Author

Lisa Pasierb

Defense Date

8-26-2005

Graduation Date

2005

Availability

Immediate Access

Submission Type

dissertation

Degree Name

PhD

Department

Chemistry and Biochemistry

School

Bayer School of Natural and Environmental Sciences

Committee Chair

David W. Seybert

Committee Member

Mitchell E. Johnson

Committee Member

Partha Basu

Committee Member

David W. Wright

Keywords

bionucleating templates, hemozoin, histidine- rich protein II, malaria, MAPS peptides, Plasmodium falciparum

Abstract

Hemozoin formation, the consequential end product of the proteolysis of hemoglobin by Plasmodium falciparum, is essentially a biomineralization process whereby toxic free heme is aggregated into an inert crystalline solid, also known as malaria pigment or ß-hematin. The histidine-rich protein II (HPR II), isolated from the digestive vacuole of the parasite, has been implicated in the mediation of this biomineral through the protein's ability to bind heme, aggregate the biomineral, and be effectively inhibited by known antimalarials, including chloroquine. The HRP II sequence, which is comprised of 76% of histidine and alanine residues, has a specific amino acid repeat motif which is reminiscent of nucleating scaffold proteins utilized by other biological systems in biomineralization processes. Using a peptide dendrimer previously developed in our laboratory as a functional HRP II mimic, we examined two domain repeats, Ala-His-His-Ala-His-His-Ala-Ala-Asp and Ala-His-His-Ala-Ala-Asp-Ala-His-His, as putative hemozoin nucleating sequences. Results indicated the Ala-His-His-Ala-His-His-Ala-Ala-Asp repeat of peptide dendrimer BNT II was the most probable nucleating domain within the HRP II sequence. Site-directed mutagenesis studies were then utilized to elucidate the role of the nucleating domain per active site amino acids.

Format

PDF

Language

English

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