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Functional consequences of the inhibition of Malaria S-adenosylmethionine decarboxylase as a key regulator of polyamine and methionine metabolism
Thesis (PhD)--University of Pretoria, 2010.
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University of Pretoria
2013
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| _version_ | 1867613667200073728 |
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| access_status_str | Open Access |
| author2 | Louw, Abraham Izak |
| author_browse | Louw, Abraham Izak |
| author_facet | Louw, Abraham Izak |
| collection | Thesis |
| dc_rights_str_mv | © 2010 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Thesis (PhD)--University of Pretoria, 2010. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/25743 |
| institution | University of Pretoria (South Africa) |
| last_indexed | 2026-06-10T12:39:47.098Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2013 |
| publishDateRange | 2013 |
| publishDateSort | 2013 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/25743 Functional consequences of the inhibition of Malaria S-adenosylmethionine decarboxylase as a key regulator of polyamine and methionine metabolism Louw, Abraham Izak Birkholtz, Lyn-Marie salome.smit@tuks.co.za Smit, Salome Methionine metabolism Malaria S-adenosylmethionine decarboxylase Mosquito Parasite UCTD Thesis (PhD)--University of Pretoria, 2010. Malaria presents a global health risk that is becoming increasingly difficult to treat due to increased resistance of both the parasite and mosquito to all known drugs. Identification of novel drug targets are therefore essential in the fight against malaria. Polyamines are small flexible polycations that are represented by three basic polyamines. The interaction of polyamines with various macromolecules may lead to stabilisation of DNA, regulation of transcription, replication, and also have an important role in cellular differentiation, proliferation, growth and division. Therefore, disruption of polyamine biosynthesis presents a unique drug target worth exploiting. Polyamine biosynthesis in P. falciparum is regulated by a unique bifunctional S-adenosylmethionine decarboxylase/ornithine decarboxylase (AdoMetDC/ODC) complex, which is unique to P. falciparum and differs completely from human polyamine biosyntehsis. The inhibition of AdoMetDC induces spermidine and subsequent spermine depletion within the parasite that ultimately results in cell cycle arrest. A functional genomics approach was used within this study to identify a global response of the parasite due to the inhibition of AdoMetDC with the irreversible inhibitor, MDL73811. The proteomics approach was optimised for conditions specific to our laboratory with regard to protein extraction, Plasmodial protein quantification, spot detection and finally protein identification by mass spectrometry (MS). This methodology resulted in reliable spot detection and achieved a 95% success rate in MS/MS identification of protein spots. Application of this methodology to the analyses of the Plasmodial ring and trophozoite proteomes ultimately resulted in the identification of 125 protein spots from the Plasmodial ring and trophozoite stages, which also confirmed stage specific protein production. Various protein isoforms were present which may be of significant biological importance within the Plasmodial parasite during development in the intraerythrocytic developmental cycle. Subsequent application of the 2-DE methodology to the proteome of AdoMetDC inhibited parasites resulted in the identification of 61 unique Plasmodial protein groups that were differentially affected by the inhibition of AdoMetDC in 2 time points. The transcriptome of AdoMetDC inhibited parasites were also investigated at 3 time points. Investigation into the transcriptome revealed the differential regulation of 549 transcripts, which included the differential regulation of polyamine specific transcripts. Inhibition of AdoMetDC provided a unique polyamine specific transcriptomic signature profile that demonstrated unique interactions between AdoMetDC inhibition and folate biosynthesis, redox metabolism and cytoskeleton biogenesis. The results presented provide evidence that the parasite responds to AdoMetDC inhibition by the regulation of the transcriptome and proteome in an attempt to alleviate the effects of AdoMetDC inhibition. Further analyses of the metabolome also provided evidence for the tight regulation of the AdoMet cycle. Overall, this study demonstrated important functional consequences as a result of AdoMetDC inhibition. Biochemistry unrestricted 2013-09-06T23:56:14Z 2011-06-27 2013-09-06T23:56:14Z 2011-04-07 2010 2011-06-22 Thesis Smit, S 2010, Functional consequences of the inhibition of Malaria S-adenosylmethionine decarboxylase as a key regulator of polyamine and methionine metabolism, PhD thesis, University of Pretoria, Pretoria, viewed yymmdd < http://hdl.handle.net/2263/25743 > D11/374/ag http://hdl.handle.net/2263/25743 http://upetd.up.ac.za/thesis/available/etd-06222011-081539/ © 2010 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf application/pdf University of Pretoria |
| spellingShingle | Methionine metabolism Malaria S-adenosylmethionine decarboxylase Mosquito Parasite UCTD Functional consequences of the inhibition of Malaria S-adenosylmethionine decarboxylase as a key regulator of polyamine and methionine metabolism |
| title | Functional consequences of the inhibition of Malaria S-adenosylmethionine decarboxylase as a key regulator of polyamine and methionine metabolism |
| title_full | Functional consequences of the inhibition of Malaria S-adenosylmethionine decarboxylase as a key regulator of polyamine and methionine metabolism |
| title_fullStr | Functional consequences of the inhibition of Malaria S-adenosylmethionine decarboxylase as a key regulator of polyamine and methionine metabolism |
| title_full_unstemmed | Functional consequences of the inhibition of Malaria S-adenosylmethionine decarboxylase as a key regulator of polyamine and methionine metabolism |
| title_short | Functional consequences of the inhibition of Malaria S-adenosylmethionine decarboxylase as a key regulator of polyamine and methionine metabolism |
| title_sort | functional consequences of the inhibition of malaria s adenosylmethionine decarboxylase as a key regulator of polyamine and methionine metabolism |
| topic | Methionine metabolism Malaria S-adenosylmethionine decarboxylase Mosquito Parasite UCTD |
| url | http://hdl.handle.net/2263/25743 http://upetd.up.ac.za/thesis/available/etd-06222011-081539/ |