A systems biology approach uncovers cellular strategies used by Methylobacterium extorquens AM1 during the switch from multi- to single-carbon growth.
BACKGROUND
When organisms experience environmental change, how does their metabolic network reset and adapt to the new condition? Methylobacterium extorquens is a bacterium capable of growth on both multi- and single-carbon compounds. These different modes of growth utilize dramatically different central metabolic pathways with limited pathway overlap.


RESULTS
This study focused on the mechanisms of metabolic adaptation occurring during the transition from succinate growth (predicted to be energy-limited) to methanol growth (predicted to be reducing-power-limited), analyzing changes in carbon flux, gene expression, metabolites and enzymatic activities over time. Initially, cells experienced metabolic imbalance with excretion of metabolites, changes in nucleotide levels and cessation of cell growth. Though assimilatory pathways were induced rapidly, a transient block in carbon flow to biomass synthesis occurred, and enzymatic assays suggested methylene tetrahydrofolate dehydrogenase as one control point. This "downstream priming" mechanism ensures that significant carbon flux through these pathways does not occur until they are fully induced, precluding the buildup of toxic intermediates. Most metabolites that are required for growth on both carbon sources did not change significantly, even though transcripts and enzymatic activities required for their production changed radically, underscoring the concept of metabolic setpoints.


CONCLUSIONS
This multi-level approach has resulted in new insights into the metabolic strategies carried out to effect this shift between two dramatically different modes of growth and identified a number of potential flux control and regulatory check points as a further step toward understanding metabolic adaptation and the cellular strategies employed to maintain metabolic setpoints.
Department of Chemical Engineering, University of Washington, Seattle, Washington, USA. eskovran@u.washington.edu
Elizabeth
E
Skovran
Gregory J
GJ
Crowther
Xiaofeng
X
Guo
Song
S
Yang
Mary E
ME
Lidstrom
D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002244:Carbon / Q000378:metabolism* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004734:Energy Metabolism / Q000235:genetics / Q000502:physiology*; D005557:Formaldehyde / Q000378:metabolism / Q000494:pharmacology; D005561:Formates / Q000378:metabolism / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial; D053858:Metabolic Networks and Pathways; D000432:Methanol / Q000378:metabolism / Q000494:pharmacology; D020601:Methylobacterium extorquens / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010084:Oxidation-Reduction; D019802:Succinic Acid / Q000378:metabolism / Q000494:pharmacology; D049490:Systems Biology / Q000379:methods*
D001426:Bacterial Proteins; D005561:Formates; C030544:formic acid; D005557:Formaldehyde; D002244:Carbon; D019802:Succinic Acid; D000432:Methanol