Verlag des Forschungszentrums Jülich
JUEL-3912
This work describes a Metabolic Modeling Tool (MMT) software for pathway anal-
ysis that is based on a relational database. It has been developed and applied to
experimental data during this Ph.D. thesis. The software can be used to define and
analyze dynamic pathway models based on non-linear kinetic rate equations. The
design of the MMT software differs from other available pathway modeling tools in
a variety of things. With respect to model definition, the tool has no limitations in
dimension and it is based on a relational database that stores all model information
and results. In order to allow definition of a large number of models the tool has a
structured approach that allows to build groups of models and groups of parameter
fittings. Groups share e.g. the metabolic pathway or kinetic equations.
With respect to simulation and parameter fitting, MMT provides high flexibility.
Parameters can e.g. be optimized or set to experimental data values or initial condi-
tions can be optimized. Stoichiometric coefficients can also be subject to parameter
fitting. Additionally simulation time is variable and artificial noise can be added
to the calculated values to simulate experimental data. The software creates a C-
Code with the system of differential equations and also with the explicit derivatives
with respect to initial conditions and parameters, thus providing a complete set of
sensitivity functions.
The tool allows not on I y visualization of the solution of the differential equations
but also of each individual flux between compounds. These values correspond to the
kinetic equations over time and are helpful in analyzing simulation and parameter
fitting results.
MMT was applied to the central metabolic pathways of Escherichia coli. Data from
fast sampling experiments (Glucose pulse experiments, 4 sampIes per second over
40 seconds) was used for parameter fitting. Some metabolic regulation phenomena
in relation to these experiments are discussed in this thesis.
This thesis is based on research at the Unit of Theoretical Biology of the Mathemat-
ics and Natural Sciences Department at the Rheinisch Friedrich- Wilhelms-University
Bonn, Germany. The work was conducted at the facilities of the Institute of Biotech-
nology 2 of the Research Center Jülich, Germany.
Hurlebaus, Jochen
A Pathway Modeling Tool for Metabolic Engineering
XI, 184 S., 2001
Identification of metabolic regulation is a key point in metabolic engineering.
Metabolic regulation phenomena depend on intracellular compounds such as en-
zymes, metabolites, nucleotides and cofactors. Quantitative knowledge about these
compounds in combination with the known network of metabolic pathways allows the
construction of mathematical models that describe the dynamic changes in metabo-
lite concentrations over time. The models are high-dimensional systems of ordinary,
non-linear differential equations. To solve the problems of this approach (setup of
the equations that describe the metabolic pathways in form of kinetic rate equations
and the parameter identification of the system parameters) , a variety of pathway
modeling software has been developed over the last years.
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