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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM070297-02
Application #
6877982
Study Section
Special Emphasis Panel (ZRG1-F08 (20))
Program Officer
Marino, Pamela
Project Start
2004-03-12
Project End
2007-03-11
Budget Start
2005-03-12
Budget End
2006-03-11
Support Year
2
Fiscal Year
2005
Total Cost
$48,296
Indirect Cost
Name
University of Washington
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Skovran, Elizabeth; Crowther, Gregory J; Guo, Xiaofeng et al. (2010) A systems biology approach uncovers cellular strategies used by Methylobacterium extorquens AM1 during the switch from multi- to single-carbon growth. PLoS One 5:e14091
Crowther, Gregory J; Kosaly, George; Lidstrom, Mary E (2008) Formate as the main branch point for methylotrophic metabolism in Methylobacterium extorquens AM1. J Bacteriol 190:5057-62