Modular design of central metabolism in methylotrophs

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DESCRIPTION (provided by applicant): This proposal addresses the open question of how central metabolic pathways adapt to changes in environmental and intracellular conditions. A growing body of work suggests that metabolism is organized into functional units, or modules that are selectively activated and suppressed according to the metabolic needs of the cell. The proposed research directly addresses this hypothesis by assessing how changes in the availability of certain nutrients alter the metabolic fluxes within and between modules in a methylotrophic bacterium. Specifically, the aims of this proposal are to (1) predict (with mathematical models) how the central metabolic fluxes of methylotrophic bacteria adjust to environmental changes affecting the production and consumption of acetyl CoA and (2) compare these predictions to empirical measurements of the fluxes. Acetyl CoA is a key metabolic intermediate that links three distinct modules of methylotrophic metabolism; therefore this work should reveal the extent to which a modular view of metabolism (grounded in flux-balance and energy-balance analysis) can explain the observed changes in flux (measured with 13C label tracing). The facultative methylotroph Methylobacterium extorquens AM1 is an attractive model system for this work because (i) the necessary tools are all in hand; (ii) protocols are available to alter metabolic outcomes; and (iii) methylotroph metabolic pathways, when fully understood, could potentially be harnessed to produce commercially important chemicals with a minimum of hazardous waste.