Transcript The activity reaction core and plasticity of metabolic networks

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
Using FBA on in silico models:
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H. pylori
E. coli
S. cerevisiae
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
Structural plasticity
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Changes in the active reaction set
Metabolic core
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Definition
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Metabolic cores in different organisms:
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The set of reactions that are active under all conditions
H. pylori: 138 of 381 (36.2%)
E. coli: 90 of 758 (11.9%)
S. cerevisiae: 33 of 1172 (2.8%)
Property
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The reactions in the metabolic core form a single connected
cluster.
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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S. cerevisiae: all 33
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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.
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%
Explanation
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Little flexibility for biomass production in H. pylori
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Higher metabolic flexibility in E. coli and S. cerevisiae
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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.
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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Activating and repressive regulatory links
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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
Synchronization
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Flux correlation
mRNA expression correlation
All data are of E. coli.
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..
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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