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dc.contributor.author Kingsbury, JM
dc.contributor.author McCusker, JH
dc.coverage.spatial England
dc.date.accessioned 2011-06-21T17:27:29Z
dc.date.issued 2010-03
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/20019084
dc.identifier mic.0.034348-0
dc.identifier.citation Microbiology, 2010, 156 (Pt 3), pp. 929 - 939
dc.identifier.uri http://hdl.handle.net/10161/4165
dc.description.abstract The isoleucine and valine biosynthetic enzyme acetolactate synthase (Ilv2p) is an attractive antifungal drug target, since the isoleucine and valine biosynthetic pathway is not present in mammals, Saccharomyces cerevisiae ilv2Delta mutants do not survive in vivo, Cryptococcus neoformans ilv2 mutants are avirulent, and both S. cerevisiae and Cr. neoformans ilv2 mutants die upon isoleucine and valine starvation. To further explore the potential of Ilv2p as an antifungal drug target, we disrupted Candida albicans ILV2, and demonstrated that Ca. albicans ilv2Delta mutants were significantly attenuated in virulence, and were also profoundly starvation-cidal, with a greater than 100-fold reduction in viability after only 4 h of isoleucine and valine starvation. As fungicidal starvation would be advantageous for drug design, we explored the basis of the starvation-cidal phenotype in both S. cerevisiae and Ca. albicans ilv2Delta mutants. Since the mutation of ILV1, required for the first step of isoleucine biosynthesis, did not suppress the ilv2Delta starvation-cidal defects in either species, the cidal phenotype was not due to alpha-ketobutyrate accumulation. We found that starvation for isoleucine alone was more deleterious in Ca. albicans than in S. cerevisiae, and starvation for valine was more deleterious than for isoleucine in both species. Interestingly, while the target of rapamycin (TOR) pathway inhibitor rapamycin further reduced S. cerevisiae ilv2Delta starvation viability, it increased Ca. albicans ilv1Delta and ilv2Delta viability. Furthermore, the recovery from starvation was dependent on the carbon source present during recovery for S. cerevisiae ilv2Delta mutants, reminiscent of isoleucine and valine starvation inducing a viable but non-culturable-like state in this species, while Ca. albicans ilv1Delta and ilv2 Delta viability was influenced by the carbon source present during starvation, supporting a role for glucose wasting in the Ca. albicans cidal phenotype.
dc.format.extent 929 - 939
dc.language eng
dc.language.iso en_US en_US
dc.relation.ispartof Microbiology
dc.relation.isversionof 10.1099/mic.0.034348-0
dc.subject Acetolactate Synthase
dc.subject Animals
dc.subject Antifungal Agents
dc.subject Candida albicans
dc.subject Carbon
dc.subject Fungal Proteins
dc.subject Isoleucine
dc.subject Male
dc.subject Mice
dc.subject Microbial Viability
dc.subject Mutation
dc.subject Phenotype
dc.subject Saccharomyces cerevisiae
dc.subject Sirolimus
dc.subject Valine
dc.subject Virulence
dc.title Cytocidal amino acid starvation of Saccharomyces cerevisiae and Candida albicans acetolactate synthase (ilv2{Delta}) mutants is influenced by the carbon source and rapamycin.
dc.title.alternative en_US
dc.type Journal Article
dc.description.version Version of Record en_US
duke.date.pubdate 2010-3-0 en_US
duke.description.endpage 939 en_US
duke.description.issue en_US
duke.description.startpage 929 en_US
duke.description.volume 156 en_US
dc.relation.journal Microbiology-Sgm en_US
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/20019084
pubs.issue Pt 3
pubs.organisational-group /Duke
pubs.organisational-group /Duke/School of Medicine
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments
pubs.organisational-group /Duke/School of Medicine/Basic Science Departments/Molecular Genetics and Microbiology
pubs.publication-status Published
pubs.volume 156
dc.identifier.eissn 1465-2080

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