Login (DCU Staff Only)
Login (DCU Staff Only)

DORAS | DCU Research Repository

Explore open access research and scholarly works from DCU

Advanced Search

Purification of P. c; chabaudi aminopeptidase, and antimalarial effects of the aminopeptidase inhibitor bestatin

Nnankya-Kitaka, Mary-Frances (1997) Purification of P. c; chabaudi aminopeptidase, and antimalarial effects of the aminopeptidase inhibitor bestatin. PhD thesis, Dublin City University.

Abstract
The malarial parasite utilises amino acids drawn from the host haemoglobin for it's intraerythrocytic development. The endopeptidases described to date will only produce peptides from host haemoglobin. In order to obtain free aminoacids for incorporation in malarial proteins the malarial parasite requires exopeptidases (i.e. aminopeptidases and carboxypeptidases). Aminopeptidase activity was described in human malarial parasites Plasmodium falciparum rodent malarial parasites Plasmodium chabaudi chabaudi and Plasmodium berghei. These enzymes were shown to be inhibited by the aminopeptidase inhibitor bestatin. In light of these findings, the antimalarial effects of bestatin were investigated both in vitro and in vivo. Bestatin inhibited the in vitro growth of P. c. chabaudi, of chloroquine sensitive P. falciparum clone FCH5.C2 and chloroquine resistant P. falciparum clone K 1/Thailand. P. chabaudi infection is naturally lethal to male mice whereas female mice develop protective immunity against a similar infection. In vivo investigation of the effects of bestatin showed that this aminopeptidase inhibitor could induce self-healing of P. c. chabaudi infection in male CD1 mice. The aminopeptidase was purified by a combination of sizeexclusion HPLC and affinity chromatography and, alternatively, by a combination of size-exclusion HPLC and anion exchange chromatography. The aminopeptidase activity appears to be composed of four different aminopeptidases with an apparent monomeric molecular weight range of 60 to 70 kDa. Comparative studies of the inhibition of the P. c. chabaudi and porcine kidney aminopeptidase by bestatin indicate that the active site of the malarial aminopeptidase could differ to the mammalian aminopeptidase. Nucleotide probes/primers to clone this aminopeptidase(s) have been designed from the sequences of bestatin and metal ions binding site of several leucine aminopeptidases. This thesis shows that the malarial aminopeptidase is a potential chemotherapeutic target with bestatin and/or bestatin analogues as potential antimalarial drugs. The difference between the binding site of bestatin on mammalian and malarial aminopeptidase could be exploited for the design of drugs that would be specific to the malarial parasite enzyme.
Metadata
Item Type:Thesis (PhD)
Date of Award:1997
Refereed:No
Supervisor(s):Dalton, John P.
Uncontrolled Keywords:Malaria; Drugs Analysis; Aminopeptidase activity; Bestatin
Subjects:Biological Sciences > Biotechnology
Humanities > Biological Sciences > Biotechnology
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Biotechnology
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
ID Code:19141
Deposited On:04 Sep 2013 11:08 by Celine Campbell . Last Modified 04 Oct 2013 16:02
Documents

Full text available as:

[thumbnail of Mary_F_Nnankya-Kitaka_20130626155019.pdf]
Preview
PDF - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
Creative Commons: Attribution-Noncommercial-No Derivative Works 3.0
4MB
Downloads

Downloads

Downloads per month over past year

Archive Staff Only: edit this record