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Metabolite essentiality elucidates robustness of Escherichia coli metabolism
Complex biological systems are very robust to genetic and environmental
changes at all levels of organization. Many biological functions of Escherichia
coli metabolism can be sustained against single-gene or even multiple-gene
mutations by using redundant or alternative pathways. Thus, only a limited
number of genes have been identified to be lethal to the cell. In this regard,
the reaction-centric gene deletion study has a limitation in understanding the
metabolic robustness. Here, we report the use of flux-sum, which is the
summation of all incoming or outgoing fluxes around a particular metabolite
under pseudo-steady state conditions, as a good conserved property for
elucidating such robustness of E. coli from the metabolite point of view. The
functional behavior, as well as the structural and evolutionary properties of
metabolites essential to the cell survival, was investigated by means of a
constraints-based flux analysis under perturbed conditions. The essential
metabolites are capable of maintaining a steady flux-sum even against severe
perturbation by actively redistributing the relevant fluxes. Disrupting the
flux-sum maintenance was found to suppress cell growth. This approach of
analyzing metabolite essentiality provides insight into cellular robustness and
concomitant fragility, which can be used for several applications, including
the development of new drugs for treating pathogens.Comment: Supplements available at
http://stat.kaist.ac.kr/publication/2007/PJKim_pnas_supplement.pd
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