Date of Award

1991

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Roger Laine

Abstract

Plasmodium falciparum is the parasite responsible for a major loss of human life due to malaria. The biochemistry of invasion of the parasite into human red cells is the subject of much study and controversy. The receptor mediated endocytosis of the parasite into the red cells is postulated to involve at least two major receptors on the cells. Earlier work focussed on glycophorin of red cells as a likely receptor. The present study focussed on the role of erythroglycan, the N-linked carbohydrate chain of band 3 of human red cells in the invasion process. Erythroglycan showed high levels of inhibition of malaria parasite invasion into human red blood cells. This implied its role as a receptor for invasion. These studies were corroborated by other studies such as affinity binding of parasite proteins. A 118 kDa protein is being reported for the first time as specific erythroglycan binding parasite protein. The involvement of erythroglycan in parasite recognition was also corroborated by studies with red cells defective in the carbohydrate portion of band 3 from a HEMPAS patient. HEMPAS is characterized by a truncated erythroglycan. Parasite growth and invasion was decreased in HEMPAS cells compared with normal cells. Structural studies of erythroglycan were carried out using smaller synthetic erythroglycan-like saccharides. High resolution NMR afforded information about anomeric configuration, epimer order, ring size and, most important, the linkage between saccharidic residues. Information obtained from such a study was used for the first time to discern the structure of intact, underivatized, high molecular weight (7 kDa) erythroglycan. NMR titration studies were performed on Concanavalin A-methyl glucopyranoside. Analysis of thermodynamic parameters indicated unfavorable entropy but favorable enthalpy of binding. This indicates involvement of hydrogen bonds and van der Waal's forces. The model experiment can be applied to the study of larger biological systems.

Pages

242

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