The activity reaction core and plasticity of metabolic networks by AmnaKhan

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									The activity reaction core and plasticity of metabolic networks
Almaas E., Oltvai Z.N. & Barabasi A.-L. 01/04/2006

The idea
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To examine the utilization and relative flux rates of each metabolic reaction in a wide range of simulated environmental conditions
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30,000 randomly and uniformly chosen optimal growth conditions (randomly assigning values for metabolic-uptake reactions) and all single-carbon-source minimal medium conditions sufficient for growth
H. pylori E. coli S. cerevisiae

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Using FBA on in silico models:
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Observations
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Flux plasticity
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Changes in the fluxes of already active reactions when the organism is shifted from one growth condition to another Changes in the active reaction set

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Structural plasticity
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Metabolic core
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Definition
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The set of reactions that are active under all conditions

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Metabolic cores in different organisms:
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H. pylori: 138 of 381 (36.2%) E. coli: 90 of 758 (11.9%) S. cerevisiae: 33 of 1172 (2.8%) The reactions in the metabolic core form a single connected cluster.

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Property
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The metabolic core of E. coli

Essentiality of reactions in metabolic core
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Two types of reactions in metabolic core
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Reactions that are essential for growth under all conditions
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H. pylori: no data in the paper E. coli: 81 out of 90
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Experimental data: 74.7% of the enzymes that catalyze core metabolic reactions are essential, compared with a 19.6% lethality fraction of the noncore enzymes. Experimental data: 84% of the core enzymes are essential, whereas 15.6% of noncore enzymes are essential.

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S. cerevisiae: all 33
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Reactions that are required for optimal metabolic performance
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When assuming a 10% reduction in the growth rate, the size of the metabolic core becomes 83 in E. coli.

Size of the metabolic cores
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Metabolic cores in different organisms:
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H. pylori: 36.2% E. coli: 11.9% S. cerevisiae: 2.8%
Little flexibility for biomass production in H. pylori
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Explanation
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61% of the H. pylori reactions are active on average.
On average, 35.3% and 19.7% of the reactions are required in E. coli and S. cerevisiae, respectively. Alternative pathways: 20 out of the 51 biomass constituents in E. coli are not produced by the core.

Higher metabolic flexibility in E. coli and S. cerevisiae
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The more reactions a metabolic network possesses, the stronger is the network-induced redundancy, and the smaller is the core.

Conservation of the metabolic core
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The average core enzyme in E. coli has orthologs in 71.7% of the 32 reference bacteria. While the noncore enzymes have an evolutionary retention of only 47.7%. This difference is not a simple consequence of the high-lethality fraction of the core enzymes.
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Random selection of 90 enzymes with a 74.7% lethality ratio has an average evolutionary retetion of only 63.4%

Maintaining the core’s integrity is a collective need of the organism.

Regulatory control on metabolic core
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mRNA half-lives
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Average half-life for the core enzymes: 14.0 min Average half-life for the noncore enzymes: 10.5 min
Extended core: a set of 234 reactions that are active in more than 90% of the 30,000 simulated growth conditions Core enzyme-encoding operons: 52.3% repressive; 35.7% activating; and 10% dual interactions Noncore enzyme-encoding operons: 45% repressive; 45% activating; and 10% dual interactions Flux correlation mRNA expression correlation
All data are of E. coli.

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Activating and repressive regulatory links
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Synchronization
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Practical implications
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The core enzymes may prove effective antibiotic targets. Currently used antibiotics:
Fosfomycin and cycloserine inhibit cell-wall peptidoglycan.  Sulfonamides and trimethoprim inhibit tetrahydrofolte biosynthesis.  Both pathways are present in H. pylori and E. coli.
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Summary of our previous work
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Production efficiency of amino acids
Energy requirement  Redox balance  Charge balance  Carrier molecules  Internal structure of the network
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Coupling mechanisms in amino acid synthesis
Complementary needs in currency/carrier molecules  Irreversible flow of energy/redox potential
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Further work
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Extend the analysis to all biomass constituents instead of only amino acids
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Straightforward extension but attention should be paid to constituent molecules with large number of carbon atoms..

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Coupling mechanisms
Quite complicated for yeast and E.coli  It might be okay if the problem is not completely solved now.
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