Victoria University

The Characterization of TA-289, a Novel Antifungal from Fusarium sp.

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dc.contributor.advisor Bellows, David
dc.contributor.advisor Atkinson, Paul Quek, Natelle C H 2011-11-04T01:24:27Z 2011-11-04T01:24:27Z 2011 2011
dc.description.abstract Natural products offer vast structural and chemical diversity highly sought after in drug discovery research. Saccharomyces cerevisiae makes an ideal model eukaryotic organism for drug mode-of-action studies owing to ease of growth, sophistication of genetic tools and overall homology to higher eukaryotes. Equisetin and a closely related novel natural product, TA-289, are cytotoxic to fermenting yeast, but seemingly less so when yeast actively respire. Cell cycle analyses by flow cytometry revealed a cell cycle block at S-G2/M phase caused by TA-289; previously described oxidative stress-inducing compounds causing cell cycle delay led to further investigation in the involvement of equisetin and TA-289 in mitochondrial-mediated generation of reactive oxygen species. Chemical genomic profiling involving genome-wide scans of yeast deletion mutant strains for TA-289 sensitivity revealed sensitization of genes involved in the mitochondria, DNA damage repair and oxidative stress responses, consistent with a possible mechanism-of-action at the mitochondrion. Flow cytometric detection of reactive oxygen species (ROS) generation caused by TA-289 suggests that the compound may induce cell death via ROS production. The generation of a mutant strain resistant to TA-289 also displayed resistance to a known oxidant, H2O2, at concentrations that were cytotoxic to wild-type cells. The resistant mutant displayed a higher basal level of ROS production compared to the wild-type parent, indicating that the resistance mutation led to an up-regulation of antioxidant capacity which provides cell survival in the presence of TA-289. Yeast mitochondrial morphology was visualized by confocal light microscopy, where it was observed that cells treated with TA-289 displayed abnormal mitochondria phenotypes, further indicating that the compound is acting primarily at the mitochondrion. Similar effects observed with equisetin treatment suggest that both compounds share the same mechanism, eliciting cell death via ROS production in the mitochondrial respiratory chain. en_NZ
dc.language.iso en_NZ
dc.publisher Victoria University of Wellington en_NZ
dc.subject Drug en_NZ
dc.subject Oxidative stress en_NZ
dc.subject Saccharomyces cerevisiae en_NZ
dc.title The Characterization of TA-289, a Novel Antifungal from Fusarium sp. en_NZ
dc.type Text en_NZ
vuwschema.contributor.unit School of Biological Sciences en_NZ
vuwschema.subject.marsden 270199 Biochemistry and Cell Biology not Elsewhere Classified en_NZ
vuwschema.type.vuw Awarded Research Masters Thesis en_NZ Biotechnology en_NZ Victoria University of Wellington en_NZ Master's en_NZ Master of Science en_NZ
vuwschema.subject.anzsrcfor 069999 Biological Sciences not elsewhere classified en_NZ

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