tin bonds. The reactivity of the tin-phenyl bond was found to depend greatly on the structure of the carbohydrate ligand. Evidence of increased co-ordination in solution was found for the mono-halo derivatives of methyl 5-deoxy-2,3-O-isopropylidine-5-triphenylstannyl-beta-D-ribofuranoside and 5-deoxy-1,2-O-isopropylidine-5-triphenylstannyl-alpha-D-xylofuranose. The molecular structures of 5-deoxy-5-iododiphenylstannyl-1,2-O-isopropylidine-alpha-D-xylofuranose and 5-deoxy-5-diiododiphenylstannyl-1,2-O-isopropylidene-alpha-D-xylofuranose were determined. In the solid-state the geometry about the tin atoms was found to be distorted trigonal bipyramidal.