Date of Award

Summer 2009

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Biological Sciences

Program/Concentration

Biology

Committee Director

Roland A. Cooper

Committee Member

Wayne L. Hynes

Committee Member

Christopher Osgood

Call Number for Print

Special Collections LD4331.B46 S64 2009

Abstract

A leading infectious cause of death, malaria threatens approximately half of the world's population, and drug-resistant strains of Plasmodium falciparum have created immense difficulty in chemotherapy of the disease. The artemisinin (ART) class of antimalarials may represent a powerful solution. In addition to their safety, effectiveness, and moderate cost, they are the only drugs in use for which there has been no widespread evidence of clinical resistance. The exact parasiticidal mechanism of ART is highly contested, but evidence suggests that protein alkylation may play a role in cytotoxicity. in vitro essays were performed using yeast hexokinase (HK) to demonstrate a hypothesized relationship between alkylation by ART and activity inhibition of a model enzyme. ART, in the presence of ferrous iron, irreversibly inhibited HK phosphotransferase activity. The drug's endoperoxide bridge was essential for activity against HK, indicating that inhibition is mediated by radicals. MALDI-TOF mass spectrometry failed to detect ART adducts of inhibited HK, however, which suggests that alkylation may not be responsible for inhibition of enzymatic activity. Further, although alkylation of thiols by ART has been confirmed and was hypothesized as the means of inhibition of HK, solvolysis-released adducts of ART and Thiopropyl Sepharose SB resin were not observed by thin-layer chromatography. Loss of protein function through ART-induced oxidation, which has already been implicated in membrane damage, is therefore proposed as a component of the in vivo mechanism of ART.

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DOI

10.25777/mftx-4d14

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