(667f) A Functional Genomics Analysis of Central Carbon Metabolism Evolution In Yeasts

Metabolic processes within a cell produce the energy and small molecule building blocks necessary for all cellular functions, and central carbon metabolism ? the key metabolic module governing energy sources ? is the cornerstone of these processes. Despite this key role, we understand surprisingly little about the function and evolution of central carbon metabolism on a systems scale. For example, how did the respiro-fermentative metabolic state (common to log-phase Saccharomyces cerevisiae and to many cancer cells) evolve and what are its adaptive advantages? In this project we perform a comparative experimental and computational study of the function, regulation, and evolution of central carbon metabolism in thirteen Ascomycota fungi spanning 300 million years of evolution. Using advanced metabolomics methods, we systematically measure metabolite concentrations and fluxes under a variety of metabolic and genetic perturbations in each species. We can then integrate these metabolic profiles with expression profiles collected in our lab under the same conditions and identify functional metabolic modules of co-varying metabolites and genes in each species. We use a novel computational approach to identify orthologous modules across species and reconstruct their evolution. The evolutionary reconstruction predicts conserved functional entities as well as major evolutionary changes in metabolic function and regulation. Our evolutionary model will be validated and refined by deleting predicted key genes in all relevant species in our model and using the same metabolomics-based approach to profile their responses. This innovative comparative metabolomic approach will provide insights into the function and evolution of distinct metabolic strategies and establish a new systems-level approach for the study of metabolic systems.