Chemical genomics in yeast
Subtitle: linking biologically active compounds to their intracellular targets
By: by Ainslie Bennett Parsons.
Published: 2006
Language: eng
Number of pages: 148
ISBN-13: 9780494160190
Description: Target specific chemical inhibitors are highly valuable as both research tools and therapeutic leads, but it is often difficult to identify their mechanism of action or cellular target. Here I have studied genome-wide chemical-genetic interaction profiles in the budding yeast Saccharomyces cerevisiae , by testing the complete set of viable deletion mutants for hypersensitivity to inhibitory compounds. Integration of chemical-genetic and genetic interaction data reveals information about the mode of action of bioactive compounds. First, in a series of proof-of-concept experiments I showed that because a loss-of-function mutation in a gene encoding the target of an inhibitory compound models the primary effect of the compound, crossing such a mutation into the set of viable mutants and scoring the resultant double mutants for reduced fitness generates a genetic interaction profile for the target gene resembling the chemical-genetic interaction profile of its inhibitory compound. Therefore, clustering the compound-specific profiles with a compendium of large-scale genetic interaction profiles enables the identification of target pathways or proteins and thus provides a powerful means for inferring mechanism of action. In the second phase of this project, I expanded our matrix of chemical-genetic interactions by profiling 85 diverse compounds and natural product extracts, including a number of human therapeutics, using parallel fitness tests and a microarray-based readout. Hierarchical clustering of the dataset associates compounds of similar mode of action and reveals insight into the cellular pathways affected by the compounds. In particular, my analysis establishes a cell membrane target for papuamide B, a high molecular weight cyclic lipopeptide with potent anti-fungal and anti-HIV activity.
Notes: Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3569.

Thesis (Ph.D.)--University of Toronto, 2006.

Includes bibliographic references.

Electronic version licensed for access by U. of T. users.